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Classifications

Harrison's Part

Channelopathy

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Mappings

ICD-10-CM

ICD10CM:G43.4 Hemiplegic migraine

semapv:ManualMappingCuration

ICD-11 Foundation

icd11f:1827007904 Familial hemiplegic migraine

semapv:ManualMappingCuration

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Inheritance

1

Autosomal dominant HP:0000006

FHM caused by a heterozygous pathogenic variant in ATP1A2, CACNA1A, PRRT2 or SCN1A is inherited in an autosomal dominant manner, with a 50% recurrence risk for each child of an affected individual. Because the FHM diagnosis itself requires an affected relative, most probands have an affected parent; apparently simplex cases may reflect a de novo variant or an asymptomatic transmitting parent. Penetrance is high but incomplete, and expressivity is markedly variable - within a single pedigree the same variant can produce infrequent pure hemiplegic attacks in one carrier and attacks with coma or prolonged hemiplegia in another. Both facts matter for counseling: an unaffected carrier parent is expected rather than anomalous, and a mild index case does not predict a mild course in relatives.

Autosomal dominant inheritance Penetrance: INCOMPLETE Penetrance %: 89 (CACNA1A mutation carriers; see the CACNA1A genetic record) Expressivity: VARIABLE

Show evidence (6 references)

PMID:20301562 SUPPORT Human Clinical

"FHM and simplex hemiplegic migraine caused by a heterozygous ATP1A2, CACNA1A, PRRT2, or SCN1A pathogenic variant are inherited in an autosomal dominant manner."

GeneReviews states the mode of inheritance for all four FHM genes.

PMID:20301562 SUPPORT Human Clinical

"Individuals with simplex hemiplegic migraine (i.e., individuals with an FHM-causing pathogenic variant and an apparently negative family history) may have a de novo pathogenic variant or a pathogenic variant inherited from an asymptomatic parent."

Explains why an apparently sporadic presentation does not exclude a dominant FHM-gene variant.

PMID:11439943 SUPPORT Human Clinical

"Eighty-nine percent of the subjects with mutations had attacks of hemiplegic migraine."

In 117 genotyped CACNA1A mutation carriers, 11% had no hemiplegic migraine attacks - a direct measurement of incomplete penetrance, and the source of the 89% figure recorded above. The denominator is CACNA1A carriers, so the number should not be read as a penetrance estimate for ATP1A2, SCN1A or PRRT2.

+ 3 more references

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Subtypes

3

Familial Hemiplegic Migraine Type 1 (CACNA1A) MONDO:0020756

CACNA1A hgnc:1388

Caused by heterozygous missense variants in CACNA1A encoding the alpha1A pore-forming subunit of the neuronal Cav2.1 (P/Q-type) voltage-gated calcium channel. The pathogenic variants act by gain of function, increasing presynaptic Ca2+ influx and glutamate release. Roughly 40-50% of CACNA1A-FHM families additionally show cerebellar signs, from nystagmus to a late-onset mild progressive ataxia, and the severe S218L allele is associated with coma and cerebral edema after minor head trauma.

Show evidence (2 references)

PMID:8898206 SUPPORT Human Clinical

"In FHM, we found four different missense mutations in conserved functional domains."

The original linkage and mutation study identifying missense variants in the brain P/Q-type calcium channel alpha1 subunit gene as the cause of FHM1.

PMID:20301562 SUPPORT Human Clinical

"Approximately 40%-50% of families with CACNA1A-FHM have cerebellar signs ranging from nystagmus to progressive, usually late-onset mild ataxia."

Establishes the cerebellar phenotype that distinguishes FHM1 from the other molecular subtypes.

Familial Hemiplegic Migraine Type 2 (ATP1A2) MONDO:0011232

ATP1A2 hgnc:800

Caused by heterozygous variants in ATP1A2 encoding the alpha2 subunit of the Na+/K+-ATPase, an isoform expressed almost exclusively in astrocytes in the adult brain. The variants act by loss of function of a single allele, and in the knock-in mouse the mutant protein is retained in the endoplasmic reticulum and degraded. Epilepsy is a particularly common comorbidity in ATP1A2-FHM.

Show evidence (1 reference)

PMID:12539047 SUPPORT Human Clinical

"Here we show that mutations in the gene ATP1A2 that encodes the alpha2 subunit of the Na+/K+ pump are associated with familial hemiplegic migraine type 2 (FHM2) linked to chromosome 1q23"

The gene-discovery study defining the FHM2 molecular subtype.

Familial Hemiplegic Migraine Type 3 (SCN1A) MONDO:0012320

SCN1A hgnc:10585

Caused by heterozygous missense variants in SCN1A encoding the neuronal Nav1.1 voltage-gated sodium channel, the same gene whose loss-of-function variants cause Dravet syndrome and other epilepsies. FHM3 variants act in the opposite direction, as gain of function, and Nav1.1 is the principal sodium channel of GABAergic interneurons - so FHM3 reaches cortical spreading depression by a route distinct from the glutamatergic FHM1/FHM2 mechanism.

Show evidence (2 references)

PMID:16054936 SUPPORT Human Clinical

"Sequencing of candidate genes in this region revealed a heterozygous missense mutation (Gln1489Lys) in the neuronal voltage-gated sodium channel gene SCN1A, mutations of which have been associated with epilepsy."

The gene-discovery study defining the FHM3 molecular subtype.

PMID:16054936 SUPPORT Human Clinical

"Dysfunction of the neuronal sodium channel SCN1A can cause familial hemiplegic migraine. Our findings have implications for the understanding of migraine aura. Moreover, our study reinforces the molecular links between migraine and epilepsy, two common paroxysmal disorders."

Establishes both causation and the mechanistic link between FHM3 and the epilepsies caused by the same gene.

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Mechanistic Hypotheses

9

Cortical spreading depolarization and focal aura

cortical_aura CANONICAL

The leading aura explanation, with indirect translation from model physiology to spontaneous human FHM.

Pathograph links

Facilitated Cortical Spreading Depolarization -> Reversible Hemiparesis During Aura INDIRECT UNKNOWN INTERMEDIATES The cortical aura model attributes this focal aura manifestation to propagating depolarization and subsequent suppression in the relevant cortical network. Translation from experimental CSD to spontaneous human FHM remains indirect.

Facilitated Cortical Spreading Depolarization -> Migraine with Aura INDIRECT UNKNOWN INTERMEDIATES The cortical aura model attributes this focal aura manifestation to propagating depolarization and subsequent suppression in the relevant cortical network. Translation from experimental CSD to spontaneous human FHM remains indirect.

Facilitated Cortical Spreading Depolarization -> Paresthesia During Aura INDIRECT UNKNOWN INTERMEDIATES The cortical aura model attributes this focal aura manifestation to propagating depolarization and subsequent suppression in the relevant cortical network. Translation from experimental CSD to spontaneous human FHM remains indirect.

Facilitated Cortical Spreading Depolarization -> Hypoesthesia During Aura INDIRECT UNKNOWN INTERMEDIATES The cortical aura model attributes this focal aura manifestation to propagating depolarization and subsequent suppression in the relevant cortical network. Translation from experimental CSD to spontaneous human FHM remains indirect.

Facilitated Cortical Spreading Depolarization -> Aphasia During Aura INDIRECT UNKNOWN INTERMEDIATES The cortical aura model attributes this focal aura manifestation to propagating depolarization and subsequent suppression in the relevant cortical network. Translation from experimental CSD to spontaneous human FHM remains indirect.

Facilitated Cortical Spreading Depolarization -> Scotoma During Aura INDIRECT UNKNOWN INTERMEDIATES The cortical aura model attributes this focal aura manifestation to propagating depolarization and subsequent suppression in the relevant cortical network. Translation from experimental CSD to spontaneous human FHM remains indirect.

Facilitated Cortical Spreading Depolarization -> Photopsia During Aura INDIRECT UNKNOWN INTERMEDIATES The cortical aura model attributes this focal aura manifestation to propagating depolarization and subsequent suppression in the relevant cortical network. Translation from experimental CSD to spontaneous human FHM remains indirect.

FHM3 spiking and potassium-mediated CSD initiation

fhm3_potassium EMERGING

Genetic L1649Q and acute activation experiments support a route distinct from glutamatergic initiation.

Pathograph links

Cortical Interneuron Hyperactivity -> Extracellular Potassium Accumulation DIRECT Repetitive interneuron spiking increases extracellular potassium; the precise early-phase contribution is supported but qualified in the L1649Q model.

Extracellular Potassium Accumulation -> Facilitated Cortical Spreading Depolarization DIRECT Potassium accumulation depolarizes the cortical network and facilitates CSD initiation. The genetic model supports the proposed ionic intermediary.

CSD-triggered meningeal sensitization

csd_headache EMERGING

A proposed link to headache, not an obligatory causal ordering of aura and pain.

Pathograph links

Facilitated Cortical Spreading Depolarization -> Meningeal Nociceptor Sensitization INDIRECT UNKNOWN INTERMEDIATES CSD may sensitize meningeal trigeminal nociceptors and thereby trigger headache; the source treats this step as a proposed mechanism.

Meningeal Nociceptor Sensitization -> Headache INDIRECT UNKNOWN INTERMEDIATES Sensitized meningeal nociceptors drive trigeminovascular pain signaling in the proposed CSD-triggered headache pathway.

Subcortical spread in severe FHM1

severe_fhm1_spread EMERGING

Allele-scoped mouse explanation for prolonged hemiplegia, coma and seizures, especially S218L.

Pathograph links

Facilitated Cortical Spreading Depolarization -> Subcortical Spreading Depolarization DIRECT Cortical waves spread into subcortical structures in the R192Q/S218L models, with allele-dependent distribution.

Subcortical Spreading Depolarization -> Reversible Hemiparesis During Aura INDIRECT UNKNOWN INTERMEDIATES Subcortical spreading depolarization is the authors' proposed explanation for this severe-attack manifestation; the anatomical extent and clinical translation remain allele-dependent.

Subcortical Spreading Depolarization -> Coma INDIRECT UNKNOWN INTERMEDIATES Subcortical spreading depolarization is the authors' proposed explanation for this severe-attack manifestation; the anatomical extent and clinical translation remain allele-dependent.

Subcortical Spreading Depolarization -> Seizures INDIRECT UNKNOWN INTERMEDIATES Subcortical spreading depolarization is the authors' proposed explanation for this severe-attack manifestation; the anatomical extent and clinical translation remain allele-dependent.

FHM1 cerebellar current abnormalities

fhm1_cerebellar EMERGING

Selected FHM1 alleles alter Purkinje firing or contribute to neuronal loss; this does not encompass all CACNA1A disorders.

Pathograph links

Cav2.1 Calcium Channel Gain of Function -> Purkinje Cell Firing Dysregulation DIRECT S218L Cav2.1 gating increases Purkinje excitability and disrupts firing patterns.

Cav2.1 Calcium Channel Gain of Function -> Cerebellar Neuronal Degeneration INDIRECT KNOWN INTERMEDIATES Selected FHM1 current abnormalities are proposed to produce Purkinje dysfunction and neuronal loss. Intermediates: Purkinje cell dysfunction

Cav2.1 Calcium Channel Gain of Function -> Cerebellar Ataxia INDIRECT UNKNOWN INTERMEDIATES R583Q gain-of-function physiology is the family authors' explanation of cerebellar ataxia; intervening circuitry is not reconstructed for those patients.

Cav2.1 Calcium Channel Gain of Function -> Dysdiadochokinesis INDIRECT UNKNOWN INTERMEDIATES The R583Q family study interprets the observed cerebellar syndrome, including this examination sign, in terms of abnormal Cav2.1 function. This clinical attribution is broader than the S218L-specific firing experiment.

Cav2.1 Calcium Channel Gain of Function -> Lower Limb Dysmetria INDIRECT UNKNOWN INTERMEDIATES The R583Q family study interprets the observed cerebellar syndrome, including this examination sign, in terms of abnormal Cav2.1 function. This clinical attribution is broader than the S218L-specific firing experiment.

Cav2.1 Calcium Channel Gain of Function -> Positive Romberg Sign INDIRECT UNKNOWN INTERMEDIATES The authors interpret the R583Q family's interictal examination abnormalities as cerebellar changes due to channel dysfunction. This includes Romberg instability; the particular balance-control intermediary is not resolved.

Purkinje Cell Firing Dysregulation -> Cerebellar Ataxia INDIRECT UNKNOWN INTERMEDIATES Irregular Purkinje firing is proposed to cause ataxia in the S218L model. This supports a qualified route to the clinical cerebellar phenotype without proving every progressive human ataxia has the same substrate.

Cerebellar Neuronal Degeneration -> Cerebellar Atrophy DIRECT Loss of cerebellar neurons contributes to the atrophic tissue phenotype in the reviewed FHM1 model.

Calcium-channel attribution of familial psychosis

familial_psychosis EMERGING

An explicit chromosome-19 family hypothesis without a confirmed causal variant or defined psychiatric intermediary.

Pathograph links

Cav2.1 Calcium Channel Gain of Function -> Attack-Associated Psychosis INDIRECT UNKNOWN INTERMEDIATES A chromosome-19-linked FHM/ataxia family prompted the authors' calcium-channel hypothesis for acute psychosis. Applying the Cav2.1 gain-of-function framework to that family remains provisional.

Cav2.1 Calcium Channel Gain of Function -> Attack-Associated Anxiety INDIRECT UNKNOWN INTERMEDIATES The authors' calcium-channel hypothesis concerns acute psychotic episodes explicitly including anxiety in this chromosome-19-linked FHM family. Applying the Cav2.1 gain-of-function framework remains provisional; neither a specific variant nor a separate component-specific circuit was established.

Cav2.1 Calcium Channel Gain of Function -> Visual Hallucinations INDIRECT UNKNOWN INTERMEDIATES The authors' calcium-channel hypothesis concerns acute psychotic episodes explicitly including visual hallucinations in this chromosome-19-linked FHM family. Applying the Cav2.1 gain-of-function framework remains provisional; neither a specific variant nor a separate component-specific circuit was established.

Case-scoped vasogenic edema

fhm2_vasogenic_edema EMERGING

One severe ATP1A2-FHM attack showed barrier opening preceding edema, interpreted as vasogenic.

Pathograph links

Blood-Brain Barrier Disruption -> Cerebral Edema INDIRECT KNOWN INTERMEDIATES The case authors interpret delayed edema after barrier opening as vasogenic fluid accumulation. Intermediates: Vasogenic fluid accumulation

Severe-attack neuronal injury and acquired cognitive decline

severe_attack_injury EMERGING

The childhood regression hypothesis draws on clinical course and juvenile-rat spreading-depression injury, not a proven universal developmental mechanism.

Pathograph links

Facilitated Cortical Spreading Depolarization -> Attack-Associated Neuronal Injury INDIRECT UNKNOWN INTERMEDIATES Repeated depolarization can injure juvenile rat brain; applying that result to repeated severe FHM attacks remains a provisional model-translation hypothesis.

Attack-Associated Neuronal Injury -> Progressive Cognitive Deterioration INDIRECT UNKNOWN INTERMEDIATES The review proposes severe-attack brain injury as the cause of cognitive decline in children who initially developed normally. This does not establish the route in every T666M family or in static intellectual disability.

Exploratory neuroimmune contribution in R583Q-FHM

cytokine_hypothesis EMERGING

Two-carrier serum observations motivate possible nociceptive and neurodegenerative cytokine actions. Reverse causation and effects shared with ordinary migraine remain unresolved.

Pathograph links

Proposed Cytokine-Mediated Neuroinflammation -> Cerebellar Neuronal Degeneration INDIRECT UNKNOWN INTERMEDIATES Pro-apoptotic cytokines are proposed contributors to cerebellar degeneration in the R583Q family; reverse causation remains possible.

Proposed Cytokine-Mediated Neuroinflammation -> Meningeal Nociceptor Sensitization INDIRECT UNKNOWN INTERMEDIATES The combined pro-nociceptive cytokine profile is proposed to act in the trigeminovascular system.

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Discussions and Knowledge Gaps

5

Do the three FHM genes lower the cortical spreading depression threshold through one shared final mechanism, or through separate routes that happen to converge on the same clinical outcome?

KNOWLEDGE GAP OPEN gap_fhm_shared_csd_convergence

Attached to

pathophysiology#Facilitated Cortical Spreading Depolarization pathophysiology#Increased Cortical Glutamatergic Excitability pathophysiology#Cortical Interneuron Hyperactivity

FHM1 and FHM2 have experimentally supported glutamatergic routes to CSD; the W887R/+ clearance deficit is directly measured in the 2016 study. FHM3 differs: acute activation experiments and the L1649Q knock-in support interneuron spiking and potassium accumulation without requiring glutamatergic synaptic transmission for initiation. A universal quantitative threshold-setting mechanism across the three subtypes remains unresolved, and these data do not establish the PRRT2 route.

Proposed experiments

Cross-subtype comparison of CSD threshold determinants

exp_fhm_cross_subtype_csd_threshold

Measure CSD threshold together with extracellular K+ and glutamate transients in FHM1 (CACNA1A), FHM2 (ATP1A2) and FHM3 (SCN1A) knock-in cortex under one protocol, then test whether blocking glutamatergic transmission or buffering extracellular K+ abolishes the threshold shift in each. A K+ manipulation that rescues all three, where glutamatergic blockade rescues only FHM1 and FHM2, would establish extracellular K+ as the shared final common path rather than glutamate.

Show evidence (3 references)

PMID:27354390 SUPPORT In Vitro

"Using ceftriaxone treatment of FHM2 mutants and partial inhibition of glutamate transporters in wild-type mice, we obtain evidence that defective glutamate clearance can account for most of the facilitation of CSD initiation in FHM2-knockin mice"

CSD recordings in cortical slices after mutant-mouse treatment or transporter inhibition support a causal clearance contribution. Ceftriaxone produced only a small rescue and did not restore perisynaptic astrocytic transporter density; this is not evidence of clinical drug efficacy.

PMID:34491914 SUPPORT In Vitro

"Here, we show that acute pharmacological activation of NaV1.1 (the main Na+ channel of interneurons) or optogenetic-induced hyperactivity of GABAergic interneurons is sufficient to ignite CSD in the neocortex by spiking-generated extracellular K+ build-up."

Pharmacologic and optogenetic acute-slice experiments support the spiking/potassium route; they mimic FHM3 activity rather than carrying an FHM allele.

PMID:34546973 SUPPORT INDIRECT In Vitro

"Brain slice recordings using K+-sensitive electrodes revealed an increase in extracellular K+ in the early phase of CSD in heterozygous mice, likely representing the mechanistic link between interneuron hyperactivity and CSD initiation."

The L1649Q genetic model independently supports the potassium intermediary, which the authors explicitly qualify as likely.

Does the reduced cortical spreading depression threshold measured in FHM knock-in mice actually explain the hemiparetic aura of a human FHM attack?

HUMAN MODEL MISMATCH OPEN mismatch_fhm_csd_human_attack

Attached to

pathophysiology#Facilitated Cortical Spreading Depolarization phenotypes#Reversible Hemiparesis During Aura

FHM1, FHM2 and FHM3 models show facilitated CSD, while the CSD-to-human-aura relation remains the leading clinical hypothesis rather than a directly recorded spontaneous FHM event. Qualified causal edges preserve that explanatory relation. Experimentally evoked thresholds measure susceptibility, and W887R heterozygotes showed no apparent clinical phenotype despite facilitated CSD. That negative result remains in animal-model evidence and limitations; it is not a clinical-restatement mechanism node.

Proposed experiments

Non-invasive detection of a CSD correlate during a human FHM attack

exp_fhm_human_csd_correlate

Capture spontaneous or provoked attacks in genotyped FHM patients using serial perfusion and diffusion MRI or MEG timed to aura onset, and test whether a propagating wavefront traverses the motor cortex with the timing and direction predicted by CSD, and whether its speed and threshold differ between FHM1, FHM2 and FHM3 carriers as the mouse models predict.

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/books/NBK1388/ SUPPORT INDIRECT Other

"Accumulating evidence supports the hypothesis that the electrophysiologic correlate underlying migraine aura is cortical spreading depolarization (CSD)"

GeneReviews presents CSD as the hypothesized electrophysiologic basis of aura. Together with its clinical localization of aura to cortex or brainstem, this supports a qualified route to cortical motor, sensory, visual and language manifestations; it is not a direct recording during human FHM attacks.

Which individual aura components explain the reported brainstem composite?

INTERPRETATION OPEN fhm_brainstem_component_scope

The 69% figure is for any basilar-type symptom in 147 Danish FHM patients. It cannot quantify vertigo, tinnitus, dysarthria, diplopia, hyperacusis or transient ataxia separately. The primary abstract establishes ordering and the composite, while the full phenotype table was unavailable through attempted publisher and author-copy routes. The later clinical review explicitly lists individual HM manifestations, whose familial-versus-simplex component denominators remain unresolved. No composite phenotype is used to duplicate its constituents.

Show evidence (3 references)

PMID:12023326 SUPPORT Human Clinical

"In addition, 69% had basilar migraine (BM) symptoms during FHM attacks."

The Danish population-based study reports a 69% composite for any basilar-type symptoms in 147 FHM patients. It does not give the individual component frequencies in the accessible abstract.

PMID:12023326 SUPPORT Human Clinical

"The order of the aura symptoms was usually visual, followed by sensory, aphasic, motor and, lastly, basilar-type migraine symptoms."

The Danish FHM cohort reports the usual ordering of aura modalities, with basilar-type symptoms last. This supports the discussion of the composite's timing, not a frequency for any particular component.

PMID:38674378 SUPPORT Human Clinical

"Other accompanying features during the attacks may include seizure, fever, bilateral visual defects, brainstem aura with vertigo, ataxia, hyperacusia, dysarthria, disturbed consciousness, tinnitus, and, in severe cases, coma"

The later clinical review lists individual manifestations across hemiplegic migraine. It does not establish that this enumeration matches the components or denominators of the separate Danish FHM composite, and does not provide familial-only component frequencies.

Which routes account for brainstem, cognitive and febrile findings beyond the modeled cortical and severe-allele pathways?

KNOWLEDGE GAP OPEN fhm_residual_clinical_routes

Attached to

phenotypes#Vertigo During Aura phenotypes#Tinnitus During Aura phenotypes#Dysarthria phenotypes#Diplopia During Aura phenotypes#Hyperacusis During Aura phenotypes#Ataxia During Aura phenotypes#Drowsiness During Attacks phenotypes#Confusion During Attacks phenotypes#Nystagmus phenotypes#Fever During Severe Attacks phenotypes#Intellectual Disability phenotypes#Memory Impairment phenotypes#Learning Disability phenotypes#Nausea phenotypes#Vomiting phenotypes#Photophobia phenotypes#Phonophobia

The reviewed sources establish occurrence or syndrome/allele attribution, but do not resolve the particular upstream causal route for these findings. Brainstem localization alone does not establish cortical depolarization as the cause of each brainstem manifestation. Nystagmus is a cerebellar sign, but the S218L Purkinje firing experiment tests ataxia rather than ocular-motor dysfunction. Drowsiness and confusion are not automatically coma, and the severe-allele subcortical-spread hypothesis should not be transferred to all altered-awareness symptoms. Developmental disability in selected ATP1A2 variants and prolonged memory/learning problems are not all consequences of attack injury. Fever lacks a demonstrated thermoregulatory mechanism. The family authors' channel hypothesis covers the observed psychotic episodes, including anxiety and visual hallucinations. All three have the same provisional, family-scoped channel attribution; their unspecified intermediate circuits do not negate that broader hypothesis. These are attribution or translation gaps, not missing clinical observations. The reviewed FHM family data establish nausea, vomiting and sensory intolerance, but do not identify their autonomic or sensory-integration routes; a nociceptive pain mechanism alone does not establish these additional effects. The family authors' cerebellar attribution is represented by qualified channel-level links to coordination signs and Romberg instability, without asserting a specific balance-control intermediary.

Show evidence (3 references)

PMID:15159495 SUPPORT Human Clinical

"D718N and P979L may predispose to seizures and mental retardation."

The primary ATP1A2 family study attributes this developmental association to particular variants; it is not a general consequence of all FHM alleles.

PMID:10202246 SUPPORT Human Clinical

"Here we report on a family with familial hemiplegic migraine and cerebellar ataxia with recurrent episodes of acute paranoid psychosis with anxiety and visual hallucinations associated with migraine attacks."

The primary family report directly describes these attack-associated psychiatric observations. Linkage and phenotype supported a chromosome-19 hypothesis; a specific pathogenic CACNA1A variant was not established in this abstract.

url:https://www.ncbi.nlm.nih.gov/books/NBK1388/ SUPPORT INDIRECT Other

"Accumulating evidence supports the hypothesis that the electrophysiologic correlate underlying migraine aura is cortical spreading depolarization (CSD)"

GeneReviews presents CSD as the hypothesized electrophysiologic basis of aura. Together with its clinical localization of aura to cortex or brainstem, this supports a qualified route to cortical motor, sensory, visual and language manifestations; it is not a direct recording during human FHM attacks.

Which additional findings can be assigned specifically to familial hemiplegic migraine?

INTERPRETATION OPEN fhm_missing_candidate_scope

Whole-source review added specific visual/sensory aura, brainstem components, prolonged cognitive and psychiatric findings. The R583Q father/daughter primary report directly supports nausea, vomiting, photophobia, phonophobia and specific cerebellar examination findings, independently of general migraine descriptions or management advice. Its two mutation-negative relatives are not counted as molecular FHM1. Pediatric encephalopathy pools mix familial and simplex cases; PRRT2 hypersomnia cohorts do not resolve a familial-only clinical denominator. Surveillance for developmental delay is advice rather than clinical occurrence. Serum cytokines are exploratory readouts and their causal role is a separate hypothesis.

Show evidence (1 reference)

PMID:12023326 SUPPORT Human Clinical

"FHM patients most often had all four 'typical' aura symptoms (visual, sensory, aphasic and motor symptoms) and all had at least two of these aura symptoms during FHM attacks."

The primary familial cohort establishes typical aura modalities, but its accessible abstract does not quantify the additional associated symptoms.

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Pathophysiology

15

Cav2.1 Calcium Channel Gain of Function

FHM1 missense variants in CACNA1A produce a gain of function of the neuronal Cav2.1 (P/Q-type) voltage-gated calcium channel. In the R192Q knock-in mouse the effect is measured directly as increased Cav2.1 current density in cerebellar neurons and enhanced neurotransmission at the neuromuscular junction.

Calcium-channel attribution of familial psychosis FHM1 cerebellar current abnormalities

neuron CL:0000540

CACNA1A hgnc:1388

Genetic context CACNA1A hgnc:1388 allele_type: MISSENSE zygosity: HETEROZYGOUS functional_impact_category: GAIN_OF_FUNCTION

Heterozygous missense variants in conserved functional domains of the alpha1A subunit; the archetypal pure-FHM allele is R192Q and the severe allele is S218L.

voltage-gated calcium channel activity GO:0005245 ↑ INCREASED

brain UBERON:0000955

Downstream

Increased Cortical Glutamatergic Excitability Increased presynaptic calcium influx enhances release at cortical excitatory synapses in FHM1 models.

Purkinje Cell Firing Dysregulation S218L Cav2.1 gating increases Purkinje excitability and disrupts firing patterns.

Cerebellar Neuronal Degeneration Selected FHM1 current abnormalities are proposed to produce Purkinje dysfunction and neuronal loss.

Attack-Associated Psychosis A chromosome-19-linked FHM/ataxia family prompted the authors' calcium-channel hypothesis for acute psychosis. Applying the Cav2.1 gain-of-function framework to that family remains provisional.

Cerebellar Ataxia R583Q gain-of-function physiology is the family authors' explanation of cerebellar ataxia; intervening circuitry is not reconstructed for those patients.

Dysdiadochokinesis The R583Q family study interprets the observed cerebellar syndrome, including this examination sign, in terms of abnormal Cav2.1 function. This clinical attribution is broader than the S218L-specific firing experiment.

Lower Limb Dysmetria The R583Q family study interprets the observed cerebellar syndrome, including this examination sign, in terms of abnormal Cav2.1 function. This clinical attribution is broader than the S218L-specific firing experiment.

Positive Romberg Sign The authors interpret the R583Q family's interictal examination abnormalities as cerebellar changes due to channel dysfunction. This includes Romberg instability; the particular balance-control intermediary is not resolved.

Attack-Associated Anxiety The authors' calcium-channel hypothesis concerns acute psychotic episodes explicitly including anxiety in this chromosome-19-linked FHM family. Applying the Cav2.1 gain-of-function framework remains provisional; neither a specific variant nor a separate component-specific circuit was established.

Visual Hallucinations The authors' calcium-channel hypothesis concerns acute psychotic episodes explicitly including visual hallucinations in this chromosome-19-linked FHM family. Applying the Cav2.1 gain-of-function framework remains provisional; neither a specific variant nor a separate component-specific circuit was established.

Show evidence (1 reference)

PMID:15003170 SUPPORT Model Organism

"We generated a knockin mouse model carrying the human pure FHM-1 R192Q mutation and found multiple gain-of-function effects. These include increased Ca(v)2.1 current density in cerebellar neurons, enhanced neurotransmission at the neuromuscular junction"

Direct electrophysiological demonstration that the FHM1 variant is a gain-of-function change in Cav2.1 channel activity.

Astrocytic Na+/K+-ATPase Alpha2 Loss of Function

FHM2 variants in ATP1A2 cause loss of function of a single allele of the alpha2 subunit of the Na+/K+ pump. The alpha2 isoform is expressed almost exclusively in astrocytes in the adult brain, where the pump maintains the Na+ gradient that drives astrocytic glutamate and potassium reuptake. In the W887R knock-in mouse the mutant protein is retained in the endoplasmic reticulum and degraded, so the defect is a reduction in functional pump rather than a dominant-negative pump.

astrocyte CL:0000127

ATP1A2 hgnc:800

Genetic context ATP1A2 hgnc:800 zygosity: HETEROZYGOUS functional_impact_category: LOSS_OF_FUNCTION

Heterozygous ATP1A2 variants acting through haploinsufficiency of the astrocytic alpha2 Na+/K+ pump.

P-type sodium:potassium-exchanging transporter activity GO:0005391 ↓ DECREASED

brain UBERON:0000955

Animal models

Atp1a2 W887R knock-in mouse (FHM2) Mouse recapitulates The molecular lesion itself: mutant alpha2 protein is strongly reduced in the brain of heterozygous mutants, consistent with ER retention and proteasomal degradation.

Downstream

Impaired Astrocytic Glutamate and Potassium Clearance The W887R/+ model has reduced alpha2 pump abundance together with directly measured astrocytic glutamate and potassium clearance deficits.

Show evidence (3 references)

PMID:12539047 SUPPORT In Vitro

"Functional data indicate that the putative pathogenetic mechanism is triggered by a loss of function of a single allele of ATP1A2."

Establishes haploinsufficiency, not gain of function, as the FHM2 molecular mechanism.

PMID:21731499 SUPPORT Model Organism

"mutations of the α2-subunit of the Na,K-ATPase, an isoform almost exclusively expressed in astrocytes in the adult brain"

Localizes the affected pump to astrocytes, which is what makes the FHM2 mechanism a glial clearance defect rather than a neuronal channel defect.

PMID:21731499 SUPPORT Model Organism

"The mutant α2 Na,K-ATPase protein was barely detectable in the brain of homozygous mutants and strongly reduced in the brain of heterozygous mutants, likely as a consequence of endoplasmic reticulum retention and subsequent proteasomal degradation"

Identifies the cell-biological route from variant to reduced pump function in the knock-in model.

Nav1.1 Sodium Channel Gain of Function

FHM3 missense variants in SCN1A produce a gain of function of the neuronal Nav1.1 sodium channel. The archetypal Q1489K variant alters the hinged-lid domain critical for fast inactivation and accelerates recovery from fast inactivation two- to four-fold; other FHM3 alleles increase persistent sodium current. This is the opposite direction of effect to the SCN1A loss-of-function variants that cause Dravet syndrome and related epilepsies.

GABAergic neuron CL:0000617

SCN1A hgnc:10585

Genetic context SCN1A hgnc:10585 allele_type: MISSENSE zygosity: HETEROZYGOUS functional_impact_category: GAIN_OF_FUNCTION

Heterozygous missense variants such as Q1489K in the fast-inactivation hinged-lid domain of Nav1.1.

voltage-gated sodium channel activity GO:0005248 ↑ INCREASED

neocortex UBERON:0001950

Downstream

Cortical Interneuron Hyperactivity FHM3 L1649Q impaired inactivation increases fast-spiking interneuron activity in the genetic mouse model.

Show evidence (3 references)

PMID:16054936 SUPPORT In Vitro

"Whole-cell recordings in transiently transfected tsA201 cells expressing the highly homologous SCN5A sodium channel showed that the mutation induces a two-fold to four-fold accelerated recovery from fast inactivation without altering any of the other channel parameters investigated."

The original functional characterization of the FHM3 Q1489K variant as an inactivation-kinetics gain of function. Note the recordings were made in a homologous surrogate channel (SCN5A), not Nav1.1 itself.

PMID:34491914 SUPPORT In Vitro

"We and others have provided evidence that, in contrast to epileptogenic mutations, FHM3 mutations cause gain of function of the channel, often increasing persistent current and inducing hyperexcitability of transfected GABAergic neurons in primary culture"

Confirms the gain-of-function direction across FHM3 alleles and places the effect in GABAergic neurons, contrasting it with epileptogenic SCN1A loss of function.

PMID:34546973 SUPPORT In Vitro

"We found L1649Q to cause a gain-of-function effect with an impaired Na+-channel inactivation and increased ramp Na+ currents leading to hyperactivity of fast-spiking inhibitory interneurons."

Recordings from neurons of the L1649Q knock-in establish the FHM-specific channel-to-interneuron relation. This does not import the loss-of-function mechanism of Dravet syndrome.

Increased Cortical Glutamatergic Excitability

The convergence point of the FHM1 and FHM2 arms. Increased presynaptic Ca2+ influx (FHM1) and reduced astrocytic reuptake (FHM2) both raise glutamate concentration at cortical excitatory synapses, disrupting the excitation-inhibition balance in favour of neuronal hyperactivity. In FHM1 mice the effect is synapse-specific: excitatory neurotransmission at pyramidal cell synapses is enhanced while inhibitory neurotransmission at fast-spiking interneuron synapses is unaltered.

pyramidal neuron CL:0000598

glutamatergic synaptic transmission GO:0035249 ↑ INCREASED

neocortex UBERON:0001950

Animal models

Cacna1a R192Q knock-in mouse (FHM1, pure hemiplegic migraine allele) Mouse recapitulates Cortical microcultures and slices from this model show increased action-potential-evoked Ca2+ influx and increased glutamate release probability at pyramidal-cell synapses, with fast-spiking interneuron synapses unaltered - the synapse specificity that makes this an excitation-inhibition imbalance rather than a global change.

Downstream

Facilitated Cortical Spreading Depolarization Enhanced excitatory release facilitates CSD initiation in FHM1 cortical preparations.

Show evidence (2 references)

PMID:19285472 SUPPORT In Vitro

"We show gain of function of excitatory neurotransmission due to increased action-potential-evoked Ca(2+) influx and increased probability of glutamate release at pyramidal cell synapses but unaltered inhibitory neurotransmission at fast-spiking interneuron synapses."

Establishes the synapse-specific enhancement of glutamate release as the cellular consequence of the FHM1 channel gain of function.

PMID:19285472 SUPPORT In Vitro

"The synapse-specific effect of FHM1 mutations points to disruption of excitation-inhibition balance and neuronal hyperactivity as the basis for episodic vulnerability to CSD ignition in migraine."

States the excitation-inhibition imbalance framing that links this node to the spreading-depression threshold node.

Impaired Astrocytic Glutamate and Potassium Clearance

W887R/+ FHM2 cortical slices have directly measured reductions in astrocytic glutamate and potassium clearance. Reduced perisynaptic GLT-1a accompanies alpha2 pump deficiency. Pharmacological perturbation supports defective glutamate clearance as a major contributor to easier CSD initiation; potassium buffering may contribute differently to propagation. These model results do not quantify clearance during human attacks.

astrocyte CL:0000127

L-glutamate import across plasma membrane GO:0098712 ↓ DECREASED potassium ion transmembrane transport GO:0071805 ↓ DECREASED

Downstream

Increased Cortical Glutamatergic Excitability Reduced glutamate removal increases excitatory transmitter availability; the authors interpret excessive cortical glutamatergic transmission as the route to CSD susceptibility.

Facilitated Cortical Spreading Depolarization The experimentally supported net clearance-to-CSD relation is retained alongside the proposed glutamatergic intermediary.

Show evidence (1 reference)

PMID:27354390 SUPPORT In Vitro

"Here, we show reduced rates of glutamate and K(+) clearance by cortical astrocytes during neuronal activity and reduced density of GLT-1a glutamate transporters in cortical perisynaptic astrocytic processes in heterozygous FHM2-knockin mice"

Patch-clamp recordings in acute W887R/+ cortical slices directly measured slower astrocytic clearance, with reduced perisynaptic GLT-1a in tissue microscopy. This updates the unmeasured 2011 hypothesis; the ex vivo functional claim is graded IN_VITRO.

Cortical Interneuron Hyperactivity

FHM3 gain of function increases fast-spiking inhibitory interneuron activity. The L1649Q knock-in confirms this genetic route, while acute NaV1.1 enhancement and optogenetic activation show that spiking can ignite CSD through extracellular potassium build-up. GABAergic synaptic transmission itself is not required for initiation.

FHM3 spiking and potassium-mediated CSD initiation

GABAergic neuron CL:0000617

neocortex UBERON:0001950

Downstream

Extracellular Potassium Accumulation Repetitive interneuron spiking increases extracellular potassium; the precise early-phase contribution is supported but qualified in the L1649Q model.

Show evidence (2 references)

PMID:34546973 SUPPORT In Vitro

"We found L1649Q to cause a gain-of-function effect with an impaired Na+-channel inactivation and increased ramp Na+ currents leading to hyperactivity of fast-spiking inhibitory interneurons."

Recordings from neurons of the L1649Q knock-in establish the FHM-specific channel-to-interneuron relation. This does not import the loss-of-function mechanism of Dravet syndrome.

PMID:34491914 SUPPORT In Vitro

"Here, we show that acute pharmacological activation of NaV1.1 (the main Na+ channel of interneurons) or optogenetic-induced hyperactivity of GABAergic interneurons is sufficient to ignite CSD in the neocortex by spiking-generated extracellular K+ build-up."

Pharmacologic and optogenetic acute-slice experiments support the spiking/potassium route; they mimic FHM3 activity rather than carrying an FHM allele.

Facilitated Cortical Spreading Depolarization

A propagating wave of neuronal and glial depolarization followed by depression of cortical activity is facilitated in models of FHM1, FHM2 and FHM3. Reduced triggering threshold is an assay readout of this susceptibility. FHM1/FHM2 models also show faster propagation, whereas the L1649Q FHM3 model did not show increased in vivo propagation speed. CSD is the leading explanation of aura, with human FHM translation remaining indirect.

Cortical spreading depolarization and focal aura CSD-triggered meningeal sensitization Severe-attack neuronal injury and acquired cognitive decline Subcortical spread in severe FHM1

neuron CL:0000540 astrocyte CL:0000127

cortical spreading depolarization GO:0051899 ↑ INCREASED

neocortex UBERON:0001950

Animal models

Cacna1a R192Q knock-in mouse (FHM1, pure hemiplegic migraine allele) Mouse recapitulates The in vivo CSD threshold and velocity measurement that grounds the unifying node of this entry.

Cacna1a S218L knock-in mouse (FHM1, severe allele) Mouse recapitulates An exaggerated version of the R192Q threshold phenotype, with multiple CSD events following a single trigger.

Atp1a2 W887R knock-in mouse (FHM2) Mouse recapitulates The FHM2 in vivo threshold and velocity measurement, matching the FHM1 result and supporting the convergence drawn at this node.

Downstream

Reversible Hemiparesis During Aura The cortical aura model attributes this focal aura manifestation to propagating depolarization and subsequent suppression in the relevant cortical network. Translation from experimental CSD to spontaneous human FHM remains indirect.

Migraine with Aura The cortical aura model attributes this focal aura manifestation to propagating depolarization and subsequent suppression in the relevant cortical network. Translation from experimental CSD to spontaneous human FHM remains indirect.

Paresthesia During Aura The cortical aura model attributes this focal aura manifestation to propagating depolarization and subsequent suppression in the relevant cortical network. Translation from experimental CSD to spontaneous human FHM remains indirect.

Hypoesthesia During Aura The cortical aura model attributes this focal aura manifestation to propagating depolarization and subsequent suppression in the relevant cortical network. Translation from experimental CSD to spontaneous human FHM remains indirect.

Aphasia During Aura The cortical aura model attributes this focal aura manifestation to propagating depolarization and subsequent suppression in the relevant cortical network. Translation from experimental CSD to spontaneous human FHM remains indirect.

Scotoma During Aura The cortical aura model attributes this focal aura manifestation to propagating depolarization and subsequent suppression in the relevant cortical network. Translation from experimental CSD to spontaneous human FHM remains indirect.

Photopsia During Aura The cortical aura model attributes this focal aura manifestation to propagating depolarization and subsequent suppression in the relevant cortical network. Translation from experimental CSD to spontaneous human FHM remains indirect.

Meningeal Nociceptor Sensitization CSD may sensitize meningeal trigeminal nociceptors and thereby trigger headache; the source treats this step as a proposed mechanism.

Subcortical Spreading Depolarization Cortical waves spread into subcortical structures in the R192Q/S218L models, with allele-dependent distribution.

Attack-Associated Neuronal Injury Repeated depolarization can injure juvenile rat brain; applying that result to repeated severe FHM attacks remains a provisional model-translation hypothesis.

Show evidence (5 references)

PMID:15003170 SUPPORT Model Organism

"in the intact animal, a reduced threshold and increased velocity of cortical spreading depression (CSD; the likely mechanism for the migraine aura). Our data show that the increased susceptibility for CSD and aura in migraine may be due to cortical hyperexcitability."

The FHM1 in vivo measurement of a lowered CSD threshold, and the framing of cortical hyperexcitability as its cause.

PMID:21731499 SUPPORT Model Organism

"In vivo analysis of cortical spreading depression (CSD), the phenomenon underlying migraine aura, revealed a decreased induction threshold and an increased velocity of propagation in the heterozygous FHM2 mouse."

The matching FHM2 in vivo measurement.

PMID:21731499 SUPPORT Model Organism

"The demonstration that FHM2 and FHM1 mutations share the ability to facilitate induction and propagation of CSD in mouse models further support the role of CSD as a key migraine trigger."

States the convergence of the two arms on a shared CSD-facilitation phenotype.

+ 2 more references

Extracellular Potassium Accumulation

Mechanism confidence: Provisional

Spiking-generated extracellular potassium build-up couples interneuron hyperactivity to CSD initiation in FHM3 experimental systems.

FHM3 spiking and potassium-mediated CSD initiation

Downstream

Facilitated Cortical Spreading Depolarization Potassium accumulation depolarizes the cortical network and facilitates CSD initiation. The genetic model supports the proposed ionic intermediary.

Show evidence (2 references)

PMID:34491914 SUPPORT In Vitro

"Here, we show that acute pharmacological activation of NaV1.1 (the main Na+ channel of interneurons) or optogenetic-induced hyperactivity of GABAergic interneurons is sufficient to ignite CSD in the neocortex by spiking-generated extracellular K+ build-up."

Pharmacologic and optogenetic acute-slice experiments support the spiking/potassium route; they mimic FHM3 activity rather than carrying an FHM allele.

PMID:34546973 SUPPORT INDIRECT In Vitro

"Brain slice recordings using K+-sensitive electrodes revealed an increase in extracellular K+ in the early phase of CSD in heterozygous mice, likely representing the mechanistic link between interneuron hyperactivity and CSD initiation."

The L1649Q genetic model independently supports the potassium intermediary, which the authors explicitly qualify as likely.

Meningeal Nociceptor Sensitization

Mechanism confidence: Provisional

Sensitization of meningeal trigeminal afferents is a proposed link between CSD and migraine headache.

CSD-triggered meningeal sensitization

Downstream

Headache Sensitized meningeal nociceptors drive trigeminovascular pain signaling in the proposed CSD-triggered headache pathway.

Show evidence (1 reference)

PMID:34491914 SUPPORT INDIRECT Other

"SD-induced cortical spreading depression (CSD) of spontaneous activity causes migraine aura and could induce migraine headache by sensitization of meningeal nociceptors"

This is the paper's background mechanistic hypothesis, not a headache outcome measured in its slice or optogenetic experiments. The CSD-to-headache relation remains qualified.

Subcortical Spreading Depolarization

Mechanism confidence: Provisional

Spreading depolarization enters striatum in R192Q and more extensive subcortical structures in S218L mice, offering an allele-scoped explanation for severe attack manifestations.

Subcortical spread in severe FHM1

Downstream

Reversible Hemiparesis During Aura Subcortical spreading depolarization is the authors' proposed explanation for this severe-attack manifestation; the anatomical extent and clinical translation remain allele-dependent.

Coma Subcortical spreading depolarization is the authors' proposed explanation for this severe-attack manifestation; the anatomical extent and clinical translation remain allele-dependent.

Seizures Subcortical spreading depolarization is the authors' proposed explanation for this severe-attack manifestation; the anatomical extent and clinical translation remain allele-dependent.

Show evidence (1 reference)

PMID:21490217 SUPPORT Model Organism

"We showed that unlike the wild type, cortical spreading depression readily propagated into subcortical structures in both familial hemiplegic migraine type 1 mutants."

Multielectrode recordings, diffusion MRI and c-fos mapping in R192Q and S218L mice demonstrate subcortical spread. Hippocampal/thalamic spread was specific to the severe S218L model; R192Q spread was limited to striatum.

Purkinje Cell Firing Dysregulation

Mechanism confidence: Provisional

S218L Cav2.1 gain of function lowers Purkinje-cell spike thresholds and disrupts firing regularity, a proposed substrate for cerebellar ataxia.

FHM1 cerebellar current abnormalities

Downstream

Cerebellar Ataxia Irregular Purkinje firing is proposed to cause ataxia in the S218L model. This supports a qualified route to the clinical cerebellar phenotype without proving every progressive human ataxia has the same substrate.

Show evidence (2 references)

PMID:23115190 SUPPORT In Vitro

"Here, we demonstrate that the S218L mutation causes a negative shift of voltage dependence of Ca(V)2.1 channels of mouse Purkinje cells and results in lowered thresholds for somatic action potentials and dendritic Ca(2+) spikes and in disrupted firing patterns."

Purkinje-cell electrophysiology directly supports the S218L channel-to-firing relation. It does not generalize this effect to CACNA1A loss-of-function ataxias.

PMID:23115190 SUPPORT INDIRECT Model Organism

"The current data suggest that abnormalities in Purkinje cell firing contributes to cerebellar ataxia induced by the S218L mutation"

The authors infer a causal firing-to-ataxia route from electrophysiology and improved mouse motor performance with channel modulation. The translational inference is explicitly limited to the S218L model.

Cerebellar Neuronal Degeneration

Mechanism confidence: Provisional

Neuronal loss is a proposed consequence of selected ataxia-associated FHM1 current abnormalities; it provides a substrate for cerebellar tissue atrophy.

FHM1 cerebellar current abnormalities

Downstream

Cerebellar Atrophy Loss of cerebellar neurons contributes to the atrophic tissue phenotype in the reviewed FHM1 model.

Show evidence (1 reference)

PMID:25143767 SUPPORT INDIRECT Other

"FHM1 with ataxia is attributable to specific mutations that differ from mutations that cause pure FHM1 and have peculiar consequences on cerebellar Cav2.1 currents that lead to profound Purkinje cell dysfunction and to neuronal loss with atrophy."

The mechanistic review attributes cerebellar neuronal loss and atrophy to selected FHM1 current abnormalities. This synthesis supports a qualified degeneration route, not a human histological demonstration across all CACNA1A families.

Blood-Brain Barrier Disruption

Mechanism confidence: Provisional

Cortical barrier leakage preceded delayed edema in one ATP1A2-FHM attack. The cause of barrier disruption upstream of this observed tissue lesion remains unresolved.

Case-scoped vasogenic edema

Downstream

Cerebral Edema The case authors interpret delayed edema after barrier opening as vasogenic fluid accumulation.

Show evidence (1 reference)

PMID:15985592 SUPPORT Human Clinical

"Quantitative analysis of early gadolinium-enhanced MRI revealed a mild but significant left-hemispheric blood-brain barrier (BBB) opening limited to the cortex and preceding cortical edema."

The severe ATP1A2-FHM case provides direct serial-imaging evidence of cortical edema and earlier barrier leakage.

Attack-Associated Neuronal Injury

Mechanism confidence: Provisional

Neuronal injury after severe or repeated attacks is a proposed substrate for stepwise cognitive decline in a subset of children with FHM, supported indirectly by juvenile-rat spreading-depression experiments.

Severe-attack neuronal injury and acquired cognitive decline

Downstream

Progressive Cognitive Deterioration The review proposes severe-attack brain injury as the cause of cognitive decline in children who initially developed normally. This does not establish the route in every T666M family or in static intellectual disability.

Show evidence (2 references)

PMID:25143767 SUPPORT INDIRECT Model Organism

"Repetitive cortical SD enhanced the production of dark neurons, reduced the mean volume of normal neurons, increased the number of apoptotic neurons"

The review summarizes neuronal injury after repeated spreading depression in juvenile rats. These animals are not FHM knock-ins; transfer to severe childhood FHM is hypothetical.

PMID:25143767 SUPPORT INDIRECT Other

"Severe attacks are suggested to result in permanent brain damage and atrophy as well as cognitive deterioration in the few children with normal early development and a notable stepwise developmental regression after the onset of severe FHM attacks."

The review describes a proposed attack-injury route in a specific severe childhood course, not a demonstrated explanation for the T666M family or all developmental disability.

Proposed Cytokine-Mediated Neuroinflammation

Mechanism confidence: Hypothetical

A hypothesis of cytokine action on neural and trigeminovascular tissues motivated by exploratory serum profiles in two R583Q-FHM carriers. Serum changes are readouts of a proposed state, and may instead be consequences of recurrent disease.

Exploratory neuroimmune contribution in R583Q-FHM

Downstream

Cerebellar Neuronal Degeneration Pro-apoptotic cytokines are proposed contributors to cerebellar degeneration in the R583Q family; reverse causation remains possible.

Meningeal Nociceptor Sensitization The combined pro-nociceptive cytokine profile is proposed to act in the trigeminovascular system.

Show evidence (2 references)

DOI:10.3389/fncel.2017.00263 SUPPORT INDIRECT Other

"High levels of certain pro-apoptotic cytokines may have contributed to the cerebellar degenerat ion seen in the mutation carriers"

The authors propose a cytokine contribution to cerebellar degeneration in two R583Q carriers. They explicitly acknowledge that altered cytokines could instead be secondary to disease or pain.

DOI:10.3389/fncel.2017.00263 SUPPORT INDIRECT Other

"Thus, combined pro-nociceptive and pro-inﬂammatory action of cytokines IL-6, IL-18, CXCL1, LIF , and MIF could occur in the trigeminovascular system, which comprises of peripheral trigeminal neurons and vessels in meninges located outside the brain blood barrier, that might explain speciﬁc..."

This is the family authors' proposed neuroimmune pain mechanism, based on serum profiles and external experimental work. Neither cytokine action in patient meninges nor clinical benefit from cytokine blockade was tested.

⬡

Pathograph

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Phenotypes

39

Digestive 2

Nausea HP:0002018

Temporal: TRANSIENT

Show evidence (2 references)

DOI:10.3389/fncel.2017.00263 SUPPORT Human Clinical

"Headache was typically localized to the left temporal region of the head and associated with photo- and phonophobia, nausea and occasional vomiting."

Patient D, a genetically confirmed R583Q carrier with an affected father, had all four associated symptoms. This clinical observation does not imply a population frequency; "occasional" describes her vomiting within attacks.

DOI:10.3389/fncel.2017.00263 SUPPORT Human Clinical

"Headaches usually present on one side, often last several hours, and are accompanied by nausea and intolerance to light and sound."

Patient F, the genetically confirmed R583Q father, reported nausea accompanying his headaches. This supports the father component of the description alongside the daughter’s separately quoted history, without implying a population frequency.

Vomiting HP:0002013

Temporal: TRANSIENT

Show evidence (1 reference)

DOI:10.3389/fncel.2017.00263 SUPPORT Human Clinical

"Headache was typically localized to the left temporal region of the head and associated with photo- and phonophobia, nausea and occasional vomiting."

Patient D, a genetically confirmed R583Q carrier with an affected father, had all four associated symptoms. This clinical observation does not imply a population frequency; "occasional" describes her vomiting within attacks.

Ear 2

Vertigo During Aura HP:0002321

Temporal: TRANSIENT

No frequency is asserted. The 69% population figure is for brainstem symptoms as a group, and the source that names the individual symptoms does not break them down.

Show evidence (1 reference)

PMID:38674378 SUPPORT Human Clinical

"bilateral visual defects, brainstem aura with vertigo, ataxia, hyperacusia, dysarthria, disturbed consciousness, tinnitus"

Names vertigo as a brainstem aura feature of hemiplegic migraine.

Tinnitus During Aura HP:0000360

Temporal: TRANSIENT

Show evidence (1 reference)

PMID:38674378 SUPPORT Human Clinical

"hyperacusia, dysarthria, disturbed consciousness, tinnitus, and, in severe cases, coma"

Names tinnitus as a brainstem aura feature of hemiplegic migraine.

Eye 5

Nystagmus HP:0000639

Show evidence (1 reference)

PMID:20301562 SUPPORT Human Clinical

"have cerebellar signs ranging from nystagmus to progressive, usually late-onset mild ataxia"

Names nystagmus as part of the CACNA1A-FHM cerebellar spectrum.

Scotoma During Aura HP:0000575

Temporal: TRANSIENT

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/books/NBK1388/ SUPPORT Human Clinical

"Visual disturbances can include scotoma (blind spots), photopsia (flashing lights), fortification spectra (zigzag pattern), and diplopia (double vision)."

GeneReviews describes these individual visual aura manifestations in its FHM clinical description. The list establishes occurrence, without individual frequencies.

Photopsia During Aura HP:0030786

Temporal: TRANSIENT

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/books/NBK1388/ SUPPORT Human Clinical

"Visual disturbances can include scotoma (blind spots), photopsia (flashing lights), fortification spectra (zigzag pattern), and diplopia (double vision)."

GeneReviews describes these individual visual aura manifestations in its FHM clinical description. The list establishes occurrence, without individual frequencies.

Diplopia During Aura HP:0000651

Temporal: TRANSIENT

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/books/NBK1388/ SUPPORT Human Clinical

"Visual disturbances can include scotoma (blind spots), photopsia (flashing lights), fortification spectra (zigzag pattern), and diplopia (double vision)."

GeneReviews describes these individual visual aura manifestations in its FHM clinical description. The list establishes occurrence, without individual frequencies.

Photophobia HP:0000613

Temporal: TRANSIENT

Show evidence (2 references)

DOI:10.3389/fncel.2017.00263 SUPPORT Human Clinical

"Headache was typically localized to the left temporal region of the head and associated with photo- and phonophobia, nausea and occasional vomiting."

Patient D, a genetically confirmed R583Q carrier with an affected father, had all four associated symptoms. This clinical observation does not imply a population frequency; "occasional" describes her vomiting within attacks.

DOI:10.3389/fncel.2017.00263 SUPPORT Human Clinical

"Headaches usually present on one side, often last several hours, and are accompanied by nausea and intolerance to light and sound."

Patient F, the genetically confirmed R583Q father, reported light intolerance accompanying his headaches. This independently supports headache-associated photophobia in this family, without implying a population frequency.

Immune 2

Increased Serum Interleukin 6 Increased circulating interleukin 6 concentration HP:0030783

Show evidence (1 reference)

DOI:10.3389/fncel.2017.00263 SUPPORT Human Clinical

"We found an increased serum levels or IL-6 in both FHM1 patients (D and F), as well as in the two migraine with aura patients without the genetic mutation (B and S)."

IL-6 was increased in the two R583Q-FHM carriers and the two migraine-with-aura relatives without the mutation; the study is too small for statistical inference.

Increased Serum Interleukin 18 Increased circulating interleukin 18 concentration HP:0034447

Show evidence (1 reference)

DOI:10.3389/fncel.2017.00263 SUPPORT Human Clinical

"pro-inﬂammatory cytokine IL-18 is also up-regulated in serum of all migraine patients, albeit stronger in patients with the gene mutation."

Serum IL-18 was higher in the two FHM1 carriers and their mutation-negative migraine relatives. This is an exploratory blood assay, not proof of local CNS inflammation.

Metabolism 2

Cerebral Edema HP:0002181

Temporal: TRANSIENT

Show evidence (2 references)

PMID:19438926 SUPPORT Human Clinical

"delayed cerebral oedema and coma following minor head trauma"

Documents cerebral edema in the severe attack phenotype.

PMID:15985592 SUPPORT Human Clinical

"Quantitative analysis of early gadolinium-enhanced MRI revealed a mild but significant left-hemispheric blood-brain barrier (BBB) opening limited to the cortex and preceding cortical edema."

The severe ATP1A2-FHM case provides direct serial-imaging evidence of cortical edema and earlier barrier leakage.

Fever During Severe Attacks HP:0001945

Temporal: TRANSIENT

Show evidence (1 reference)

PMID:10408534 SUPPORT Human Clinical

"hemiplegia was associated with acutely altered consciousness and fever lasting several days"

Reports fever as a feature of severe prolonged FHM attacks.

Nervous System 26

Reversible Hemiparesis During Aura HP:0001269

Temporal: TRANSIENT

Show evidence (1 reference)

PMID:20301562 SUPPORT Human Clinical

"in whom the aura includes fully reversible motor weakness and visual, sensory, or language symptoms"

The diagnostic criterion establishing reversible motor weakness as obligatory.

Migraine with Aura VERY_FREQUENT HP:0002077

Show evidence (1 reference)

PMID:20301562 SUPPORT Human Clinical

"Familial hemiplegic migraine (FHM) falls within the category of migraine with aura."

Places FHM inside migraine with aura, which is why the aura is obligatory rather than occasional.

Headache VERY_FREQUENT HP:0002315

The 99% figure is from the Danish population-based FHM cohort, not from genetically selected severe-allele carriers.

Show evidence (2 references)

PMID:32430436 SUPPORT Human Clinical

"Hemiplegic migraine (HM) is a clinically and genetically heterogeneous condition with attacks of headache and motor weakness"

Establishes headache as a core attack feature alongside weakness.

PMID:12023326 SUPPORT Human Clinical

"Headache was present in 99% of FHM patients during FHM attacks"

The population-based Danish series included 147 affected individuals in 44 families; 99% had headache with attacks. This supports VERY_FREQUENT within that FHM cohort.

Paresthesia During Aura HP:0003401

Temporal: TRANSIENT

Show evidence (1 reference)

PMID:20301562 SUPPORT Human Clinical

"sensory loss (e.g., numbness or paresthesias of the face or an extremity)"

Names the sensory aura modality in FHM.

Aphasia During Aura HP:0002381

Temporal: TRANSIENT

Show evidence (1 reference)

PMID:20301562 SUPPORT Human Clinical

"In migraine with aura (including FHM) the neurologic symptoms of aura are unequivocally localizable to the cerebral cortex or brain stem and include visual disturbance (most common), sensory loss (e.g., numbness or paresthesias of the face or an extremity), and dysphasia (difficulty with speech)."

Names the language aura modality in FHM.

Dysarthria HP:0001260

Temporal: TRANSIENT

Show evidence (1 reference)

PMID:38674378 SUPPORT Human Clinical

"brainstem aura with vertigo, ataxia, hyperacusia, dysarthria, disturbed consciousness"

Names dysarthria as a brainstem aura feature of hemiplegic migraine.

Cerebellar Ataxia Progressive cerebellar ataxia HP:0002073

GeneReviews estimates cerebellar signs in 40%-50% of CACNA1A-FHM families. Neither that family-level composite nor the 83% nystagmus-or-ataxia figure in selected carriers quantifies individual progressive ataxia.

Show evidence (2 references)

PMID:20301562 SUPPORT Human Clinical

"Approximately 40%-50% of families with CACNA1A-FHM have cerebellar signs ranging from nystagmus to progressive, usually late-onset mild ataxia."

The estimate concerns families with any cerebellar signs, combining nystagmus and ataxia. It establishes the spectrum but cannot quantify progressive ataxia in individual patients.

PMID:10408534 SUPPORT Human Clinical

"She, as well as her affected sister, developed a permanent, late-onset cerebellar ataxia and cerebellar atrophy evident on MRI."

Direct observation of persistent cerebellar ataxia and MRI atrophy in two sisters with the R583Q CACNA1A variant.

Seizures HP:0001250

Show evidence (3 references)

url:https://www.ncbi.nlm.nih.gov/books/NBK1388/ SUPPORT Human Clinical

"Seizures during severe attacks have been reported in some families"

The complete GeneReviews sentence identifies these families as ATP1A2-FHM and describes accompanying coma and encephalopathy. The uninterrupted quoted span establishes clinical seizure occurrence rather than treatment advice.

PMID:33839563 SUPPORT Human Clinical

"there were 28 families and 195 individuals, 78 of whom had epilepsy; 30 patients had focal epilepsy and 30 patients had generalized epilepsy."

The review selected published families with FHM and epilepsy. The 78/195 count describes that ascertained literature pool, not the prevalence of epilepsy among all people with FHM.

PMID:33839563 SUPPORT Human Clinical

"Mutations in all three and possibly four FHM genes can cause epilepsy. Contrary to our expectations, the well-known epilepsy gene SCN1A mutations are not the leading cause; the highest number of cases associated with epilepsy belongs to the ATP1A2 mutation."

Establishes that epilepsy is not confined to the SCN1A subtype and is most often reported with ATP1A2.

Coma HP:0001259

Temporal: TRANSIENT

Show evidence (1 reference)

PMID:15985592 SUPPORT Human Clinical

"The authors report a patient with familial hemiplegic migraine type II who developed a long-lasting attack including fever, right-sided hemiplegia, aphasia, and coma."

An ATP1A2-FHM case directly establishes coma during a severe attack, without relying on simplex pediatric cases or transferring all S218L carriers into familial disease.

Intellectual Disability HP:0001249

Show evidence (2 references)

PMID:32430436 SUPPORT Human Clinical

"with attacks of headache and motor weakness which may be associated with impaired consciousness, cerebellar ataxia and intellectual disability"

Names intellectual disability among the associated features of hemiplegic migraine. The source does not quantify it, so no frequency is asserted.

PMID:15159495 SUPPORT Human Clinical

"D718N and P979L may predispose to seizures and mental retardation."

The primary ATP1A2 family study attributes this developmental association to particular variants; it is not a general consequence of all FHM alleles.

Hypoesthesia During Aura HP:0033748

Temporal: TRANSIENT

Show evidence (1 reference)

PMID:20301562 SUPPORT Human Clinical

"sensory loss (e.g., numbness or paresthesias of the face or an extremity)"

The sensory aura description includes reduced sensation as well as positive paresthesias; these are represented separately.

Hyperacusis During Aura HP:0010780

Temporal: TRANSIENT

Show evidence (1 reference)

PMID:38674378 SUPPORT Human Clinical

"bilateral visual defects, brainstem aura with vertigo, ataxia, hyperacusia, dysarthria, disturbed consciousness, tinnitus"

The clinical review explicitly lists hyperacusia. As for vertigo and tinnitus, its HM-wide scope and lack of a component denominator are retained; the 69% FHM composite is not assigned to this symptom.

Ataxia During Aura HP:0001251

Temporal: TRANSIENT

Show evidence (1 reference)

PMID:38674378 SUPPORT Human Clinical

"brainstem aura with vertigo, ataxia, hyperacusia, dysarthria, disturbed consciousness"

This clinical review lists attack-associated ataxia; it does not identify a progressive cerebellar course or a symptom-specific frequency.

Drowsiness During Attacks HP:0002329

Temporal: TRANSIENT

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/books/NBK1388/ SUPPORT Human Clinical

"Some confusion and/or drowsiness may be present even without dysphasia."

The FHM clinical description distinguishes these altered-awareness manifestations from dysphasia.

Confusion During Attacks HP:0001289

Temporal: TRANSIENT

Show evidence (1 reference)

PMID:12756131 SUPPORT Human Clinical

"In 1 family, some affected members with the mutation had attacks with confusion but without hemiparesis."

The primary study of five unrelated T666M families documents confusion attacks in one pedigree. This does not make every episode a diagnostic hemiplegic attack.

Cerebellar Atrophy HP:0001272

Show evidence (1 reference)

PMID:10408534 SUPPORT Human Clinical

"She, as well as her affected sister, developed a permanent, late-onset cerebellar ataxia and cerebellar atrophy evident on MRI."

Direct MRI observation in two affected sisters with the R583Q allele.

Memory Impairment HP:0002354

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/books/NBK1388/ SUPPORT Human Clinical

"Persistent attention and memory loss can last weeks to months"

GeneReviews reports the prolonged cognitive sequelae in its FHM clinical description, citing the T666M family study. No frequency or permanent course is inferred.

Learning Disability Specific learning disability HP:0001328

Show evidence (1 reference)

url:https://www.ncbi.nlm.nih.gov/books/NBK1388/ SUPPORT Human Clinical

"associated interictal symptoms and signs (nystagmus, episodic or progressive ataxia, learning disability, epilepsy)"

GeneReviews describes learning disability among interictal findings in genetically identified FHM. Surveillance advice alone is not used as evidence of occurrence.

Attack-Associated Psychosis HP:0000709

Temporal: TRANSIENT

Show evidence (1 reference)

PMID:10202246 SUPPORT Human Clinical

"Here we report on a family with familial hemiplegic migraine and cerebellar ataxia with recurrent episodes of acute paranoid psychosis with anxiety and visual hallucinations associated with migraine attacks."

The primary family report directly describes these attack-associated psychiatric observations. Linkage and phenotype supported a chromosome-19 hypothesis; a specific pathogenic CACNA1A variant was not established in this abstract.

Attack-Associated Anxiety HP:0000739

Temporal: TRANSIENT

Show evidence (1 reference)

PMID:10202246 SUPPORT Human Clinical

"Here we report on a family with familial hemiplegic migraine and cerebellar ataxia with recurrent episodes of acute paranoid psychosis with anxiety and visual hallucinations associated with migraine attacks."

The primary family report directly describes these attack-associated psychiatric observations. Linkage and phenotype supported a chromosome-19 hypothesis; a specific pathogenic CACNA1A variant was not established in this abstract.

Visual Hallucinations HP:0002367

Show evidence (1 reference)

PMID:10202246 SUPPORT Human Clinical

"Here we report on a family with familial hemiplegic migraine and cerebellar ataxia with recurrent episodes of acute paranoid psychosis with anxiety and visual hallucinations associated with migraine attacks."

The primary family report directly describes these attack-associated psychiatric observations. Linkage and phenotype supported a chromosome-19 hypothesis; a specific pathogenic CACNA1A variant was not established in this abstract.

Phonophobia HP:0002183

Temporal: TRANSIENT

Show evidence (2 references)

DOI:10.3389/fncel.2017.00263 SUPPORT Human Clinical

"Headache was typically localized to the left temporal region of the head and associated with photo- and phonophobia, nausea and occasional vomiting."

Patient D, a genetically confirmed R583Q carrier with an affected father, had all four associated symptoms. This clinical observation does not imply a population frequency; "occasional" describes her vomiting within attacks.

DOI:10.3389/fncel.2017.00263 SUPPORT Human Clinical

"Headaches usually present on one side, often last several hours, and are accompanied by nausea and intolerance to light and sound."

Patient F, the genetically confirmed R583Q father, reported sound intolerance accompanying his headaches. This supports headache-associated phonophobia, without assigning it to brainstem aura or implying a population frequency.

Dysdiadochokinesis HP:0002075

Show evidence (2 references)

DOI:10.3389/fncel.2017.00263 SUPPORT Human Clinical

"Neurological examination reveals minor signs of adiadochokinesia (right > left) and heel-knee probe which is slightly asymmetrical with hypermetria on the right side."

Patient D had these interictal examination findings. They are cerebellar signs in a genetically confirmed FHM1 family, not inferred from the broad ataxia label.

DOI:10.3389/fncel.2017.00263 SUPPORT Human Clinical

"Tendon reﬂexes are normal and symmetrical, however, slight adiadochokinesia with prevalence on the right side as well as hypermetria on the right side of the heel-knee test is detecte d."

Patient F, the genetically confirmed R583Q father, had right-predominant adiadochokinesia on interictal examination. This complements his daughter’s separately quoted examination and does not establish a disease-wide frequency.

Lower Limb Dysmetria HP:0020035

Show evidence (2 references)

DOI:10.3389/fncel.2017.00263 SUPPORT Human Clinical

"Neurological examination reveals minor signs of adiadochokinesia (right > left) and heel-knee probe which is slightly asymmetrical with hypermetria on the right side."

Patient D had these interictal examination findings. They are cerebellar signs in a genetically confirmed FHM1 family, not inferred from the broad ataxia label.

DOI:10.3389/fncel.2017.00263 SUPPORT Human Clinical

"Tendon reﬂexes are normal and symmetrical, however, slight adiadochokinesia with prevalence on the right side as well as hypermetria on the right side of the heel-knee test is detecte d."

Patient F, the genetically confirmed R583Q father, had right-sided hypermetria on heel-knee testing. This independently supports the father component of the description, alongside his daughter’s examination; it is not inferred from ataxia or MRI atrophy.

Positive Romberg Sign HP:0002403

Show evidence (1 reference)

DOI:10.3389/fncel.2017.00263 SUPPORT Human Clinical

"Also, instability in the Romberg test is detected."

Direct clinical examination of patient F. The source does not demonstrate sensory neuropathy, and tactile sensation was unaffected.

Progressive Cognitive Deterioration Mental deterioration HP:0001268

Show evidence (2 references)

PMID:12756131 SUPPORT Human Clinical

"In 1 family, patients had progressive cognitive dysfunction."

The T666M family study reports progressive cognitive dysfunction, distinct from static intellectual disability or transient confusion.

PMID:25143767 SUPPORT INDIRECT Other

"Severe attacks are suggested to result in permanent brain damage and atrophy as well as cognitive deterioration in the few children with normal early development and a notable stepwise developmental regression after the onset of severe FHM attacks."

The review describes a proposed attack-injury route in a specific severe childhood course, not a demonstrated explanation for the T666M family or all developmental disability.

🧬

Genetic Associations

6

CACNA1A

Gene: CACNA1A hgnc:1388 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

Autosomal dominant, incomplete penetrance (CACNA1A)

Show evidence (1 reference)

PMID:8898206 SUPPORT Human Clinical

"Thus, FHM and EA-2 can be considered as allelic channelopathies."

Establishes CACNA1A as causal for FHM and defines the allelic relationship with episodic ataxia type 2, which is the boundary with the CACNA1A-Related Disorder entry.

ATP1A2

Gene: ATP1A2 hgnc:800 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:12539047 SUPPORT Human Clinical

"This is the first report associating mutations of Na+K+ pump subunits to genetic diseases."

The gene-discovery report establishing ATP1A2 as causal for FHM2.

SCN1A

Gene: SCN1A hgnc:10585 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (1 reference)

PMID:16054936 SUPPORT Human Clinical

"This same mutation was present in three families with familial hemiplegic migraine."

Recurrence of the Q1489K variant across three independent families supports SCN1A causation.

PRRT2

Gene: PRRT2 hgnc:30500 gene page relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (2 references)

PMID:34649875 SUPPORT Other

"PRRT2 should be regarded as the fourth autosomal dominant gene for hemiplegic migraine and screened in any affected patient, together with the 3 other main genes."

The quoted conclusion states the authors' gene-classification and screening recommendation. The underlying observed cohort counts remain HUMAN_CLINICAL in the case-fraction evidence; this grading does not alter PRRT2 causative status.

PMID:34649875 SUPPORT Other

"Further studies are needed to understand how the same loss-of-function PRRT2 variations can lead to a wide range of neurologic phenotypes, including paroxysmal movement disorder, epilepsy, learning disabilities, sleep disorder, and hemiplegic migraine."

Records both the loss-of-function direction and the open question about how one gene produces this phenotypic range.

CACNA1H

Gene: CACNA1H hgnc:1395 gene page relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE

Show evidence (4 references)

DOI:10.1007/s12035-023-03255-5 SUPPORT Human Clinical

"Our data suggest that HM, in the absence of a single causal mutation, is a complex trait, in which an increased burden of missense variants in CACNA1H and CACNA1I may contribute to the risk of disease."

The authors' own conclusion, which is what SUSCEPTIBILITY records here - a contribution to risk, not causation.

DOI:10.1007/s12035-023-03255-5 SUPPORT Human Clinical

"Both the number of variants and number of subjects were replicated for CACNA1H"

CACNA1H is the one gene whose burden signal replicated in the independent cohort on both tests, which is why it is recorded ahead of CACNA1I.

DOI:10.3390/genes15040443 SUPPORT Human Clinical

"However, approximately 75% of HM patients are negative for these mutations, indicating there are other genes involved in disease causation."

Establishes the size of the unexplained fraction that the burden analysis above is addressing.

+ 1 more reference

CACNA1I

Gene: CACNA1I hgnc:1396 relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE

Show evidence (1 reference)

DOI:10.1007/s12035-023-03255-5 SUPPORT Human Clinical

"albeit that CACNA1I did not remain significant after multiple testing correction"

The authors explicitly qualify the replication: CACNA1I did not remain significant after multiple-testing correction. It remains a candidate association, not an established causal FHM gene.

💊

Medical Actions

8

Acetazolamide

Action: Pharmacotherapy NCIT:C15986

Agent: acetazolamide CHEBI:27690

Platform: Small molecule

A carbonic anhydrase inhibitor, tried preferentially in CACNA1A-FHM. In one family with a CACNA1A R583Q variant the proband and her affected sister reported freedom from new FHM attacks on acetazolamide, although the cerebellar ataxia continued to progress. The evidence base is case-level, in keeping with the rarity of the disorder.

Mechanism Target:

Reversible Hemiparesis During Aura — Reported to abolish new hemiplegic attacks in an acetazolamide-responsive CACNA1A family, without effect on the progressive cerebellar deficit.

Show evidence (1 reference)

PMID:10408534 SUPPORT Human Clinical

"The proband and her affected sister were treated with acetazolamide, reporting freedom from new FHM attacks but no benefit in the progression of ataxia."

Supports an attack-preventive effect, but from two related individuals in one family with no control condition; the uncontrolled case scope limits causal inference.

Show evidence (1 reference)

PMID:20301562 SUPPORT Other

"A trial of acetazolamide for individuals with CACNA1A-FHM or a trial of prophylactic migraine medications (e.g., tricyclic antidepressants, beta-blockers, calcium channel blockers, anti-seizure medications) for all FHM types may be warranted for frequent attacks."

GeneReviews management guidance recommending an acetazolamide trial specifically for the CACNA1A subtype.

Acute Attack Analgesia with NSAIDs and Non-Narcotic Analgesics

Action: Pharmacotherapy NCIT:C15986

Agent: nonsteroidal anti-inflammatory drug NCIT:C257

Platform: Small molecule

NSAIDs and non-narcotic analgesics are described for acute headache control. The source is usual-practice advice, not a comparative FHM trial; vasoconstrictor avoidance is recorded separately.

Target Phenotypes: Headache HP:0002315

Show evidence (1 reference)

PMID:41552155 SUPPORT Other

"Acute management focuses on pain control using nonsteroidal anti-inflammatory drugs (NSAIDs) and non-narcotic analgesics."

States the acute-phase management approach. This is a narrative review section of a single case report, so it records usual practice rather than trial evidence, and no efficacy claim is attached.

Migraine Prophylaxis

Action: Pharmacotherapy NCIT:C15986

Agent: flunarizine CHEBI:135652 verapamil CHEBI:9948 lamotrigine CHEBI:6367 topiramate CHEBI:63631 valproic acid CHEBI:39867 amitriptyline CHEBI:2666

Platform: Small molecule

A trial of standard prophylactic migraine medication - tricyclic antidepressants, beta-blockers, calcium channel blockers or anti-seizure medications - may be warranted for frequent attacks in any FHM subtype. Note that because hemiplegic migraine is rare, most published treatment data are case studies rather than trials.

Show evidence (4 references)

PMID:41552155 SUPPORT Other

"Commonly used agents include flunarizine, verapamil, lamotrigine, acetazolamide, topiramate, valproic acid, and amitriptyline"

Names the individual agents used for prophylaxis, which is what the therapeutic_agent list above records. Acetazolamide appears in the same list and has its own treatment entry.

PMID:41552155 SUPPORT Other

"While evidence from randomized trials is unavailable, case series suggest potential benefit."

States the strength of the evidence for these agents explicitly. No efficacy claim is made here, which limits inference.

PMID:20301562 SUPPORT Other

"a trial of prophylactic migraine medications (e.g., tricyclic antidepressants, beta-blockers, calcium channel blockers, anti-seizure medications) for all FHM types may be warranted for frequent attacks"

GeneReviews management guidance for prophylaxis across all FHM molecular subtypes.

+ 1 more reference

Anti-Seizure Medication for Comorbid Epilepsy

Action: Pharmacotherapy NCIT:C15986

Agent: anticonvulsant agent NCIT:C264

Platform: Small molecule

Anti-seizure treatment where seizures occur, which is particularly relevant in ATP1A2-FHM. Drug-resistant epilepsy is rare across all FHM genotypes.

Target Phenotypes: Seizure HP:0001250

Show evidence (2 references)

PMID:20301562 SUPPORT Other

"Anti-seizure treatment may be necessary for seizures, which are prevalent in ATP1A2-FHM."

GeneReviews management guidance for the epilepsy comorbidity.

PMID:33839563 SUPPORT Human Clinical

"In 60 patients for whom the epilepsy prognosis was evaluated, only 3.5% of patients were drug-resistant, and the remainder had a self-limited course or responded to anti-epileptic drug treatment."

Supports a generally favourable epilepsy prognosis, relevant to counseling.

Corticosteroids for Attack-Associated Cerebral Edema

Action: Pharmacotherapy NCIT:C15986

Agent: corticosteroid CHEBI:50858

Platform: Small molecule

Corticosteroids in children with cerebral edema, to reduce life-threatening manifestations of a severe attack.

Target Phenotypes: Cerebral edema HP:0002181

Show evidence (1 reference)

PMID:20301562 SUPPORT Other

"Corticosteroids in children with cerebral edema to reduce life-threatening manifestations."

GeneReviews management guidance for the severe cerebral-edema attack phenotype.

Avoidance of Vasoconstricting Agents and Cerebral Angiography

Action: Supportive Care NCIT:C15747

Platform: Behavioral / lifestyle

A management constraint rather than an intervention. GeneReviews lists vasoconstricting agents (which includes the triptans and ergots used in ordinary migraine) as agents to avoid because of stroke risk, and cerebral angiography as a circumstance to avoid because it may precipitate a severe attack. This is the main way FHM management diverges from typical migraine with aura.

Show evidence (2 references)

PMID:20301562 SUPPORT Other

"Agents/circumstances to avoid: Vasoconstricting agents because of the risk of stroke; cerebral angiography as it may precipitate a severe attack."

The GeneReviews Agents/Circumstances to Avoid section, recorded verbatim because it is a safety constraint.

PMID:41552155 SUPPORT Other

"Triptans and ergot derivatives are contraindicated because of their vasoconstrictive effects and potential risk of inducing ischemia."

Names the specific drug classes that "vasoconstricting agents" refers to in the GeneReviews wording above, and states the reason.

Genetic Counseling

Action: Genetic Counseling NCIT:C15240

Platform: Behavioral / lifestyle

Autosomal dominant inheritance with a 50% recurrence risk per child. Once the family variant is known, prenatal and preimplantation genetic testing are possible.

Show evidence (1 reference)

PMID:20301562 SUPPORT Other

"Each child of an individual with FHM has a 50% chance of inheriting the pathogenic variant. Once an FHM-causing pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible."

GeneReviews genetic counseling guidance.

Neurologic Surveillance

Action: Supportive Care NCIT:C15747

Platform: Behavioral / lifestyle

Annual or more frequent neurologic evaluation for change in attack frequency or seizures, and for emergence of a movement disorder, developmental delay or learning disability.

Show evidence (1 reference)

PMID:20301562 SUPPORT Other

"Surveillance: Neurologic evaluation to assess change in attack frequency and/or seizures, development of movement disorder, developmental delay, and/or learning disability annually or more frequently for worsening symptoms."

GeneReviews surveillance guidance.

🌍

Environmental Factors

3

Minor head trauma

exposure_term is left with a free-text preferred_term and no ontology binding. ECTO was searched for a head-trauma, head-injury, physical-trauma or mechanical-force exposure class and has none; the OLS ECTO index returns only chemical and anatomical hits for those strings. No term beats a wrong term, so nothing is bound here. Practical consequence recorded in the source literature: avoidance of contact sports and repetitive head injury is reasonable for patients whose severe attacks are trauma-triggered. That is a management inference from this trigger rather than a tested intervention, so it is not curated as a treatment.

Mild head injury is the best characterized attack trigger in FHM and the one with the clearest mechanistic reading. It does not cause the disorder; it precipitates an attack in a cortex whose spreading-depression threshold is already genetically lowered, and in the severe CACNA1A S218L allele the attack it precipitates can be a prolonged one with delayed cerebral edema and coma. The S218L knock-in mouse reproduces this: its cortex responds to a single weak stimulus with multiple spreading-depression events, which is the proposed reason a trivial injury has a non-trivial consequence.

Show evidence (1 reference)

PMID:38674378 SUPPORT Human Clinical

"Common factors, such as viral infection, physical and emotional stress, and head trauma, have been found to trigger HM"

Establishes head trauma as a recognized trigger of hemiplegic migraine generally, not only in the S218L genotype.

Mechanism Target:

TRIGGERS Facilitated Cortical Spreading Depolarization — The source supports attack triggering in susceptible FHM/HM patients or models. Placement at facilitated CSD is a physiological hypothesis; the precise exposure-to-depolarization route is not established by this observation.

Show evidence (1 reference)

PMID:20186955 SUPPORT Model Organism

"The particularly low CSD threshold and the strong tendency to respond with multiple CSD events make the S218L cortex highly vulnerable to weak stimuli"

States the mechanism by which a weak stimulus such as minor trauma triggers spreading depression in this genotype. Mouse data, hence MODEL_ORGANISM.

TRIGGERS Cerebral Edema — In patients carrying the S218L allele, minor head trauma is the reported precipitant of the severe attack phenotype with delayed cerebral edema and coma.

Show evidence (2 references)

PMID:19438926 SUPPORT Human Clinical

"This CACNA1A mutation has been associated with HM, delayed cerebral oedema and coma following minor head trauma."

The human observation linking minor head trauma to the severe attack phenotype in S218L carriers.

PMID:20186955 SUPPORT Human Clinical

"the S218L CACNA1A mutation causes a dramatic hemiplegic migraine syndrome that is associated with ataxia, seizures, and severe, sometimes fatal, brain edema often triggered by only a mild head trauma"

Restates the human trauma-edema association that this knock-in model was built to explain.

Physical and emotional stress

ECTO has no exposure class for psychosocial or emotional stress, so exposure_term is left unbound, as it is for the head-trauma entry above. Sleep disruption and bright light are named in the second snippet but are not curated as their own entries, because neither source characterizes them beyond the list.

Physical or emotional stress is a reported precipitant of attacks, in common with migraine generally. It is recorded as an attack trigger acting on the same threshold node, not as a cause of the disorder.

Show evidence (1 reference)

PMID:41552155 SUPPORT Human Clinical

"the attacks are frequently triggered by factors such as stress, sleep disturbances, bright lights, or intense emotional stimuli"

A second source listing stress, and adding sleep disruption and sensory stimuli, among attack triggers.

Mechanism Target:

TRIGGERS Facilitated Cortical Spreading Depolarization — The source supports attack triggering in susceptible FHM/HM patients or models. Placement at facilitated CSD is a physiological hypothesis; the precise exposure-to-depolarization route is not established by this observation.

Show evidence (1 reference)

PMID:38674378 SUPPORT Human Clinical

"Common factors, such as viral infection, physical and emotional stress, and head trauma, have been found to trigger HM"

Names physical and emotional stress as attack triggers.

Viral infection and febrile illness

No infectious agent is curated for this entry. Viral illness precipitates attacks in an already-susceptible brain; it is not an etiologic agent, and no specific organism is implicated.

Intercurrent viral illness and fever are reported precipitants of attacks. Fever also occurs during severe attacks as a manifestation rather than a trigger, and the two are not the same claim - this entry is the trigger.

Show evidence (1 reference)

PMID:38674378 SUPPORT Human Clinical

"Common factors, such as viral infection, physical and emotional stress, and head trauma, have been found to trigger HM"

Establishes viral infection as a recognized precipitant in hemiplegic migraine. Recorded at the entry level as well as on the mechanism link because the two are different claims - that the exposure is relevant to this disease at all, and that it acts on the threshold node.

Mechanism Target:

TRIGGERS Facilitated Cortical Spreading Depolarization — The source supports attack triggering in susceptible FHM/HM patients or models. Placement at facilitated CSD is a physiological hypothesis; the precise exposure-to-depolarization route is not established by this observation.

Show evidence (1 reference)

PMID:38674378 SUPPORT Human Clinical

"Common factors, such as viral infection, physical and emotional stress, and head trauma, have been found to trigger HM"

Names viral infection as an attack trigger.

🔬

Diagnosis

3

ICHD-Based Clinical Diagnosis (Required. A molecular result is confirmatory but is not needed to make the diagnosis.)

FHM is diagnosed clinically, on a three-part criterion set: the proband fulfils the criteria for migraine with aura, the aura includes fully reversible motor weakness together with visual, sensory or language symptoms, and at least one first- or second-degree relative has attacks meeting the same hemiplegic-migraine criteria. The third clause is what separates FHM from sporadic hemiplegic migraine; it is a statement about family history, not about mechanism.

clinical diagnostic evaluation against the ICHD criteria NCIT:C18020

The Danish reference programme is cached abstract-only, so the two quotes above are the strongest claims it can support here. It is cited for the general diagnostic framework, not for any FHM-specific criterion; the FHM-specific criteria come from GeneReviews and ICHD-3.

Show evidence (4 references)

PMID:20301562 SUPPORT Human Clinical

"The clinical diagnosis of FHM can be established in a proband: (1) who fulfills criteria for migraine with aura; (2) in whom the aura includes fully reversible motor weakness and visual, sensory, or language symptoms; and (3) who has at least one first- or second-degree relative with similar..."

The GeneReviews Diagnosis/Testing statement of the three-part clinical criteria, which is what this diagnosis entry records.

PMID:41552155 SUPPORT Human Clinical

"include recurrent episodes of migraine with fully reversible motor weakness and other aura symptoms (visual, sensory, or language-related)"

Restates the criteria in ICHD-3 terms and adds the aura timing, confirming that the GeneReviews formulation tracks the current classification.

DOI:10.1186/s10194-021-01228-4 SUPPORT Other

"The guideline first describes how to examine and diagnose the headache patient and how headache treatment is organized in Denmark."

A current national reference programme covering the examination and diagnosis of the headache patient, which is the general clinical framework within which the FHM-specific criteria above are applied. It is a consensus guideline rather than a study, hence evidence_source OTHER.

+ 1 more reference

Molecular Genetic Testing of ATP1A2, CACNA1A, PRRT2 and SCN1A (Confirmatory. Positive in a minority of clinically diagnosed patients.)

Identification of a heterozygous pathogenic variant in one of the four hemiplegic-migraine genes establishes the molecular diagnosis and assigns the subtype. It is confirmatory rather than required: a large majority of clinically diagnosed patients are mutation-negative on these four genes, so a negative panel does not exclude FHM.

molecular genetic testing of the hemiplegic-migraine genes NCIT:C15709

Show evidence (5 references)

PMID:20301562 SUPPORT Human Clinical

"The molecular diagnosis can be established in a proband by identification of a heterozygous pathogenic variant in ATP1A2, CACNA1A, PRRT2, or SCN1A."

The GeneReviews molecular-diagnosis sentence, naming the four genes that constitute the diagnostic panel.

PMID:34649875 SUPPORT Other

"PRRT2 should be regarded as the fourth autosomal dominant gene for hemiplegic migraine and screened in any affected patient, together with the 3 other main genes."

Supports testing all four genes rather than the classical three, which is why PRRT2 appears in the panel above.

PMID:41552155 SUPPORT Human Clinical

"However, routine genetic testing is not required for diagnosis and is reserved for atypical or severe cases."

Establishes that the test is confirmatory rather than diagnostic, which is what the presence field records.

+ 2 more references

Neuroimaging to Exclude Stroke and Other Secondary Causes (Typically normal. Used to exclude alternative diagnoses, not to confirm FHM.)

Because the motor deficit mimics an acute cerebrovascular event, patients are commonly imaged urgently. Structural imaging is typically normal in hemiplegic migraine, and its role is exclusion of infarction, haemorrhage and other secondary causes rather than positive confirmation of FHM.

neuroimaging NCIT:C173635

Show evidence (3 references)

PMID:41552155 SUPPORT Human Clinical

"Given its overlapping presentation with cerebrovascular events, hemiplegic migraine can easily be mistaken for ischemic stroke or TIA."

Establishes the differential that drives urgent imaging in a suspected attack.

PMID:41552155 SUPPORT Human Clinical

"Although structural imaging is often normal in hemiplegic migraine, early presentation before symptom resolution can prompt unnecessary therapy."

Records that a normal scan is the expected finding, so imaging is an exclusion test here. This is a single case report with a literature discussion, so no frequency is asserted.

DOI:10.3389/fped.2023.1214837 SUPPORT Human Clinical

"Physicians should consider HM in the differential diagnosis of patients presenting with somnolence, coma, or convulsion without structural, epileptic, infectious, or inflammatory explanation."

States the paediatric version of the exclusion logic: once structural, epileptic, infectious and inflammatory causes are excluded, hemiplegic migraine belongs in the differential rather than being a diagnosis of last resort.

📈

Progression

2

Childhood onset and first years

Age: First attack under 18 years

In a genetically confirmed paediatric FHM cohort, attacks were infrequent from the outset - only four of nine patients had a further attack during the first year - and attack duration differed markedly by genotype, being far longer in the CACNA1A group than in the ATP1A2 group.

Show evidence (1 reference)

PMID:37326332 SUPPORT Human Clinical

"The aim of this study was to describe a cohort of pediatric patients with genetically confirmed familial hemiplegic migraine (FHM). ... We selected patients who met International Classification of Headache Disorders, third edition criteria for FHM, who had a molecular diagnosis, and whose first..."

Identifies genetically confirmed pediatric familial hemiplegic migraine with first attacks before eighteen, genotype-specific attack durations and first-year recurrence in four of nine patients.

Long-term follow-up

Age: Mean 7.4 years of follow-up from onset Duration: Mean 7.4 years (range 3-10)

Over follow-up the course was benign in this cohort: attacks remained infrequent, improved with time, and no new neurological disorder or deterioration in neurological or cognitive function appeared. This is the natural-history counterpart of the severe-attack phenotypes recorded in phenotypes, and the two are not in conflict - severe attacks are real but are not the usual course.

Show evidence (4 references)

PMID:37326332 SUPPORT Human Clinical

"Over the course of follow-up, the attack frequency overall was 0.4 attacks/year without a difference between the two groups (CACNA1A and ATP1A2)."

Quantifies long-term attack frequency.

PMID:37326332 SUPPORT Human Clinical

"The study data show that most of our patients with early-onset FHM experienced infrequent and non-severe attacks, which improved over time."

The authors' summary of the course. Nine patients, single-arm, so this is a cohort description rather than a prognosis, and no frequency band is asserted anywhere from it.

PMID:37326332 SUPPORT Human Clinical

"the clinical course revealed neither the appearance of novel neurological disorders or a deterioration of basic neurological or cognitive functioning"

A negative finding worth recording: no progressive neurological or cognitive decline over a mean 7.4 years, which bounds the intellectual disability and cerebellar phenotypes curated elsewhere in this entry.

+ 1 more reference

📊

Prevalence

3

Denmark (nationwide case-finding, hemiplegic migraine overall)

Point Prevalence 10.0 per 100,000 1–9 per 10,000

The 0.01% figure is for hemiplegic migraine as a whole. The same study found familial and sporadic forms to be about equally frequent, so the familial form alone is roughly half this rate; a separate FHM-only prevalence has not been established, so the combined figure is recorded with this caveat rather than a derived number.

Show evidence (1 reference)

PMID:12110112 SUPPORT Human Clinical

"Based on the identified number of affected patients the prevalence of HM at the end of 1999 was estimated to be 0.01% in Denmark, where the familial and sporadic form were equally frequent."

Nationwide capture-recapture case-finding gives the population prevalence of hemiplegic migraine and establishes that familial and sporadic forms contribute about equally.

Reported literature estimate for FHM specifically

Point Prevalence 3.0 per 100,000 1–9 per 100,000

0.003%, i.e. about 3 per 100,000. This is the familial form alone, as against the 0.01% figure for hemiplegic migraine as a whole recorded above, and is consistent with the Danish finding that familial and sporadic forms are about equally frequent. It is a review's summary of several primary sources rather than a single measurement, so it is recorded alongside the Danish figure rather than replacing it.

Show evidence (1 reference)

PMID:38674378 SUPPORT Human Clinical

"FHM is a rare disorder with an estimated low prevalence rate of 0.003%"

The FHM-specific prevalence estimate, distinct from the hemiplegic-migraine-overall figure recorded above.

Denmark (nationwide case-finding, sex ratio)

Point Prevalence

Female predominance of 3:1 in the same nationwide survey.

Show evidence (1 reference)

PMID:12110112 SUPPORT Human Clinical

"The HM sex ratio (M:F) was 1:3."

Establishes the female predominance of hemiplegic migraine.

🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Familial Hemiplegic Migraine:

Migraine with aura MONDO:0005475

Overlapping Features FHM sits inside the migraine-with-aura category and shares its cortical spreading depression biology; what separates them is the obligatory reversible motor weakness in FHM and the family history requirement.

Distinguishing Features

Motor weakness is obligatory in FHM and absent in ordinary migraine with aura.
FHM requires at least one affected first- or second-degree relative.
FHM deficits can last hours to days and outlast the headache, whereas typical aura symptoms resolve within an hour.
Familial non-hemiplegic migraine with aura is the nearer differential than sporadic migraine with aura, because it shares the familial aggregation without the motor weakness. It too differs from population migraine with aura - earlier onset, later cessation, more severe aura - so a family history plus a severe aura is not by itself evidence of FHM.

Show evidence (3 references)

PMID:20301562 SUPPORT Human Clinical

"The clinical diagnosis of FHM can be established in a proband: (1) who fulfills criteria for migraine with aura; (2) in whom the aura includes fully reversible motor weakness and visual, sensory, or language symptoms; and (3) who has at least one first- or second-degree relative with similar..."

States the three criteria that separate FHM from ordinary migraine with aura.

PMID:15196299 SUPPORT Human Clinical

"Several clinical characteristics of familial NHMA differed from migraine with aura in the general population: firstly, the age at onset was lower, secondly, the age at cessation was higher, thirdly, aura symptoms were more severe and finally, the co-occurrence of migraine without aura was higher..."

Characterizes familial non-hemiplegic migraine with aura, the sibling entity ascertained by the same Danish group and methodology as the FHM series used elsewhere in this entry. It shows that early onset and severe aura in a family are features of familial migraine with aura in general, not discriminators for FHM - the motor weakness is.

PMID:15196299 SUPPORT Human Clinical

"Visual aura occurred in almost every NHMA attack."

The comparator for the FHM aura profile: visual aura dominates familial non-hemiplegic attacks, whereas FHM attacks usually carry all four typical aura modalities together.

Alternating hemiplegia of childhood MONDO:0016241

Overlapping Features AHC shares episodic hemiplegia with FHM and, like FHM2, involves a Na+/K+-ATPase alpha subunit - but the two are different genes, not one shared locus. AHC is caused by ATP1A3 and FHM2 by ATP1A2, paralogous alpha isoforms of the same pump with different cellular distributions (ATP1A3 is neuronal, ATP1A2 astrocytic in the adult brain). The overlap is therefore family-level paralogy rather than allelism, and the inheritance patterns differ correspondingly: AHC is usually sporadic and de novo, whereas the FHM diagnosis requires an affected first- or second-degree relative.

Distinguishing Features

AHC is an ATP1A3 disorder; ATP1A2 is the FHM2 gene, and sporadic AHC has not been attributed to ATP1A2.
AHC begins in infancy, typically before 18 months, with attacks that alternate sides, remit with sleep, and carry dystonia and nystagmus.
Headache is the dominant feature of an FHM attack and is not required in AHC; AHC additionally carries persistent developmental impairment between attacks, which FHM does not.
AHC arises mostly from de novo variants and is usually sporadic, whereas autosomal dominant transmission with an affected relative is definitional for FHM.

Show evidence (2 references)

PMID:22842232 SUPPORT Human Clinical

"This work identifies de novo ATP1A3 mutations as the primary cause of AHC and offers insight into disease pathophysiology by expanding the spectrum of phenotypes associated with mutations in ATP1A3."

Establishes ATP1A3 as the AHC gene, which is what separates AHC from the ATP1A2-associated FHM2 subtype curated here.

PMID:22842232 SUPPORT Human Clinical

"To date, no cases of sporadic AHC have been attributed to ATP1A2 mutations."

States the gene boundary directly: the FHM2 gene ATP1A2 does not account for sporadic AHC, so the shared Na+/K+-ATPase involvement is paralogy between two disorders rather than a shared cause.

Sporadic hemiplegic migraine

Overlapping Features Clinically and genetically indistinguishable from FHM apart from the absence of an affected first- or second-degree relative; it is about as common as the familial form, and an apparently negative family history does not exclude an FHM-gene variant.

Distinguishing Features

No affected first- or second-degree relative with hemiplegic attacks.
May carry a de novo variant in an FHM gene, or one inherited from an asymptomatic parent, so molecular testing does not distinguish the two.

Show evidence (1 reference)

PMID:12110112 SUPPORT Human Clinical

"147 were familial HM from 44 different families, 105 were sporadic HM and 39 were unclassifiable HM."

Shows sporadic hemiplegic migraine to be comparably frequent in population-based case-finding.

Stroke and transient ischemic attack

Overlapping Features Any condition causing transitory focal neurological signs enters the differential; the breadth of that differential is why neuroimaging and workup are recommended before settling on hemiplegic migraine, and it is the reason vasoconstricting agents are avoided.

Distinguishing Features

FHM deficits develop gradually and are fully reversible, with a stereotyped attack pattern and a positive family history.
Neuroimaging, CSF analysis and EEG are used to exclude structural and vascular causes.

Show evidence (1 reference)

PMID:32430436 SUPPORT Human Clinical

"The differential diagnosis of HM is broad, including other types of migraine and any condition that can cause transitory neurological signs and symptoms. Neuroimaging, cerebrospinal fluid analysis and electroencephalography are useful, but the diagnosis is clinical with a genetic confirmation."

States the breadth of the differential and the role of investigations in excluding mimics.

🔬

Clinical Trials

2

NCT00541736 NOT_APPLICABLE COMPLETED

Glyceryl trinitrate (GTN) provocation in genotyped FHM patients and healthy volunteers, 30 participants, completed 2008. A mechanistic study, not a treatment trial: GTN reliably provokes migraine in ordinary migraine sufferers, so the question was whether an FHM gene defect changes that response. It is recorded here because it is one of only two registered interventional studies in this disorder, and because a negative or divergent provocation response bears on the entry's mechanism.

Target Phenotypes: Headache HP:0002315 Migraine with aura HP:0002077

Show evidence (1 reference)

clinicaltrials:NCT00541736 SUPPORT Human Clinical

"The aim of the present study is to explore the importance of migraine genes on the headache/migraine responses after GTN in FHM-patients and healthy volunteers."

The registered aim, which establishes this as a gene-directed provocation study rather than a therapeutic trial.

NCT00358839 NOT_APPLICABLE COMPLETED

Calcitonin gene-related peptide (CGRP) infusion in genetically confirmed FHM1 and FHM2 patients and controls, enrollment 20, completed 2006. Like the GTN study it is a mechanistic provocation paradigm, and it is the more directly relevant of the two here because it tests the CGRP pathway that underlies the modern migraine-specific drug classes in patients whose causal ion-transport lesion is known.

Target Phenotypes: Headache HP:0002315

Show evidence (1 reference)

clinicaltrials:NCT00358839 SUPPORT Human Clinical

"The aim of the present study is to explore functional consequences of migraine gene mutations on their responses to Calcitonin Gene Related Peptide (CGRP)infusion."

The registered aim, establishing the genotype-stratified CGRP provocation design.

🐁

Animal Models

3

Cacna1a R192Q knock-in mouse (FHM1, pure hemiplegic migraine allele)

The founding FHM1 model, carrying the human R192Q allele that causes pure hemiplegic migraine without cerebellar signs. It supplies the in vivo measurement on which this entry's central mechanistic claim rests - a reduced cortical spreading depression threshold and increased propagation velocity in the intact animal - and, through the companion synaptic study, the reason for it: a synapse-specific gain of function at excitatory pyramidal-cell synapses with inhibitory transmission left intact.

Species

Mouse

Genotype

Cacna1a R192Q knock-in (human pure FHM1 allele)

Genes

CACNA1A hgnc:1388

Publication

PMID:15003170

Pathograph links

Facilitated Cortical Spreading Depolarization recapitulates fidelity: moderate The in vivo CSD threshold and velocity measurement that grounds the unifying node of this entry.

Limitations: The threshold is measured as susceptibility to an experimentally applied stimulus in anaesthetised mouse cortex, which is not the same quantity as whatever initiates a spontaneous human attack. The mouse cortex is also lissencephalic and lacks the motor-cortex geometry a wave would have to traverse to produce human hemiparesis. This link is the structural counterpart of the HUMAN_MODEL_MISMATCH discussion.

Readouts

Cortical spreading depression induction threshold

Stimulus intensity required to ignite CSD in the intact animal.

cortical spreading depolarization GO:0051899 ↑ INCREASED

Direction: DECREASED

Interpretation: A lower induction threshold is the direct measurement behind the threshold node.

Show evidence (1 reference)

PMID:15003170 SUPPORT Model Organism

"in the intact animal, a reduced threshold and increased velocity of cortical spreading depression"

Reports the threshold measurement in vivo.

Cortical spreading depression propagation velocity

Speed at which the depolarization wave travels across cortex.

Direction: INCREASED

Interpretation: Faster propagation accompanies the lowered threshold, so the cortex both enters and spreads CSD more readily.

Show evidence (1 reference)

PMID:15003170 SUPPORT Model Organism

"a reduced threshold and increased velocity of cortical spreading depression (CSD; the likely mechanism for the migraine aura)"

Reports the propagation-velocity measurement in vivo.

Show evidence (1 reference)

PMID:15003170 SUPPORT Model Organism

"Our data show that the increased susceptibility for CSD and aura in migraine may be due to cortical hyperexcitability."

The authors' interpretation of what this model demonstrates about the threshold node, as distinct from the individual measurements recorded as readouts below.

Increased Cortical Glutamatergic Excitability recapitulates fidelity: moderate Cortical microcultures and slices from this model show increased action-potential-evoked Ca2+ influx and increased glutamate release probability at pyramidal-cell synapses, with fast-spiking interneuron synapses unaltered - the synapse specificity that makes this an excitation-inhibition imbalance rather than a global change.

Limitations: Measured in microcultures and acute slices rather than in the intact animal, and the causative link to CSD is established in an in vitro CSD model.

Readouts

Glutamate release probability at cortical pyramidal cell synapses

glutamate secretion GO:0014047 ↑ INCREASED

Direction: INCREASED

Interpretation: The presynaptic measurement that connects Cav2.1 gain of function to cortical hyperexcitability.

Show evidence (1 reference)

PMID:19285472 SUPPORT In Vitro

"increased action-potential-evoked Ca(2+) influx and increased probability of glutamate release at pyramidal cell synapses but unaltered inhibitory neurotransmission at fast-spiking interneuron synapses"

Reports the synapse-specific presynaptic measurement. Neuronal microcultures and brain slices, hence IN_VITRO rather than MODEL_ORGANISM.

Show evidence (1 reference)

PMID:19285472 SUPPORT In Vitro

"Using an in vitro model of CSD, we show a causative link between enhanced glutamate release and CSD facilitation."

Establishes that the synaptic change in this model is causative for CSD facilitation, which is why the model is treated as informative for this node.

Show evidence (1 reference)

PMID:15003170 SUPPORT Model Organism

"The R192Q FHM-1 mouse is a promising animal model to study migraine mechanisms and treatments."

The authors' own framing of this knock-in as a model for the human mechanism, which is what the links below rely on.

Cacna1a S218L knock-in mouse (FHM1, severe allele)

The severe-allele counterpart of the R192Q model. It is the model that explains why a trivial head injury has a non-trivial consequence in S218L carriers: the mutant cortex not only has a lower CSD threshold than R192Q but responds to a single stimulus with repeated CSD events, making it vulnerable to weak stimuli. The two FHM1 models together give an allele-severity gradient that matches the human one. The model was built to explain the trauma-triggered cerebral edema of the human S218L syndrome, and the authors present the low threshold and repeated CSD events as its mechanistic basis. PARTIALLY, not fully: the cited work offers the CSD phenotype as a proposed mechanistic basis for the severe human syndrome rather than reporting trauma-triggered cerebral edema as a measured outcome in the mouse. The link records the proposed explanation, not a reproduced clinical event.

Species

Mouse

Genotype

Cacna1a S218L knock-in (human severe FHM1 allele)

Genes

CACNA1A hgnc:1388

Publication

PMID:20186955

Pathograph links

Facilitated Cortical Spreading Depolarization recapitulates fidelity: high An exaggerated version of the R192Q threshold phenotype, with multiple CSD events following a single trigger.

Limitations: The same anaesthetised-cortex and species caveats as the R192Q model apply. HIGH here refers to correspondence with the human S218L syndrome specifically, which is the narrowest and best-matched of the FHM genotype-phenotype pairings; it should not be read as a claim about FHM in general.

Readouts

Cortical spreading depression induction threshold

Stimulus required to induce CSD; the measured threshold is decreased.

Direction: DECREASED

Interpretation: The vastly reduced threshold plus repeated events after one stimulus is what distinguishes the severe allele from R192Q, where one stimulus typically yields one event.

Show evidence (1 reference)

PMID:20186955 SUPPORT Model Organism

"an exquisite sensitivity to cortical spreading depression (CSD), with a vastly reduced triggering threshold, an increased propagation velocity, and frequently multiple CSD events after a single stimulus"

Reports the threshold, velocity and event-count measurements.

Cortical spreading depression propagation velocity

Speed of the propagating CSD wave; this increases rather than decreases.

Direction: INCREASED

Interpretation: The propagation-speed readout is distinct from the induction threshold.

Show evidence (1 reference)

PMID:20186955 SUPPORT Model Organism

"an exquisite sensitivity to cortical spreading depression (CSD), with a vastly reduced triggering threshold, an increased propagation velocity, and frequently multiple CSD events after a single stimulus"

Reports the threshold, velocity and event-count measurements.

Repeated CSD events after a single stimulus

Multiple events after one trigger in S218L mice.

Direction: INCREASED

Interpretation: Repeated events distinguish the severe S218L response from the typical single R192Q event.

Show evidence (2 references)

PMID:20186955 SUPPORT Model Organism

"an exquisite sensitivity to cortical spreading depression (CSD), with a vastly reduced triggering threshold, an increased propagation velocity, and frequently multiple CSD events after a single stimulus"

Reports the threshold, velocity and event-count measurements.

+ 1 more reference

Show evidence (1 reference)

PMID:20186955 SUPPORT Model Organism

"We introduced the S218L mutation into the mouse Cacna1a gene and studied the mechanisms for the S218L syndrome by analyzing the phenotypic, molecular, and electrophysiological consequences."

Establishes that this is a knock-in of the human allele characterized phenotypically, molecularly and electrophysiologically, which is what makes it informative for the threshold node.

Show evidence (2 references)

PMID:20186955 SUPPORT Model Organism

"Cacna1a(S218L) mice faithfully mimic the associated clinical features of the human S218L syndrome."

The authors' assessment of phenotypic correspondence, which is the basis for the HIGH fidelity assigned to the threshold link below.

PMID:20186955 SUPPORT Model Organism

"may provide a mechanistic basis for the dramatic phenotype seen in S218L mice and patients. Thus, the S218L mouse model may prove a valuable tool to further elucidate mechanisms underlying migraine, seizures, ataxia, and trauma-triggered cerebral edema."

The authors propose a mechanistic basis for the severe syndrome; this is not a demonstration of trauma-triggered edema in the mouse.

Atp1a2 W887R knock-in mouse (FHM2)

The first FHM2 model. It is the source of two separate claims in this entry: that the FHM2 variant acts by loss of the alpha2 pump through ER retention and proteasomal degradation, and that the resulting cortex has a lowered CSD threshold - the finding that lets FHM1 and FHM2 be drawn as converging on one node. It is also the entry's clearest negative result: heterozygous mutants have the cortical phenotype without any apparent clinical phenotype. The heterozygous FHM2 mouse - the genotype that matches the human heterozygous patient - shows no apparent clinical phenotype despite carrying the cortical CSD phenotype. The model reproduces the mechanism and not the disease. This is the negative result behind the entry's HUMAN_MODEL_MISMATCH discussion, and it is a substantive one: it means the step from a lowered CSD threshold to an episodic hemiparetic attack is not demonstrated in the one model where both could have been observed together. Mouse hemiparesis is also harder to ascertain than human hemiparesis, so absence of an apparent phenotype is weaker than a demonstration of absence - but it is what the cited work reports.

Species

Mouse

Genotype

Atp1a2 W887R knock-in, heterozygous (homozygotes die after birth)

Genes

ATP1A2 hgnc:800

Publication

PMID:21731499

Pathograph links

Facilitated Cortical Spreading Depolarization recapitulates fidelity: moderate The FHM2 in vivo threshold and velocity measurement, matching the FHM1 result and supporting the convergence drawn at this node.

Limitations: The 2011 study measured provoked CSD in anesthetized cortex and proposed a clearance deficit; the 2016 follow-up directly tested astrocytic clearance in slices. Neither establishes the complete spontaneous human attack phenotype.

Readouts

Cortical spreading depression induction threshold

Stimulus required to induce CSD; the measured threshold is decreased.

Direction: DECREASED

Interpretation: The FHM2 counterpart of the FHM1 threshold readout, measured in vivo in the heterozygous mutant.

Show evidence (1 reference)

PMID:21731499 SUPPORT Model Organism

"In vivo analysis of cortical spreading depression (CSD), the phenomenon underlying migraine aura, revealed a decreased induction threshold and an increased velocity of propagation in the heterozygous FHM2 mouse."

Reports the in vivo threshold and velocity measurements.

Cortical spreading depression propagation velocity

Speed of the propagating CSD wave; this increases rather than decreases.

Direction: INCREASED

Interpretation: The propagation-speed readout is distinct from the induction threshold.

Show evidence (1 reference)

PMID:21731499 SUPPORT Model Organism

"In vivo analysis of cortical spreading depression (CSD), the phenomenon underlying migraine aura, revealed a decreased induction threshold and an increased velocity of propagation in the heterozygous FHM2 mouse."

Reports the in vivo threshold and velocity measurements.

Show evidence (1 reference)

PMID:21731499 SUPPORT Model Organism

"The demonstration that FHM2 and FHM1 mutations share the ability to facilitate induction and propagation of CSD in mouse models further support the role of CSD as a key migraine trigger."

The authors' statement of what this model contributes to the shared threshold node, which is the convergence claim that node makes.

Astrocytic Na+/K+-ATPase Alpha2 Loss of Function recapitulates fidelity: moderate The molecular lesion itself: mutant alpha2 protein is strongly reduced in the brain of heterozygous mutants, consistent with ER retention and proteasomal degradation.

Limitations: Protein loss is measured in mouse brain; the ER-retention and degradation mechanism is demonstrated in transfected cells rather than in vivo.

Readouts

Brain alpha2 Na,K-ATPase protein abundance

Direction: DECREASED

Interpretation: Reduced protein rather than altered pump kinetics is the readout that makes this a loss-of-function node.

Show evidence (1 reference)

PMID:21731499 SUPPORT Model Organism

"The mutant alpha2 Na,K-ATPase protein was barely detectable in the brain of homozygous mutants and strongly reduced in the brain of heterozygous mutants"

Reports the protein-abundance measurement.

Show evidence (1 reference)

PMID:21731499 SUPPORT In Vitro

"likely as a consequence of endoplasmic reticulum retention and subsequent proteasomal degradation, as we demonstrate in transfected cells"

The mechanism by which the variant produces loss of function. Graded IN_VITRO because the authors state that this part was shown in transfected cells rather than in the mouse.

Show evidence (2 references)

PMID:21731499 SUPPORT Model Organism

"We generated the first FHM2 knock-in mouse model carrying the human W887R mutation in the Atp1a2 orthologous gene."

Establishes the model and its genotype.

PMID:21731499 REFUTE Model Organism

"Homozygous Atp1a2(R887/R887) mutants died just after birth, while heterozygous Atp1a2(+/R887) mice showed no apparent clinical phenotype."

Reports directly that the heterozygous model does not display a clinical phenotype, which is what a FAILS_TO_RECAPITULATE link asserts.

{ }

Source YAML

click to show

name: Familial Hemiplegic Migraine
creation_date: "2026-08-27T00:00:00Z"
category: Mendelian
description: >-
  Familial hemiplegic migraine (FHM) is a rare autosomal dominant subtype of migraine with aura in
  which the aura obligatorily includes fully reversible motor weakness (hemiparesis) alongside visual,
  sensory, or language symptoms, in a proband with at least one affected first- or second-degree
  relative. Three genes encoding ion-transport proteins define the classical molecular subtypes -
  CACNA1A (Cav2.1, FHM1), ATP1A2 (astrocytic Na+/K+-ATPase alpha2, FHM2) and SCN1A (Nav1.1, FHM3)
  - and PRRT2 is now recognized as a fourth hemiplegic-migraine gene. Experimental models of the
  three classical ion-transport subtypes show facilitated cortical spreading depolarization, the
  leading physiological explanation for aura. The intervening route from PRRT2 loss to FHM attacks
  remains less resolved. FHM has served as a Mendelian model for migraine aura biology more generally.
synonyms:
- FHM
- hereditary hemiplegic migraine
disease_term:
  preferred_term: familial hemiplegic migraine
  term:
    id: MONDO:0000700
    label: familial hemiplegic migraine
parents:
- Migraine with aura
- Channelopathy
notes: >-
  Scope and boundaries with adjacent entries. This entry is the disease-centred view of hemiplegic
  migraine across all four genes; the gene-centred view of CACNA1A (which also spans episodic ataxia
  type 2, SCA6 and DEE42) lives in CACNA1A-Related Disorder, which already carries "Familial Hemiplegic
  Migraine Type 1" as a molecular subtype. Migraine with aura carries the general (non-hemiplegic)
  aura biology and explicitly excludes hemiplegic migraine from its scope; FHM-associated aura components,
  headache and additional manifestations are curated here with their clinical and molecular scope.
  Alternating Hemiplegia of Childhood is an ATP1A3 disorder that overlaps FHM through episodic hemiplegia
  and the Na+/K+-ATPase family but is a separate entity, curated as a differential diagnosis in both
  directions.

  Sporadic hemiplegic migraine (SHM) shares the ICHD phenotype and the same genes but by definition
  lacks an affected first- or second-degree relative; it is not curated here as a subtype because
  the family-history criterion, not the mechanism, is what separates it. It is roughly as common
  as FHM in population-based case-finding.

  PRRT2 is deliberately NOT curated as a numbered subtype, and specifically not as "FHM4". The FHM4
  designation does exist - OMIM %607516, mirrored by MONDO:0800335 "migraine, familial hemiplegic,
  4" - but it is a gene-less concept: MedGen's record for it (UID 334830, the concept MONDO:0800335
  mirrors) lists no associated gene, and MONDO gives it no definition, no OMIM gene cross-reference
  and no causal-gene relationship. PRRT2 is therefore not FHM4 under another name, and numbering
  it as a fourth subtype here would assert an equivalence the source ontologies do not make. Two
  further reasons keep PRRT2 in the genetic section: its mechanism (synaptic protein, loss of function)
  is not an ion-transport defect of the kind that unifies FHM1-3, and the authors who established
  PRRT2 as a hemiplegic-migraine gene state that the specific intervening route to hemiplegic attacks
  is not understood. GeneReviews describes disrupted synaptic neurotransmission and sodium/calcium-channel
  regulation after PRRT2 loss, but those synaptic effects do not by themselves establish the route
  to every FHM manifestation.

  External identifiers. The schema's DiseaseMappings container carries ICD-10-CM, ICD-11-F, MONDO
  and NCIT slots only, so two identifiers are recorded here instead: the OMIM phenotypic series OMIMPS:141500,
  which MONDO:0000700 already cross-references, and the per-subtype OMIM phenotype numbers, which
  are noted on each has_subtypes mapping. MONDO:0000700 carries no Orphanet cross-reference, so no
  ORPHA identifier is asserted for this entry.
prevalence:
- population: Denmark (nationwide case-finding, hemiplegic migraine overall)
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_per_100000: 10.0
  notes: >-
    The 0.01% figure is for hemiplegic migraine as a whole. The same study found
    familial and sporadic forms to be about equally frequent, so the familial
    form alone is roughly half this rate; a separate FHM-only prevalence has not
    been established, so the combined figure is recorded with this caveat rather
    than a derived number.
  evidence:
  - reference: PMID:12110112
    reference_title: An epidemiological survey of hemiplegic migraine.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Based on the identified number of affected patients the prevalence of HM
      at the end of 1999 was estimated to be 0.01% in Denmark, where the
      familial and sporadic form were equally frequent.
    explanation: >-
      Nationwide capture-recapture case-finding gives the population prevalence
      of hemiplegic migraine and establishes that familial and sporadic forms
      contribute about equally.
- population: Reported literature estimate for FHM specifically
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 3.0
  notes: >-
    0.003%, i.e. about 3 per 100,000. This is the familial form alone, as
    against the 0.01% figure for hemiplegic migraine as a whole recorded above,
    and is consistent with the Danish finding that familial and sporadic forms
    are about equally frequent. It is a review's summary of several primary
    sources rather than a single measurement, so it is recorded alongside the
    Danish figure rather than replacing it.
  evidence:
  - reference: PMID:38674378
    reference_title: >-
      Unravelling the Genetic Landscape of Hemiplegic Migraine: Exploring Innovative Strategies and
      Emerging Approaches.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      FHM is a rare disorder with an estimated low prevalence rate of 0.003%
    explanation: >-
      The FHM-specific prevalence estimate, distinct from the
      hemiplegic-migraine-overall figure recorded above.
- population: Denmark (nationwide case-finding, sex ratio)
  measure_type: POINT_PREVALENCE
  notes: Female predominance of 3:1 in the same nationwide survey.
  evidence:
  - reference: PMID:12110112
    reference_title: An epidemiological survey of hemiplegic migraine.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The HM sex ratio (M:F) was 1:3."
    explanation: Establishes the female predominance of hemiplegic migraine.
progression:
- phase: Childhood onset and first years
  age_range: First attack under 18 years
  notes: >-
    In a genetically confirmed paediatric FHM cohort, attacks were infrequent
    from the outset - only four of nine patients had a further attack during the
    first year - and attack duration differed markedly by genotype, being far
    longer in the CACNA1A group than in the ATP1A2 group.
  evidence:
  - reference: PMID:37326332
    reference_title: >-
      Familial hemiplegic migraine in pediatric patients: A genetic, clinical,
      and follow-up study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The aim of this study was to describe a cohort of pediatric patients with genetically
      confirmed familial hemiplegic migraine (FHM). ... We selected patients who met International
      Classification of Headache Disorders, third edition criteria for FHM, who had a molecular
      diagnosis, and whose first attack occurred under the age of 18 years. ... We enrolled nine
      patients (seven males and two females) first referred to our three centers. Three of the nine
      (33%) patients had calcium voltage-gated channel subunit alpha1 A (CACNA1A) mutations, five
      (55%) had ATPase Na+/K+ transporting subunit alpha 2 (ATP1A2) mutations, and one had both
      genetic mutations. ... The mean (SD) duration of HM attacks in the sample was 11.3 (17.1) h;
      3.8 (6.1) h in the ATP1A2 group, and 24.3 (23.5) h in the CACNA1A group. The mean (SD, range)
      duration of follow-up was 7.4 (2.2, 3-10) years. During the first year from the disorder's
      onset, only four patients had additional attacks. Over the course of follow-up, the attack
      frequency overall was 0.4 attacks/year without a difference between the two groups (CACNA1A
      and ATP1A2).
    explanation: >-
      Identifies genetically confirmed pediatric familial hemiplegic migraine with first attacks
      before eighteen, genotype-specific attack durations and first-year recurrence in four of nine
      patients.
- phase: Long-term follow-up
  age_range: Mean 7.4 years of follow-up from onset
  duration: Mean 7.4 years (range 3-10)
  notes: >-
    Over follow-up the course was benign in this cohort: attacks remained
    infrequent, improved with time, and no new neurological disorder or
    deterioration in neurological or cognitive function appeared. This is the
    natural-history counterpart of the severe-attack phenotypes recorded in
    phenotypes, and the two are not in conflict - severe attacks are real but
    are not the usual course.
  evidence:
  - reference: PMID:37326332
    reference_title: >-
      Familial hemiplegic migraine in pediatric patients: A genetic, clinical,
      and follow-up study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Over the course of follow-up, the attack frequency overall was 0.4
      attacks/year without a difference between the two groups (CACNA1A and
      ATP1A2).
    explanation: Quantifies long-term attack frequency.
  - reference: PMID:37326332
    reference_title: >-
      Familial hemiplegic migraine in pediatric patients: A genetic, clinical,
      and follow-up study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The study data show that most of our patients with early-onset FHM
      experienced infrequent and non-severe attacks, which improved over time.
    explanation: >-
      The authors' summary of the course. Nine patients, single-arm, so this is
      a cohort description rather than a prognosis, and no frequency band is
      asserted anywhere from it.
  - reference: PMID:37326332
    reference_title: >-
      Familial hemiplegic migraine in pediatric patients: A genetic, clinical,
      and follow-up study.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the clinical course revealed neither the appearance of novel neurological
      disorders or a deterioration of basic neurological or cognitive
      functioning
    explanation: >-
      A negative finding worth recording: no progressive neurological or
      cognitive decline over a mean 7.4 years, which bounds the intellectual
      disability and cerebellar phenotypes curated elsewhere in this entry.
  - reference: PMID:20301562
    reference_title: Familial Hemiplegic Migraine.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      FHM is often earlier in onset than typical migraine, frequently beginning
      in the first or second decade; the frequency of attacks tends to decrease
      with age.
    explanation: >-
      The GeneReviews statement of onset and of the decline in attack frequency
      with age, which the paediatric cohort above is consistent with.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    FHM caused by a heterozygous pathogenic variant in ATP1A2, CACNA1A, PRRT2 or
    SCN1A is inherited in an autosomal dominant manner, with a 50% recurrence
    risk for each child of an affected individual. Because the FHM diagnosis
    itself requires an affected relative, most probands have an affected parent;
    apparently simplex cases may reflect a de novo variant or an asymptomatic
    transmitting parent.

    Penetrance is high but incomplete, and expressivity is markedly variable -
    within a single pedigree the same variant can produce infrequent pure
    hemiplegic attacks in one carrier and attacks with coma or prolonged
    hemiplegia in another. Both facts matter for counseling: an unaffected
    carrier parent is expected rather than anomalous, and a mild index case
    does not predict a mild course in relatives.
  penetrance: INCOMPLETE
  penetrance_percentage: "89 (CACNA1A mutation carriers; see the CACNA1A genetic record)"
  expressivity: VARIABLE
  evidence:
  - reference: PMID:20301562
    reference_title: Familial Hemiplegic Migraine.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      FHM and simplex hemiplegic migraine caused by a heterozygous ATP1A2,
      CACNA1A, PRRT2, or SCN1A pathogenic variant are inherited in an autosomal
      dominant manner.
    explanation: GeneReviews states the mode of inheritance for all four FHM genes.
  - reference: PMID:20301562
    reference_title: Familial Hemiplegic Migraine.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individuals with simplex hemiplegic migraine (i.e., individuals with an
      FHM-causing pathogenic variant and an apparently negative family history)
      may have a de novo pathogenic variant or a pathogenic variant inherited
      from an asymptomatic parent.
    explanation: >-
      Explains why an apparently sporadic presentation does not exclude a
      dominant FHM-gene variant.
  - reference: PMID:11439943
    reference_title: >-
      The clinical spectrum of familial hemiplegic migraine associated with
      mutations in a neuronal calcium channel.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Eighty-nine percent of the subjects with mutations had attacks of
      hemiplegic migraine.
    explanation: >-
      In 117 genotyped CACNA1A mutation carriers, 11% had no hemiplegic migraine
      attacks - a direct measurement of incomplete penetrance, and the source of
      the 89% figure recorded above. The denominator is CACNA1A carriers, so the
      number should not be read as a penetrance estimate for ATP1A2, SCN1A or
      PRRT2.
  - reference: PMID:11439943
    reference_title: >-
      The clinical spectrum of familial hemiplegic migraine associated with
      mutations in a neuronal calcium channel.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hemiplegic migraine in subjects with mutations in CACNA1A has a broad
      clinical spectrum. This clinical variability is partially associated with
      the various types of mutations.
    explanation: >-
      Establishes variable expressivity and attributes it only partially to
      allele identity, which is why the variability is recorded as expressivity
      rather than as a genotype-phenotype rule.
  - reference: PMID:11439943
    reference_title: >-
      The clinical spectrum of familial hemiplegic migraine associated with
      mutations in a neuronal calcium channel.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One third had severe attacks with coma, prolonged hemiplegia, or both,
      with full recovery.
    explanation: >-
      Quantifies the severe end of the expressivity range within the same
      carrier series.
  - reference: PMID:41552155
    reference_title: "Hemiplegic Migraine: An Imitator of Cerebrovascular Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      These genes are transmitted in an autosomal dominant pattern with variable
      penetrance.
    explanation: >-
      A second source stating that penetrance is variable across the FHM genes
      generally, not only in CACNA1A families.
has_subtypes:
- name: FHM1
  display_name: Familial Hemiplegic Migraine Type 1 (CACNA1A)
  subtype_term:
    preferred_term: migraine, familial hemiplegic, 1
    term:
      id: MONDO:0020756
      label: migraine, familial hemiplegic, 1
  mappings:
    mondo_mappings:
    - term:
        id: MONDO:0020756
        label: migraine, familial hemiplegic, 1
      mapping_predicate: skos:exactMatch
      mapping_source: MONDO
      mapping_justification: semapv:ManualMappingCuration
      notes: >-
        MONDO carries a dedicated term for this numbered molecular subtype, so
        the mapping is exact rather than a narrowMatch under the MONDO:0000700
        parent. The corresponding OMIM phenotype entry is #141500; the schema's
        DiseaseMappings container has no OMIM slot, so that identifier is
        recorded here rather than as a separate mapping.
  classification: molecular
  description: >-
    Caused by heterozygous missense variants in CACNA1A encoding the alpha1A
    pore-forming subunit of the neuronal Cav2.1 (P/Q-type) voltage-gated calcium
    channel. The pathogenic variants act by gain of function, increasing
    presynaptic Ca2+ influx and glutamate release. Roughly 40-50% of CACNA1A-FHM
    families additionally show cerebellar signs, from nystagmus to a late-onset
    mild progressive ataxia, and the severe S218L allele is associated with
    coma and cerebral edema after minor head trauma.
  genes:
  - preferred_term: CACNA1A
    term:
      id: hgnc:1388
      label: CACNA1A
  evidence:
  - reference: PMID:8898206
    reference_title: >-
      Familial hemiplegic migraine and episodic ataxia type-2 are caused by
      mutations in the Ca2+ channel gene CACNL1A4.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In FHM, we found four different missense mutations in conserved functional
      domains.
    explanation: >-
      The original linkage and mutation study identifying missense variants in
      the brain P/Q-type calcium channel alpha1 subunit gene as the cause of FHM1.
  - reference: PMID:20301562
    reference_title: Familial Hemiplegic Migraine.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Approximately 40%-50% of families with CACNA1A-FHM have cerebellar signs
      ranging from nystagmus to progressive, usually late-onset mild ataxia.
    explanation: >-
      Establishes the cerebellar phenotype that distinguishes FHM1 from the
      other molecular subtypes.
- name: FHM2
  display_name: Familial Hemiplegic Migraine Type 2 (ATP1A2)
  subtype_term:
    preferred_term: migraine, familial hemiplegic, 2
    term:
      id: MONDO:0011232
      label: migraine, familial hemiplegic, 2
  mappings:
    mondo_mappings:
    - term:
        id: MONDO:0011232
        label: migraine, familial hemiplegic, 2
      mapping_predicate: skos:exactMatch
      mapping_source: MONDO
      mapping_justification: semapv:ManualMappingCuration
      notes: >-
        MONDO carries a dedicated term for this numbered molecular subtype, so
        the mapping is exact rather than a narrowMatch under the MONDO:0000700
        parent. The corresponding OMIM phenotype entry is #602481; the schema's
        DiseaseMappings container has no OMIM slot, so that identifier is
        recorded here rather than as a separate mapping.
  classification: molecular
  description: >-
    Caused by heterozygous variants in ATP1A2 encoding the alpha2 subunit of the
    Na+/K+-ATPase, an isoform expressed almost exclusively in astrocytes in the
    adult brain. The variants act by loss of function of a single allele, and in
    the knock-in mouse the mutant protein is retained in the endoplasmic
    reticulum and degraded. Epilepsy is a particularly common comorbidity in
    ATP1A2-FHM.
  genes:
  - preferred_term: ATP1A2
    term:
      id: hgnc:800
      label: ATP1A2
  evidence:
  - reference: PMID:12539047
    reference_title: >-
      Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump alpha2 subunit
      associated with familial hemiplegic migraine type 2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we show that mutations in the gene ATP1A2 that encodes the alpha2
      subunit of the Na+/K+ pump are associated with familial hemiplegic
      migraine type 2 (FHM2) linked to chromosome 1q23
    explanation: The gene-discovery study defining the FHM2 molecular subtype.
- name: FHM3
  display_name: Familial Hemiplegic Migraine Type 3 (SCN1A)
  subtype_term:
    preferred_term: migraine, familial hemiplegic, 3
    term:
      id: MONDO:0012320
      label: migraine, familial hemiplegic, 3
  mappings:
    mondo_mappings:
    - term:
        id: MONDO:0012320
        label: migraine, familial hemiplegic, 3
      mapping_predicate: skos:exactMatch
      mapping_source: MONDO
      mapping_justification: semapv:ManualMappingCuration
      notes: >-
        MONDO carries a dedicated term for this numbered molecular subtype, so
        the mapping is exact rather than a narrowMatch under the MONDO:0000700
        parent. The corresponding OMIM phenotype entry is #609634; the schema's
        DiseaseMappings container has no OMIM slot, so that identifier is
        recorded here rather than as a separate mapping.
  classification: molecular
  description: >-
    Caused by heterozygous missense variants in SCN1A encoding the neuronal
    Nav1.1 voltage-gated sodium channel, the same gene whose loss-of-function
    variants cause Dravet syndrome and other epilepsies. FHM3 variants act in
    the opposite direction, as gain of function, and Nav1.1 is the principal
    sodium channel of GABAergic interneurons - so FHM3 reaches cortical
    spreading depression by a route distinct from the glutamatergic
    FHM1/FHM2 mechanism.
  genes:
  - preferred_term: SCN1A
    term:
      id: hgnc:10585
      label: SCN1A
  evidence:
  - reference: PMID:16054936
    reference_title: >-
      Mutation in the neuronal voltage-gated sodium channel SCN1A in familial
      hemiplegic migraine.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sequencing of candidate genes in this region revealed a heterozygous
      missense mutation (Gln1489Lys) in the neuronal voltage-gated sodium
      channel gene SCN1A, mutations of which have been associated with epilepsy.
    explanation: The gene-discovery study defining the FHM3 molecular subtype.
  - reference: PMID:16054936
    reference_title: >-
      Mutation in the neuronal voltage-gated sodium channel SCN1A in familial
      hemiplegic migraine.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dysfunction of the neuronal sodium channel SCN1A can cause familial
      hemiplegic migraine. Our findings have implications for the understanding
      of migraine aura. Moreover, our study reinforces the molecular links
      between migraine and epilepsy, two common paroxysmal disorders.
    explanation: >-
      Establishes both causation and the mechanistic link between FHM3 and the
      epilepsies caused by the same gene.
pathophysiology:
- name: Cav2.1 Calcium Channel Gain of Function
  genes:
  - preferred_term: CACNA1A
    term:
      id: hgnc:1388
      label: CACNA1A
  biological_scale: MOLECULAR
  description: >-
    FHM1 missense variants in CACNA1A produce a gain of function of the neuronal
    Cav2.1 (P/Q-type) voltage-gated calcium channel. In the R192Q knock-in mouse
    the effect is measured directly as increased Cav2.1 current density in
    cerebellar neurons and enhanced neurotransmission at the neuromuscular
    junction.
  molecular_functions:
  - preferred_term: voltage-gated calcium channel activity
    term:
      id: GO:0005245
      label: voltage-gated calcium channel activity
    modifier: INCREASED
  genetic_context:
    gene:
      preferred_term: CACNA1A
      term:
        id: hgnc:1388
        label: CACNA1A
    allele_type: MISSENSE
    zygosity: HETEROZYGOUS
    functional_impact_category: GAIN_OF_FUNCTION
    description: >-
      Heterozygous missense variants in conserved functional domains of the
      alpha1A subunit; the archetypal pure-FHM allele is R192Q and the severe
      allele is S218L.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:15003170
    reference_title: >-
      A Cacna1a knockin migraine mouse model with increased susceptibility to cortical spreading
      depression.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We generated a knockin mouse model carrying the human pure FHM-1 R192Q
      mutation and found multiple gain-of-function effects. These include
      increased Ca(v)2.1 current density in cerebellar neurons, enhanced
      neurotransmission at the neuromuscular junction
    explanation: >-
      Direct electrophysiological demonstration that the FHM1 variant is a
      gain-of-function change in Cav2.1 channel activity.
  downstream:
  - target: Increased Cortical Glutamatergic Excitability
    description: >-
      Increased presynaptic calcium influx enhances release at cortical excitatory synapses in FHM1
      models.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:19285472
      reference_title: >-
        Enhanced excitatory transmission at cortical synapses as the basis for facilitated spreading
        depression in Ca(v)2.1 knockin migraine mice.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We show gain of function of excitatory neurotransmission due to increased
        action-potential-evoked Ca(2+) influx and increased probability of
        glutamate release at pyramidal cell synapses but unaltered inhibitory
        neurotransmission at fast-spiking interneuron synapses.
      explanation: >-
        Establishes the synapse-specific enhancement of glutamate release as the
        cellular consequence of the FHM1 channel gain of function.
  - target: Purkinje Cell Firing Dysregulation
    description: >-
      S218L Cav2.1 gating increases Purkinje excitability and disrupts firing patterns.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:23115190
      reference_title: Cerebellar ataxia by enhanced Ca(V)2.1 currents is alleviated by
        Ca2+-dependent K+-channel activators in Cacna1a(S218L) mutant mice.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Here, we demonstrate that the S218L mutation causes a negative shift of voltage dependence
        of Ca(V)2.1 channels of mouse Purkinje cells and results in lowered thresholds for somatic
        action potentials and dendritic Ca(2+) spikes and in disrupted firing patterns.
      explanation: >-
        Purkinje-cell electrophysiology directly supports the S218L channel-to-firing relation. It
        does not generalize this effect to CACNA1A loss-of-function ataxias.
    hypothesis_groups:
    - fhm1_cerebellar
  - target: Cerebellar Neuronal Degeneration
    description: >-
      Selected FHM1 current abnormalities are proposed to produce Purkinje dysfunction and neuronal
      loss.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:25143767
      reference_title: Familial hemiplegic migraine and spreading depression.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        FHM1 with ataxia is attributable to specific mutations that differ from mutations that cause
        pure FHM1 and have peculiar consequences on cerebellar Cav2.1 currents that lead to profound
        Purkinje cell dysfunction and to neuronal loss with atrophy.
      explanation: >-
        The mechanistic review attributes cerebellar neuronal loss and atrophy to selected FHM1 current
        abnormalities. This synthesis supports a qualified degeneration route, not a human histological
        demonstration across all CACNA1A families.
      directness: INDIRECT
    hypothesis_groups:
    - fhm1_cerebellar
    intermediate_mechanisms:
    - Purkinje cell dysfunction
  - target: Attack-Associated Psychosis
    description: >-
      A chromosome-19-linked FHM/ataxia family prompted the authors' calcium-channel hypothesis for
      acute psychosis. Applying the Cav2.1 gain-of-function framework to that family remains provisional.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:10202246
      reference_title: Familial hemiplegic migraine with cerebellar ataxia and paroxysmal
        psychosis.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        we hypothesize that a dysfunction of the mutated calcium channel may be involved not only
        in the development of hemiplegic migraine but also in the acute psychotic episodes observed
        in these patients.
      explanation: >-
        The family authors explicitly propose a calcium-channel explanation from chromosome-19 linkage
        and phenotype. This is a provisional attribution, without a confirmed molecular variant or
        intervening psychiatric pathway.
      directness: INDIRECT
    hypothesis_groups:
    - familial_psychosis
  - target: Cerebellar Ataxia
    description: >-
      R583Q gain-of-function physiology is the family authors' explanation of cerebellar ataxia;
      intervening circuitry is not reconstructed for those patients.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: DOI:10.3389/fncel.2017.00263
      reference_title: Cerebellar Atrophy and Changes in Cytokines Associated with the CACNA1A
        R583Q Mutation in a Russian Familial Hemiplegic Migraine Type 1 Family
      supports: SUPPORT
      evidence_source: OTHER
      snippet: |-
        it is long recognized that the gain-of-function eﬀect of
        R583Q-mutated channels can explain cerebellar atrophy and
        cerebellar ataxia in patients.
      explanation: >-
        The family investigators explicitly attribute R583Q-associated cerebellar atrophy and ataxia
        to abnormal channel function. This broad clinical attribution does not establish the S218L
        firing intermediary in R583Q carriers.
      directness: INDIRECT
    hypothesis_groups:
    - fhm1_cerebellar
  - target: Dysdiadochokinesis
    description: >-
      The R583Q family study interprets the observed cerebellar syndrome, including this examination
      sign, in terms of abnormal Cav2.1 function. This clinical attribution is broader than the S218L-specific
      firing experiment.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: DOI:10.3389/fncel.2017.00263
      reference_title: Cerebellar Atrophy and Changes in Cytokines Associated with the CACNA1A
        R583Q Mutation in a Russian Familial Hemiplegic Migraine Type 1 Family
      supports: SUPPORT
      evidence_source: OTHER
      snippet: |-
        it is long recognized that the gain-of-function eﬀect of
        R583Q-mutated channels can explain cerebellar atrophy and
        cerebellar ataxia in patients.
      explanation: >-
        The family investigators explicitly attribute R583Q-associated cerebellar atrophy and ataxia
        to abnormal channel function. This broad clinical attribution does not establish the S218L
        firing intermediary in R583Q carriers.
      directness: INDIRECT
    - reference: DOI:10.3389/fncel.2017.00263
      reference_title: Cerebellar Atrophy and Changes in Cytokines Associated with the CACNA1A
        R583Q Mutation in a Russian Familial Hemiplegic Migraine Type 1 Family
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        Neurological examination reveals minor
        signs of adiadochokinesia (right > left) and heel-knee probe
        which is slightly asymmetrical with hypermetria on the right
        side.
      explanation: >-
        Patient D had these interictal examination findings. They are cerebellar signs in a genetically
        confirmed FHM1 family, not inferred from the broad ataxia label.
    hypothesis_groups:
    - fhm1_cerebellar
  - target: Lower Limb Dysmetria
    description: >-
      The R583Q family study interprets the observed cerebellar syndrome, including this examination
      sign, in terms of abnormal Cav2.1 function. This clinical attribution is broader than the S218L-specific
      firing experiment.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: DOI:10.3389/fncel.2017.00263
      reference_title: Cerebellar Atrophy and Changes in Cytokines Associated with the CACNA1A
        R583Q Mutation in a Russian Familial Hemiplegic Migraine Type 1 Family
      supports: SUPPORT
      evidence_source: OTHER
      snippet: |-
        it is long recognized that the gain-of-function eﬀect of
        R583Q-mutated channels can explain cerebellar atrophy and
        cerebellar ataxia in patients.
      explanation: >-
        The family investigators explicitly attribute R583Q-associated cerebellar atrophy and ataxia
        to abnormal channel function. This broad clinical attribution does not establish the S218L
        firing intermediary in R583Q carriers.
      directness: INDIRECT
    - reference: DOI:10.3389/fncel.2017.00263
      reference_title: Cerebellar Atrophy and Changes in Cytokines Associated with the CACNA1A
        R583Q Mutation in a Russian Familial Hemiplegic Migraine Type 1 Family
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        Neurological examination reveals minor
        signs of adiadochokinesia (right > left) and heel-knee probe
        which is slightly asymmetrical with hypermetria on the right
        side.
      explanation: >-
        Patient D had these interictal examination findings. They are cerebellar signs in a genetically
        confirmed FHM1 family, not inferred from the broad ataxia label.
    hypothesis_groups:
    - fhm1_cerebellar
  - target: Positive Romberg Sign
    description: >-
      The authors interpret the R583Q family's interictal examination abnormalities as cerebellar
      changes due to channel dysfunction. This includes Romberg instability; the particular balance-control
      intermediary is not resolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: DOI:10.3389/fncel.2017.00263
      reference_title: Cerebellar Atrophy and Changes in Cytokines Associated with the CACNA1A
        R583Q Mutation in a Russian Familial Hemiplegic Migraine Type 1 Family
      supports: SUPPORT
      evidence_source: OTHER
      snippet: |-
        it is long recognized that the gain-of-function eﬀect of
        R583Q-mutated channels can explain cerebellar atrophy and
        cerebellar ataxia in patients.
      explanation: >-
        The family investigators explicitly attribute R583Q-associated cerebellar atrophy and ataxia
        to abnormal channel function. This broad clinical attribution does not establish the S218L
        firing intermediary in R583Q carriers.
      directness: INDIRECT
    - reference: DOI:10.3389/fncel.2017.00263
      reference_title: Cerebellar Atrophy and Changes in Cytokines Associated with the CACNA1A
        R583Q Mutation in a Russian Familial Hemiplegic Migraine Type 1 Family
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: |-
        Also, instability in the Romberg test is detected.
      explanation: >-
        Direct clinical examination of patient F. The source does not demonstrate sensory neuropathy,
        and tactile sensation was unaffected.
    hypothesis_groups:
    - fhm1_cerebellar
  - target: Attack-Associated Anxiety
    description: >-
      The authors' calcium-channel hypothesis concerns acute psychotic episodes explicitly including
      anxiety in this chromosome-19-linked FHM family. Applying the Cav2.1 gain-of-function framework
      remains provisional; neither a specific variant nor a separate component-specific circuit was
      established.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:10202246
      reference_title: Familial hemiplegic migraine with cerebellar ataxia and paroxysmal
        psychosis.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        we hypothesize that a dysfunction of the mutated calcium channel may be involved not only
        in the development of hemiplegic migraine but also in the acute psychotic episodes observed
        in these patients.
      explanation: >-
        The family authors explicitly propose a calcium-channel explanation from chromosome-19 linkage
        and phenotype. This is a provisional attribution, without a confirmed molecular variant or
        intervening psychiatric pathway.
      directness: INDIRECT
    - reference: PMID:10202246
      reference_title: Familial hemiplegic migraine with cerebellar ataxia and paroxysmal
        psychosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Here we report on a family with familial hemiplegic migraine and cerebellar ataxia with recurrent
        episodes of acute paranoid psychosis with anxiety and visual hallucinations associated with
        migraine attacks.
      explanation: >-
        The human family report explicitly places anxiety within the acute psychotic episodes covered
        by the authors' channel hypothesis. This establishes the component and its episode scope,
        not an independently demonstrated cellular pathway.
    hypothesis_groups:
    - familial_psychosis
  - target: Visual Hallucinations
    description: >-
      The authors' calcium-channel hypothesis concerns acute psychotic episodes explicitly including
      visual hallucinations in this chromosome-19-linked FHM family. Applying the Cav2.1 gain-of-function
      framework remains provisional; neither a specific variant nor a separate component-specific
      circuit was established.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:10202246
      reference_title: Familial hemiplegic migraine with cerebellar ataxia and paroxysmal
        psychosis.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        we hypothesize that a dysfunction of the mutated calcium channel may be involved not only
        in the development of hemiplegic migraine but also in the acute psychotic episodes observed
        in these patients.
      explanation: >-
        The family authors explicitly propose a calcium-channel explanation from chromosome-19 linkage
        and phenotype. This is a provisional attribution, without a confirmed molecular variant or
        intervening psychiatric pathway.
      directness: INDIRECT
    - reference: PMID:10202246
      reference_title: Familial hemiplegic migraine with cerebellar ataxia and paroxysmal
        psychosis.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Here we report on a family with familial hemiplegic migraine and cerebellar ataxia with recurrent
        episodes of acute paranoid psychosis with anxiety and visual hallucinations associated with
        migraine attacks.
      explanation: >-
        The human family report explicitly places visual hallucinations within the acute psychotic
        episodes covered by the authors' channel hypothesis. This establishes the component and its
        episode scope, not an independently demonstrated cellular pathway.
    hypothesis_groups:
    - familial_psychosis
- name: Astrocytic Na+/K+-ATPase Alpha2 Loss of Function
  genes:
  - preferred_term: ATP1A2
    term:
      id: hgnc:800
      label: ATP1A2
  biological_scale: MOLECULAR
  description: >-
    FHM2 variants in ATP1A2 cause loss of function of a single allele of the
    alpha2 subunit of the Na+/K+ pump. The alpha2 isoform is expressed almost
    exclusively in astrocytes in the adult brain, where the pump maintains the
    Na+ gradient that drives astrocytic glutamate and potassium reuptake. In the
    W887R knock-in mouse the mutant protein is retained in the endoplasmic
    reticulum and degraded, so the defect is a reduction in functional pump
    rather than a dominant-negative pump.
  molecular_functions:
  - preferred_term: P-type sodium:potassium-exchanging transporter activity
    term:
      id: GO:0005391
      label: P-type sodium:potassium-exchanging transporter activity
    modifier: DECREASED
  genetic_context:
    gene:
      preferred_term: ATP1A2
      term:
        id: hgnc:800
        label: ATP1A2
    zygosity: HETEROZYGOUS
    functional_impact_category: LOSS_OF_FUNCTION
    description: >-
      Heterozygous ATP1A2 variants acting through haploinsufficiency of the
      astrocytic alpha2 Na+/K+ pump.
  cell_types:
  - preferred_term: astrocyte
    term:
      id: CL:0000127
      label: astrocyte
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:12539047
    reference_title: >-
      Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump alpha2 subunit associated with familial
      hemiplegic migraine type 2.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Functional data indicate that the putative pathogenetic mechanism is
      triggered by a loss of function of a single allele of ATP1A2.
    explanation: >-
      Establishes haploinsufficiency, not gain of function, as the FHM2
      molecular mechanism.
  - reference: PMID:21731499
    reference_title: >-
      Increased susceptibility to cortical spreading depression in the mouse model of familial hemiplegic
      migraine type 2.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      mutations of the α2-subunit of the Na,K-ATPase, an isoform almost
      exclusively expressed in astrocytes in the adult brain
    explanation: >-
      Localizes the affected pump to astrocytes, which is what makes the FHM2
      mechanism a glial clearance defect rather than a neuronal channel defect.
  - reference: PMID:21731499
    reference_title: >-
      Increased susceptibility to cortical spreading depression in the mouse model of familial hemiplegic
      migraine type 2.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The mutant α2 Na,K-ATPase protein was barely detectable in the brain of
      homozygous mutants and strongly reduced in the brain of heterozygous
      mutants, likely as a consequence of endoplasmic reticulum retention and
      subsequent proteasomal degradation
    explanation: >-
      Identifies the cell-biological route from variant to reduced pump
      function in the knock-in model.
  downstream:
  - target: Impaired Astrocytic Glutamate and Potassium Clearance
    description: >-
      The W887R/+ model has reduced alpha2 pump abundance together with directly measured astrocytic
      glutamate and potassium clearance deficits.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27354390
      reference_title: Defective glutamate and K+ clearance by cortical astrocytes in familial
        hemiplegic migraine type 2.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Here, we show reduced rates of glutamate and K(+) clearance by cortical astrocytes during
        neuronal activity and reduced density of GLT-1a glutamate transporters in cortical perisynaptic
        astrocytic processes in heterozygous FHM2-knockin mice
      explanation: >-
        Patch-clamp recordings in acute W887R/+ cortical slices directly measured slower astrocytic
        clearance, with reduced perisynaptic GLT-1a in tissue microscopy. This updates the unmeasured
        2011 hypothesis; the ex vivo functional claim is graded IN_VITRO.
- name: Nav1.1 Sodium Channel Gain of Function
  genes:
  - preferred_term: SCN1A
    term:
      id: hgnc:10585
      label: SCN1A
  biological_scale: MOLECULAR
  description: >-
    FHM3 missense variants in SCN1A produce a gain of function of the neuronal
    Nav1.1 sodium channel. The archetypal Q1489K variant alters the hinged-lid
    domain critical for fast inactivation and accelerates recovery from fast
    inactivation two- to four-fold; other FHM3 alleles increase persistent
    sodium current. This is the opposite direction of effect to the SCN1A
    loss-of-function variants that cause Dravet syndrome and related epilepsies.
  molecular_functions:
  - preferred_term: voltage-gated sodium channel activity
    term:
      id: GO:0005248
      label: voltage-gated sodium channel activity
    modifier: INCREASED
  genetic_context:
    gene:
      preferred_term: SCN1A
      term:
        id: hgnc:10585
        label: SCN1A
    allele_type: MISSENSE
    zygosity: HETEROZYGOUS
    functional_impact_category: GAIN_OF_FUNCTION
    description: >-
      Heterozygous missense variants such as Q1489K in the fast-inactivation
      hinged-lid domain of Nav1.1.
  cell_types:
  - preferred_term: GABAergic neuron
    term:
      id: CL:0000617
      label: GABAergic neuron
  locations:
  - preferred_term: neocortex
    term:
      id: UBERON:0001950
      label: neocortex
  evidence:
  - reference: PMID:16054936
    reference_title: >-
      Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Whole-cell recordings in transiently transfected tsA201 cells expressing
      the highly homologous SCN5A sodium channel showed that the mutation
      induces a two-fold to four-fold accelerated recovery from fast
      inactivation without altering any of the other channel parameters
      investigated.
    explanation: >-
      The original functional characterization of the FHM3 Q1489K variant as an
      inactivation-kinetics gain of function. Note the recordings were made in
      a homologous surrogate channel (SCN5A), not Nav1.1 itself.
  - reference: PMID:34491914
    reference_title: >-
      Initiation of migraine-related cortical spreading depolarization by hyperactivity of GABAergic
      neurons and NaV1.1 channels.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We and others have provided evidence that, in contrast to epileptogenic
      mutations, FHM3 mutations cause gain of function of the channel, often
      increasing persistent current and inducing hyperexcitability of
      transfected GABAergic neurons in primary culture
    explanation: >-
      Confirms the gain-of-function direction across FHM3 alleles and places the
      effect in GABAergic neurons, contrasting it with epileptogenic SCN1A loss
      of function.
  - reference: PMID:34546973
    reference_title: Hyperexcitable interneurons trigger cortical spreading depression in an
      Scn1a migraine model.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We found L1649Q to cause a gain-of-function effect with an impaired Na+-channel inactivation
      and increased ramp Na+ currents leading to hyperactivity of fast-spiking inhibitory interneurons.
    explanation: >-
      Recordings from neurons of the L1649Q knock-in establish the FHM-specific channel-to-interneuron
      relation. This does not import the loss-of-function mechanism of Dravet syndrome.
  downstream:
  - target: Cortical Interneuron Hyperactivity
    description: >-
      FHM3 L1649Q impaired inactivation increases fast-spiking interneuron activity in the genetic
      mouse model.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34546973
      reference_title: Hyperexcitable interneurons trigger cortical spreading depression in an
        Scn1a migraine model.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        We found L1649Q to cause a gain-of-function effect with an impaired Na+-channel inactivation
        and increased ramp Na+ currents leading to hyperactivity of fast-spiking inhibitory interneurons.
      explanation: >-
        Recordings from neurons of the L1649Q knock-in establish the FHM-specific channel-to-interneuron
        relation. This does not import the loss-of-function mechanism of Dravet syndrome.
- name: Increased Cortical Glutamatergic Excitability
  biological_scale: CELLULAR
  description: >-
    The convergence point of the FHM1 and FHM2 arms. Increased presynaptic Ca2+
    influx (FHM1) and reduced astrocytic reuptake (FHM2) both raise glutamate
    concentration at cortical excitatory synapses, disrupting the
    excitation-inhibition balance in favour of neuronal hyperactivity. In FHM1
    mice the effect is synapse-specific: excitatory neurotransmission at
    pyramidal cell synapses is enhanced while inhibitory neurotransmission at
    fast-spiking interneuron synapses is unaltered.
  biological_processes:
  - preferred_term: glutamatergic synaptic transmission
    term:
      id: GO:0035249
      label: synaptic transmission, glutamatergic
    modifier: INCREASED
  molecular_functions: []
  cell_types:
  - preferred_term: pyramidal neuron
    term:
      id: CL:0000598
      label: pyramidal neuron
  locations:
  - preferred_term: neocortex
    term:
      id: UBERON:0001950
      label: neocortex
  evidence:
  - reference: PMID:19285472
    reference_title: >-
      Enhanced excitatory transmission at cortical synapses as the basis for facilitated spreading
      depression in Ca(v)2.1 knockin migraine mice.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We show gain of function of excitatory neurotransmission due to increased
      action-potential-evoked Ca(2+) influx and increased probability of
      glutamate release at pyramidal cell synapses but unaltered inhibitory
      neurotransmission at fast-spiking interneuron synapses.
    explanation: >-
      Establishes the synapse-specific enhancement of glutamate release as the
      cellular consequence of the FHM1 channel gain of function.
  - reference: PMID:19285472
    reference_title: >-
      Enhanced excitatory transmission at cortical synapses as the basis for facilitated spreading
      depression in Ca(v)2.1 knockin migraine mice.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The synapse-specific effect of FHM1 mutations points to disruption of
      excitation-inhibition balance and neuronal hyperactivity as the basis for
      episodic vulnerability to CSD ignition in migraine.
    explanation: >-
      States the excitation-inhibition imbalance framing that links this node to
      the spreading-depression threshold node.
  downstream:
  - target: Facilitated Cortical Spreading Depolarization
    description: >-
      Enhanced excitatory release facilitates CSD initiation in FHM1 cortical preparations.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:19285472
      reference_title: Enhanced excitatory transmission at cortical synapses as the basis for
        facilitated spreading depression in Ca(v)2.1 knockin migraine mice.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Using an in vitro model of CSD, we show a causative link between enhanced glutamate release
        and CSD facilitation.
      explanation: >-
        Experimental cortical preparations from FHM1 knock-in mice support enhanced glutamate release
        as a cause of facilitated CSD.
- name: Impaired Astrocytic Glutamate and Potassium Clearance
  biological_scale: CELLULAR
  description: >-
    W887R/+ FHM2 cortical slices have directly measured reductions in astrocytic glutamate and potassium
    clearance. Reduced perisynaptic GLT-1a accompanies alpha2 pump deficiency. Pharmacological perturbation
    supports defective glutamate clearance as a major contributor to easier CSD initiation; potassium
    buffering may contribute differently to propagation. These model results do not quantify clearance
    during human attacks.
  biological_processes:
  - preferred_term: L-glutamate import across plasma membrane
    term:
      id: GO:0098712
      label: L-glutamate import across plasma membrane
    modifier: DECREASED
  - preferred_term: potassium ion transmembrane transport
    term:
      id: GO:0071805
      label: potassium ion transmembrane transport
    modifier: DECREASED
  cell_types:
  - preferred_term: astrocyte
    term:
      id: CL:0000127
      label: astrocyte
  evidence:
  - reference: PMID:27354390
    reference_title: Defective glutamate and K+ clearance by cortical astrocytes in familial
      hemiplegic migraine type 2.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here, we show reduced rates of glutamate and K(+) clearance by cortical astrocytes during neuronal
      activity and reduced density of GLT-1a glutamate transporters in cortical perisynaptic astrocytic
      processes in heterozygous FHM2-knockin mice
    explanation: >-
      Patch-clamp recordings in acute W887R/+ cortical slices directly measured slower astrocytic
      clearance, with reduced perisynaptic GLT-1a in tissue microscopy. This updates the unmeasured
      2011 hypothesis; the ex vivo functional claim is graded IN_VITRO.
  downstream:
  - target: Increased Cortical Glutamatergic Excitability
    description: >-
      Reduced glutamate removal increases excitatory transmitter availability; the authors interpret
      excessive cortical glutamatergic transmission as the route to CSD susceptibility.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27354390
      reference_title: Defective glutamate and K+ clearance by cortical astrocytes in familial
        hemiplegic migraine type 2.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Using ceftriaxone treatment of FHM2 mutants and partial inhibition of glutamate transporters
        in wild-type mice, we obtain evidence that defective glutamate clearance can account for
        most of the facilitation of CSD initiation in FHM2-knockin mice
      explanation: >-
        CSD recordings in cortical slices after mutant-mouse treatment or transporter inhibition
        support a causal clearance contribution. Ceftriaxone produced only a small rescue and did
        not restore perisynaptic astrocytic transporter density; this is not evidence of clinical
        drug efficacy.
  - target: Facilitated Cortical Spreading Depolarization
    description: >-
      The experimentally supported net clearance-to-CSD relation is retained alongside the proposed
      glutamatergic intermediary.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27354390
      reference_title: Defective glutamate and K+ clearance by cortical astrocytes in familial
        hemiplegic migraine type 2.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Using ceftriaxone treatment of FHM2 mutants and partial inhibition of glutamate transporters
        in wild-type mice, we obtain evidence that defective glutamate clearance can account for
        most of the facilitation of CSD initiation in FHM2-knockin mice
      explanation: >-
        CSD recordings in cortical slices after mutant-mouse treatment or transporter inhibition
        support a causal clearance contribution. Ceftriaxone produced only a small rescue and did
        not restore perisynaptic astrocytic transporter density; this is not evidence of clinical
        drug efficacy.
    intermediate_mechanisms:
    - Increased cortical glutamatergic transmission
  notes: >-
    The 2011 clearance hypothesis was tested directly in 2016. The net edge to CSD summarizes the
    same route shown through glutamatergic excitation, not independent additive effects.
- name: Cortical Interneuron Hyperactivity
  biological_scale: CELLULAR
  description: >-
    FHM3 gain of function increases fast-spiking inhibitory interneuron activity. The L1649Q knock-in
    confirms this genetic route, while acute NaV1.1 enhancement and optogenetic activation show that
    spiking can ignite CSD through extracellular potassium build-up. GABAergic synaptic transmission
    itself is not required for initiation.
  biological_processes: []
  cell_types:
  - preferred_term: GABAergic neuron
    term:
      id: CL:0000617
      label: GABAergic neuron
  locations:
  - preferred_term: neocortex
    term:
      id: UBERON:0001950
      label: neocortex
  evidence:
  - reference: PMID:34546973
    reference_title: Hyperexcitable interneurons trigger cortical spreading depression in an
      Scn1a migraine model.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We found L1649Q to cause a gain-of-function effect with an impaired Na+-channel inactivation
      and increased ramp Na+ currents leading to hyperactivity of fast-spiking inhibitory interneurons.
    explanation: >-
      Recordings from neurons of the L1649Q knock-in establish the FHM-specific channel-to-interneuron
      relation. This does not import the loss-of-function mechanism of Dravet syndrome.
  - reference: PMID:34491914
    reference_title: Initiation of migraine-related cortical spreading depolarization by
      hyperactivity of GABAergic neurons and NaV1.1 channels.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here, we show that acute pharmacological activation of NaV1.1 (the main Na+ channel of interneurons)
      or optogenetic-induced hyperactivity of GABAergic interneurons is sufficient to ignite CSD
      in the neocortex by spiking-generated extracellular K+ build-up.
    explanation: >-
      Pharmacologic and optogenetic acute-slice experiments support the spiking/potassium route;
      they mimic FHM3 activity rather than carrying an FHM allele.
  downstream:
  - target: Extracellular Potassium Accumulation
    description: >-
      Repetitive interneuron spiking increases extracellular potassium; the precise early-phase contribution
      is supported but qualified in the L1649Q model.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34491914
      reference_title: Initiation of migraine-related cortical spreading depolarization by
        hyperactivity of GABAergic neurons and NaV1.1 channels.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Here, we show that acute pharmacological activation of NaV1.1 (the main Na+ channel of interneurons)
        or optogenetic-induced hyperactivity of GABAergic interneurons is sufficient to ignite CSD
        in the neocortex by spiking-generated extracellular K+ build-up.
      explanation: >-
        Pharmacologic and optogenetic acute-slice experiments support the spiking/potassium route;
        they mimic FHM3 activity rather than carrying an FHM allele.
    - reference: PMID:34546973
      reference_title: Hyperexcitable interneurons trigger cortical spreading depression in an
        Scn1a migraine model.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Brain slice recordings using K+-sensitive electrodes revealed an increase in extracellular
        K+ in the early phase of CSD in heterozygous mice, likely representing the mechanistic link
        between interneuron hyperactivity and CSD initiation.
      explanation: >-
        The L1649Q genetic model independently supports the potassium intermediary, which the authors
        explicitly qualify as likely.
      directness: INDIRECT
    hypothesis_groups:
    - fhm3_potassium
  notes: >-
    Curated as a parallel arm rather than folded into the glutamatergic node.
    The source study states that CSD initiation here did not require
    glutamatergic transmission, so asserting a single glutamate-mediated
    convergence for all three subtypes would overstate the evidence.
- name: Facilitated Cortical Spreading Depolarization
  biological_scale: TISSUE
  description: >-
    A propagating wave of neuronal and glial depolarization followed by depression of cortical activity
    is facilitated in models of FHM1, FHM2 and FHM3. Reduced triggering threshold is an assay readout
    of this susceptibility. FHM1/FHM2 models also show faster propagation, whereas the L1649Q FHM3
    model did not show increased in vivo propagation speed. CSD is the leading explanation of aura,
    with human FHM translation remaining indirect.
  biological_processes:
  - preferred_term: cortical spreading depolarization
    term:
      id: GO:0051899
      label: membrane depolarization
    modifier: INCREASED
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  - preferred_term: astrocyte
    term:
      id: CL:0000127
      label: astrocyte
  locations:
  - preferred_term: neocortex
    term:
      id: UBERON:0001950
      label: neocortex
  evidence:
  - reference: PMID:15003170
    reference_title: >-
      A Cacna1a knockin migraine mouse model with increased susceptibility to cortical spreading
      depression.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      in the intact animal, a reduced threshold and increased velocity of
      cortical spreading depression (CSD; the likely mechanism for the migraine
      aura). Our data show that the increased susceptibility for CSD and aura in
      migraine may be due to cortical hyperexcitability.
    explanation: >-
      The FHM1 in vivo measurement of a lowered CSD threshold, and the framing
      of cortical hyperexcitability as its cause.
  - reference: PMID:21731499
    reference_title: >-
      Increased susceptibility to cortical spreading depression in the mouse model of familial hemiplegic
      migraine type 2.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      In vivo analysis of cortical spreading depression (CSD), the phenomenon
      underlying migraine aura, revealed a decreased induction threshold and an
      increased velocity of propagation in the heterozygous FHM2 mouse.
    explanation: The matching FHM2 in vivo measurement.
  - reference: PMID:21731499
    reference_title: >-
      Increased susceptibility to cortical spreading depression in the mouse model of familial hemiplegic
      migraine type 2.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The demonstration that FHM2 and FHM1 mutations share the ability to
      facilitate induction and propagation of CSD in mouse models further
      support the role of CSD as a key migraine trigger.
    explanation: >-
      States the convergence of the two arms on a shared CSD-facilitation
      phenotype.
  - reference: PMID:34546973
    reference_title: Hyperexcitable interneurons trigger cortical spreading depression in an
      Scn1a migraine model.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Heterozygous Scn1aL1649Q knock-in mice compared with WT mice displayed a significantly enhanced
      susceptibility to CSD.
    explanation: >-
      The in vivo L1649Q genetic model establishes FHM3 CSD susceptibility; the corresponding propagation-speed
      result was not increased.
  - reference: PMID:34491914
    reference_title: Initiation of migraine-related cortical spreading depolarization by hyperactivity of GABAergic neurons and NaV1.1 channels.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: |-
      For optogenetic experiments, we illuminated the somatosensory cortex of VGAT-ChR2 mice with an optical fiber, monitoring CSD by LFP recordings (Figure 9, A–C). CSD was induced in 50% of VGAT-ChR2 mice and never in control littermates.
    explanation: >-
      In anesthetized mice, selective optogenetic activation of GABAergic neurons induced CSD
      in vivo. These mice did not carry an FHM mutation, so translation to FHM3 is indirect.
      This result supports the net interneuron-to-CSD relation; the potassium intermediary was
      investigated separately in slices. Direct Hm1a injection alone did not evoke recorded
      CSD, although Hm1a shortened the latency of KCl-evoked CSD.
  downstream:
  - target: Reversible Hemiparesis During Aura
    description: >-
      The cortical aura model attributes this focal aura manifestation to propagating depolarization
      and subsequent suppression in the relevant cortical network. Translation from experimental
      CSD to spontaneous human FHM remains indirect.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1388/
      reference_title: Familial Hemiplegic Migraine - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Accumulating evidence supports the hypothesis that the electrophysiologic correlate underlying
        migraine aura is cortical spreading depolarization (CSD)
      explanation: >-
        GeneReviews presents CSD as the hypothesized electrophysiologic basis of aura. Together with
        its clinical localization of aura to cortex or brainstem, this supports a qualified route
        to cortical motor, sensory, visual and language manifestations; it is not a direct recording
        during human FHM attacks.
      directness: INDIRECT
    - reference: PMID:20301562
      reference_title: Familial Hemiplegic Migraine.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        in whom the aura includes fully reversible motor weakness and visual,
        sensory, or language symptoms
      explanation: >-
        This clinical source establishes the particular aura component. Paired with the CSD hypothesis
        above, it supports the qualified cortical attribution; it is not independent experimental
        evidence of CSD during this symptom.
    hypothesis_groups:
    - cortical_aura
  - target: Migraine with Aura
    description: >-
      The cortical aura model attributes this focal aura manifestation to propagating depolarization
      and subsequent suppression in the relevant cortical network. Translation from experimental
      CSD to spontaneous human FHM remains indirect.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1388/
      reference_title: Familial Hemiplegic Migraine - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Accumulating evidence supports the hypothesis that the electrophysiologic correlate underlying
        migraine aura is cortical spreading depolarization (CSD)
      explanation: >-
        GeneReviews presents CSD as the hypothesized electrophysiologic basis of aura. Together with
        its clinical localization of aura to cortex or brainstem, this supports a qualified route
        to cortical motor, sensory, visual and language manifestations; it is not a direct recording
        during human FHM attacks.
      directness: INDIRECT
    - reference: PMID:20301562
      reference_title: Familial Hemiplegic Migraine.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Familial hemiplegic migraine (FHM) falls within the category of migraine
        with aura.
      explanation: >-
        This clinical source establishes the particular aura component. Paired with the CSD hypothesis
        above, it supports the qualified cortical attribution; it is not independent experimental
        evidence of CSD during this symptom.
    hypothesis_groups:
    - cortical_aura
  - target: Paresthesia During Aura
    description: >-
      The cortical aura model attributes this focal aura manifestation to propagating depolarization
      and subsequent suppression in the relevant cortical network. Translation from experimental
      CSD to spontaneous human FHM remains indirect.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1388/
      reference_title: Familial Hemiplegic Migraine - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Accumulating evidence supports the hypothesis that the electrophysiologic correlate underlying
        migraine aura is cortical spreading depolarization (CSD)
      explanation: >-
        GeneReviews presents CSD as the hypothesized electrophysiologic basis of aura. Together with
        its clinical localization of aura to cortex or brainstem, this supports a qualified route
        to cortical motor, sensory, visual and language manifestations; it is not a direct recording
        during human FHM attacks.
      directness: INDIRECT
    - reference: PMID:20301562
      reference_title: Familial Hemiplegic Migraine.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        sensory loss (e.g., numbness or paresthesias of the face or an extremity)
      explanation: >-
        This clinical source establishes the particular aura component. Paired with the CSD hypothesis
        above, it supports the qualified cortical attribution; it is not independent experimental
        evidence of CSD during this symptom.
    hypothesis_groups:
    - cortical_aura
  - target: Hypoesthesia During Aura
    description: >-
      The cortical aura model attributes this focal aura manifestation to propagating depolarization
      and subsequent suppression in the relevant cortical network. Translation from experimental
      CSD to spontaneous human FHM remains indirect.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1388/
      reference_title: Familial Hemiplegic Migraine - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Accumulating evidence supports the hypothesis that the electrophysiologic correlate underlying
        migraine aura is cortical spreading depolarization (CSD)
      explanation: >-
        GeneReviews presents CSD as the hypothesized electrophysiologic basis of aura. Together with
        its clinical localization of aura to cortex or brainstem, this supports a qualified route
        to cortical motor, sensory, visual and language manifestations; it is not a direct recording
        during human FHM attacks.
      directness: INDIRECT
    - reference: PMID:20301562
      reference_title: Familial Hemiplegic Migraine.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        sensory loss (e.g., numbness or paresthesias of the face or an extremity)
      explanation: >-
        This clinical source establishes the particular aura component. Paired with the CSD hypothesis
        above, it supports the qualified cortical attribution; it is not independent experimental
        evidence of CSD during this symptom.
    hypothesis_groups:
    - cortical_aura
  - target: Aphasia During Aura
    description: >-
      The cortical aura model attributes this focal aura manifestation to propagating depolarization
      and subsequent suppression in the relevant cortical network. Translation from experimental
      CSD to spontaneous human FHM remains indirect.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1388/
      reference_title: Familial Hemiplegic Migraine - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Accumulating evidence supports the hypothesis that the electrophysiologic correlate underlying
        migraine aura is cortical spreading depolarization (CSD)
      explanation: >-
        GeneReviews presents CSD as the hypothesized electrophysiologic basis of aura. Together with
        its clinical localization of aura to cortex or brainstem, this supports a qualified route
        to cortical motor, sensory, visual and language manifestations; it is not a direct recording
        during human FHM attacks.
      directness: INDIRECT
    - reference: PMID:20301562
      reference_title: Familial Hemiplegic Migraine.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In migraine with aura (including FHM) the neurologic symptoms of aura are
        unequivocally localizable to the cerebral cortex or brain stem and include
        visual disturbance (most common), sensory loss (e.g., numbness or
        paresthesias of the face or an extremity), and dysphasia (difficulty with
        speech).
      explanation: >-
        This clinical source establishes the particular aura component. Paired with the CSD hypothesis
        above, it supports the qualified cortical attribution; it is not independent experimental
        evidence of CSD during this symptom.
    hypothesis_groups:
    - cortical_aura
  - target: Scotoma During Aura
    description: >-
      The cortical aura model attributes this focal aura manifestation to propagating depolarization
      and subsequent suppression in the relevant cortical network. Translation from experimental
      CSD to spontaneous human FHM remains indirect.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1388/
      reference_title: Familial Hemiplegic Migraine - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Accumulating evidence supports the hypothesis that the electrophysiologic correlate underlying
        migraine aura is cortical spreading depolarization (CSD)
      explanation: >-
        GeneReviews presents CSD as the hypothesized electrophysiologic basis of aura. Together with
        its clinical localization of aura to cortex or brainstem, this supports a qualified route
        to cortical motor, sensory, visual and language manifestations; it is not a direct recording
        during human FHM attacks.
      directness: INDIRECT
    - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1388/
      reference_title: Familial Hemiplegic Migraine - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Visual disturbances can include scotoma (blind spots), photopsia (flashing lights), fortification
        spectra (zigzag pattern), and diplopia (double vision).
      explanation: >-
        This clinical source establishes the particular aura component. Paired with the CSD hypothesis
        above, it supports the qualified cortical attribution; it is not independent experimental
        evidence of CSD during this symptom.
    hypothesis_groups:
    - cortical_aura
  - target: Photopsia During Aura
    description: >-
      The cortical aura model attributes this focal aura manifestation to propagating depolarization
      and subsequent suppression in the relevant cortical network. Translation from experimental
      CSD to spontaneous human FHM remains indirect.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1388/
      reference_title: Familial Hemiplegic Migraine - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Accumulating evidence supports the hypothesis that the electrophysiologic correlate underlying
        migraine aura is cortical spreading depolarization (CSD)
      explanation: >-
        GeneReviews presents CSD as the hypothesized electrophysiologic basis of aura. Together with
        its clinical localization of aura to cortex or brainstem, this supports a qualified route
        to cortical motor, sensory, visual and language manifestations; it is not a direct recording
        during human FHM attacks.
      directness: INDIRECT
    - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1388/
      reference_title: Familial Hemiplegic Migraine - GeneReviews® - NCBI Bookshelf
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Visual disturbances can include scotoma (blind spots), photopsia (flashing lights), fortification
        spectra (zigzag pattern), and diplopia (double vision).
      explanation: >-
        This clinical source establishes the particular aura component. Paired with the CSD hypothesis
        above, it supports the qualified cortical attribution; it is not independent experimental
        evidence of CSD during this symptom.
    hypothesis_groups:
    - cortical_aura
  - target: Meningeal Nociceptor Sensitization
    description: >-
      CSD may sensitize meningeal trigeminal nociceptors and thereby trigger headache; the source
      treats this step as a proposed mechanism.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34491914
      reference_title: Initiation of migraine-related cortical spreading depolarization by
        hyperactivity of GABAergic neurons and NaV1.1 channels.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        SD-induced cortical spreading depression (CSD) of spontaneous activity causes migraine aura
        and could induce migraine headache by sensitization of meningeal nociceptors
      explanation: >-
        This is the paper's background mechanistic hypothesis, not a headache outcome measured in
        its slice or optogenetic experiments. The CSD-to-headache relation remains qualified.
      directness: INDIRECT
    hypothesis_groups:
    - csd_headache
  - target: Subcortical Spreading Depolarization
    description: >-
      Cortical waves spread into subcortical structures in the R192Q/S218L models, with allele-dependent
      distribution.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:21490217
      reference_title: Enhanced subcortical spreading depression in familial hemiplegic
        migraine type 1 mutant mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We showed that unlike the wild type, cortical spreading depression readily propagated into
        subcortical structures in both familial hemiplegic migraine type 1 mutants.
      explanation: >-
        Multielectrode recordings, diffusion MRI and c-fos mapping in R192Q and S218L mice demonstrate
        subcortical spread. Hippocampal/thalamic spread was specific to the severe S218L model; R192Q
        spread was limited to striatum.
    hypothesis_groups:
    - severe_fhm1_spread
  - target: Attack-Associated Neuronal Injury
    description: >-
      Repeated depolarization can injure juvenile rat brain; applying that result to repeated severe
      FHM attacks remains a provisional model-translation hypothesis.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:25143767
      reference_title: Familial hemiplegic migraine and spreading depression.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Repetitive cortical SD enhanced the production of dark neurons, reduced the mean volume of
        normal neurons, increased the number of apoptotic neurons
      explanation: >-
        The review summarizes neuronal injury after repeated spreading depression in juvenile rats.
        These animals are not FHM knock-ins; transfer to severe childhood FHM is hypothetical.
      directness: INDIRECT
    hypothesis_groups:
    - severe_attack_injury
  notes: >-
    The three classical subtypes converge on facilitated CSD through distinct cellular routes. This
    does not establish a glutamate-dependent initiation mechanism in FHM3 or a complete CSD pathway
    for PRRT2-FHM.
- name: Extracellular Potassium Accumulation
  biological_scale: CELLULAR
  description: >-
    Spiking-generated extracellular potassium build-up couples interneuron hyperactivity to CSD initiation
    in FHM3 experimental systems.
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:34491914
    reference_title: Initiation of migraine-related cortical spreading depolarization by
      hyperactivity of GABAergic neurons and NaV1.1 channels.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here, we show that acute pharmacological activation of NaV1.1 (the main Na+ channel of interneurons)
      or optogenetic-induced hyperactivity of GABAergic interneurons is sufficient to ignite CSD
      in the neocortex by spiking-generated extracellular K+ build-up.
    explanation: >-
      Pharmacologic and optogenetic acute-slice experiments support the spiking/potassium route;
      they mimic FHM3 activity rather than carrying an FHM allele.
  - reference: PMID:34546973
    reference_title: Hyperexcitable interneurons trigger cortical spreading depression in an
      Scn1a migraine model.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Brain slice recordings using K+-sensitive electrodes revealed an increase in extracellular
      K+ in the early phase of CSD in heterozygous mice, likely representing the mechanistic link
      between interneuron hyperactivity and CSD initiation.
    explanation: >-
      The L1649Q genetic model independently supports the potassium intermediary, which the authors
      explicitly qualify as likely.
    directness: INDIRECT
  downstream:
  - target: Facilitated Cortical Spreading Depolarization
    description: >-
      Potassium accumulation depolarizes the cortical network and facilitates CSD initiation. The
      genetic model supports the proposed ionic intermediary.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:34491914
      reference_title: Initiation of migraine-related cortical spreading depolarization by
        hyperactivity of GABAergic neurons and NaV1.1 channels.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Here, we show that acute pharmacological activation of NaV1.1 (the main Na+ channel of interneurons)
        or optogenetic-induced hyperactivity of GABAergic interneurons is sufficient to ignite CSD
        in the neocortex by spiking-generated extracellular K+ build-up.
      explanation: >-
        Pharmacologic and optogenetic acute-slice experiments support the spiking/potassium route;
        they mimic FHM3 activity rather than carrying an FHM allele.
    - reference: PMID:34546973
      reference_title: Hyperexcitable interneurons trigger cortical spreading depression in an
        Scn1a migraine model.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Brain slice recordings using K+-sensitive electrodes revealed an increase in extracellular
        K+ in the early phase of CSD in heterozygous mice, likely representing the mechanistic link
        between interneuron hyperactivity and CSD initiation.
      explanation: >-
        The L1649Q genetic model independently supports the potassium intermediary, which the authors
        explicitly qualify as likely.
      directness: INDIRECT
    hypothesis_groups:
    - fhm3_potassium
- name: Meningeal Nociceptor Sensitization
  biological_scale: CELLULAR
  description: >-
    Sensitization of meningeal trigeminal afferents is a proposed link between CSD and migraine headache.
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:34491914
    reference_title: Initiation of migraine-related cortical spreading depolarization by
      hyperactivity of GABAergic neurons and NaV1.1 channels.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      SD-induced cortical spreading depression (CSD) of spontaneous activity causes migraine aura
      and could induce migraine headache by sensitization of meningeal nociceptors
    explanation: >-
      This is the paper's background mechanistic hypothesis, not a headache outcome measured in its
      slice or optogenetic experiments. The CSD-to-headache relation remains qualified.
    directness: INDIRECT
  downstream:
  - target: Headache
    description: >-
      Sensitized meningeal nociceptors drive trigeminovascular pain signaling in the proposed CSD-triggered
      headache pathway.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:34491914
      reference_title: Initiation of migraine-related cortical spreading depolarization by
        hyperactivity of GABAergic neurons and NaV1.1 channels.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        SD-induced cortical spreading depression (CSD) of spontaneous activity causes migraine aura
        and could induce migraine headache by sensitization of meningeal nociceptors
      explanation: >-
        This is the paper's background mechanistic hypothesis, not a headache outcome measured in
        its slice or optogenetic experiments. The CSD-to-headache relation remains qualified.
      directness: INDIRECT
    hypothesis_groups:
    - csd_headache
- name: Subcortical Spreading Depolarization
  biological_scale: TISSUE
  description: >-
    Spreading depolarization enters striatum in R192Q and more extensive subcortical structures in
    S218L mice, offering an allele-scoped explanation for severe attack manifestations.
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:21490217
    reference_title: Enhanced subcortical spreading depression in familial hemiplegic migraine
      type 1 mutant mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We showed that unlike the wild type, cortical spreading depression readily propagated into
      subcortical structures in both familial hemiplegic migraine type 1 mutants.
    explanation: >-
      Multielectrode recordings, diffusion MRI and c-fos mapping in R192Q and S218L mice demonstrate
      subcortical spread. Hippocampal/thalamic spread was specific to the severe S218L model; R192Q
      spread was limited to striatum.
  downstream:
  - target: Reversible Hemiparesis During Aura
    description: >-
      Subcortical spreading depolarization is the authors' proposed explanation for this severe-attack
      manifestation; the anatomical extent and clinical translation remain allele-dependent.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21490217
      reference_title: Enhanced subcortical spreading depression in familial hemiplegic
        migraine type 1 mutant mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Altogether, these data show that spreading depression propagates between cortex, basal ganglia,
        diencephalon, and hippocampus in genetically susceptible brains, which could explain the
        prolonged hemiplegia, coma, and seizure phenotype in this variant of migraine with aura.
      explanation: >-
        The authors propose subcortical propagation as an explanation of prolonged motor deficits,
        coma and seizures. This is a model-derived clinical hypothesis, especially for S218L, not
        proof that every seizure or coma in FHM uses this route.
      directness: INDIRECT
    hypothesis_groups:
    - severe_fhm1_spread
  - target: Coma
    description: >-
      Subcortical spreading depolarization is the authors' proposed explanation for this severe-attack
      manifestation; the anatomical extent and clinical translation remain allele-dependent.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21490217
      reference_title: Enhanced subcortical spreading depression in familial hemiplegic
        migraine type 1 mutant mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Altogether, these data show that spreading depression propagates between cortex, basal ganglia,
        diencephalon, and hippocampus in genetically susceptible brains, which could explain the
        prolonged hemiplegia, coma, and seizure phenotype in this variant of migraine with aura.
      explanation: >-
        The authors propose subcortical propagation as an explanation of prolonged motor deficits,
        coma and seizures. This is a model-derived clinical hypothesis, especially for S218L, not
        proof that every seizure or coma in FHM uses this route.
      directness: INDIRECT
    hypothesis_groups:
    - severe_fhm1_spread
  - target: Seizures
    description: >-
      Subcortical spreading depolarization is the authors' proposed explanation for this severe-attack
      manifestation; the anatomical extent and clinical translation remain allele-dependent.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:21490217
      reference_title: Enhanced subcortical spreading depression in familial hemiplegic
        migraine type 1 mutant mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Altogether, these data show that spreading depression propagates between cortex, basal ganglia,
        diencephalon, and hippocampus in genetically susceptible brains, which could explain the
        prolonged hemiplegia, coma, and seizure phenotype in this variant of migraine with aura.
      explanation: >-
        The authors propose subcortical propagation as an explanation of prolonged motor deficits,
        coma and seizures. This is a model-derived clinical hypothesis, especially for S218L, not
        proof that every seizure or coma in FHM uses this route.
      directness: INDIRECT
    hypothesis_groups:
    - severe_fhm1_spread
- name: Purkinje Cell Firing Dysregulation
  biological_scale: CELLULAR
  description: >-
    S218L Cav2.1 gain of function lowers Purkinje-cell spike thresholds and disrupts firing regularity,
    a proposed substrate for cerebellar ataxia.
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:23115190
    reference_title: Cerebellar ataxia by enhanced Ca(V)2.1 currents is alleviated by
      Ca2+-dependent K+-channel activators in Cacna1a(S218L) mutant mice.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here, we demonstrate that the S218L mutation causes a negative shift of voltage dependence
      of Ca(V)2.1 channels of mouse Purkinje cells and results in lowered thresholds for somatic
      action potentials and dendritic Ca(2+) spikes and in disrupted firing patterns.
    explanation: >-
      Purkinje-cell electrophysiology directly supports the S218L channel-to-firing relation. It
      does not generalize this effect to CACNA1A loss-of-function ataxias.
  - reference: PMID:23115190
    reference_title: Cerebellar ataxia by enhanced Ca(V)2.1 currents is alleviated by
      Ca2+-dependent K+-channel activators in Cacna1a(S218L) mutant mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The current data suggest that abnormalities in Purkinje cell firing contributes to cerebellar
      ataxia induced by the S218L mutation
    explanation: >-
      The authors infer a causal firing-to-ataxia route from electrophysiology and improved mouse
      motor performance with channel modulation. The translational inference is explicitly limited
      to the S218L model.
    directness: INDIRECT
  downstream:
  - target: Cerebellar Ataxia
    description: >-
      Irregular Purkinje firing is proposed to cause ataxia in the S218L model. This supports a qualified
      route to the clinical cerebellar phenotype without proving every progressive human ataxia has
      the same substrate.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:23115190
      reference_title: Cerebellar ataxia by enhanced Ca(V)2.1 currents is alleviated by
        Ca2+-dependent K+-channel activators in Cacna1a(S218L) mutant mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        The current data suggest that abnormalities in Purkinje cell firing contributes to cerebellar
        ataxia induced by the S218L mutation
      explanation: >-
        The authors infer a causal firing-to-ataxia route from electrophysiology and improved mouse
        motor performance with channel modulation. The translational inference is explicitly limited
        to the S218L model.
      directness: INDIRECT
    hypothesis_groups:
    - fhm1_cerebellar
- name: Cerebellar Neuronal Degeneration
  biological_scale: CELLULAR
  description: >-
    Neuronal loss is a proposed consequence of selected ataxia-associated FHM1 current abnormalities;
    it provides a substrate for cerebellar tissue atrophy.
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:25143767
    reference_title: Familial hemiplegic migraine and spreading depression.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      FHM1 with ataxia is attributable to specific mutations that differ from mutations that cause
      pure FHM1 and have peculiar consequences on cerebellar Cav2.1 currents that lead to profound
      Purkinje cell dysfunction and to neuronal loss with atrophy.
    explanation: >-
      The mechanistic review attributes cerebellar neuronal loss and atrophy to selected FHM1 current
      abnormalities. This synthesis supports a qualified degeneration route, not a human histological
      demonstration across all CACNA1A families.
    directness: INDIRECT
  downstream:
  - target: Cerebellar Atrophy
    description: >-
      Loss of cerebellar neurons contributes to the atrophic tissue phenotype in the reviewed FHM1
      model.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:25143767
      reference_title: Familial hemiplegic migraine and spreading depression.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        FHM1 with ataxia is attributable to specific mutations that differ from mutations that cause
        pure FHM1 and have peculiar consequences on cerebellar Cav2.1 currents that lead to profound
        Purkinje cell dysfunction and to neuronal loss with atrophy.
      explanation: >-
        The mechanistic review attributes cerebellar neuronal loss and atrophy to selected FHM1 current
        abnormalities. This synthesis supports a qualified degeneration route, not a human histological
        demonstration across all CACNA1A families.
      directness: INDIRECT
    hypothesis_groups:
    - fhm1_cerebellar
- name: Blood-Brain Barrier Disruption
  biological_scale: TISSUE
  description: >-
    Cortical barrier leakage preceded delayed edema in one ATP1A2-FHM attack. The cause of barrier
    disruption upstream of this observed tissue lesion remains unresolved.
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:15985592
    reference_title: Opening of the blood-brain barrier preceding cortical edema in a severe
      attack of FHM type II.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Quantitative analysis of early gadolinium-enhanced MRI revealed a mild but significant left-hemispheric
      blood-brain barrier (BBB) opening limited to the cortex and preceding cortical edema.
    explanation: >-
      The severe ATP1A2-FHM case provides direct serial-imaging evidence of cortical edema and earlier
      barrier leakage.
  downstream:
  - target: Cerebral Edema
    description: >-
      The case authors interpret delayed edema after barrier opening as vasogenic fluid accumulation.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:15985592
      reference_title: Opening of the blood-brain barrier preceding cortical edema in a severe
        attack of FHM type II.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The findings suggest that the delayed cortical edema was vasogenic in the severe migraine
        aura variant of this ATP1A2 mutation carrier.
      explanation: >-
        Serial MRI showed barrier opening before edema in one severe FHM2 attack. The authors' vasogenic
        interpretation supports a case-scoped causal link; it does not identify the upstream molecular
        cause of barrier leakage.
      directness: INDIRECT
    hypothesis_groups:
    - fhm2_vasogenic_edema
    intermediate_mechanisms:
    - Vasogenic fluid accumulation
  role: Observed tissue effector with unresolved upstream attribution
- name: Attack-Associated Neuronal Injury
  biological_scale: CELLULAR
  description: >-
    Neuronal injury after severe or repeated attacks is a proposed substrate for stepwise cognitive
    decline in a subset of children with FHM, supported indirectly by juvenile-rat spreading-depression
    experiments.
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:25143767
    reference_title: Familial hemiplegic migraine and spreading depression.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Repetitive cortical SD enhanced the production of dark neurons, reduced the mean volume of
      normal neurons, increased the number of apoptotic neurons
    explanation: >-
      The review summarizes neuronal injury after repeated spreading depression in juvenile rats.
      These animals are not FHM knock-ins; transfer to severe childhood FHM is hypothetical.
    directness: INDIRECT
  - reference: PMID:25143767
    reference_title: Familial hemiplegic migraine and spreading depression.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Severe attacks are suggested to result in permanent brain damage and atrophy as well as cognitive
      deterioration in the few children with normal early development and a notable stepwise developmental
      regression after the onset of severe FHM attacks.
    explanation: >-
      The review describes a proposed attack-injury route in a specific severe childhood course,
      not a demonstrated explanation for the T666M family or all developmental disability.
    directness: INDIRECT
  downstream:
  - target: Progressive Cognitive Deterioration
    description: >-
      The review proposes severe-attack brain injury as the cause of cognitive decline in children
      who initially developed normally. This does not establish the route in every T666M family or
      in static intellectual disability.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:25143767
      reference_title: Familial hemiplegic migraine and spreading depression.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Severe attacks are suggested to result in permanent brain damage and atrophy as well as cognitive
        deterioration in the few children with normal early development and a notable stepwise developmental
        regression after the onset of severe FHM attacks.
      explanation: >-
        The review describes a proposed attack-injury route in a specific severe childhood course,
        not a demonstrated explanation for the T666M family or all developmental disability.
      directness: INDIRECT
    hypothesis_groups:
    - severe_attack_injury
- name: Proposed Cytokine-Mediated Neuroinflammation
  biological_scale: TISSUE
  description: >-
    A hypothesis of cytokine action on neural and trigeminovascular tissues motivated by exploratory
    serum profiles in two R583Q-FHM carriers. Serum changes are readouts of a proposed state, and
    may instead be consequences of recurrent disease.
  mechanism_confidence: HYPOTHETICAL
  evidence:
  - reference: DOI:10.3389/fncel.2017.00263
    reference_title: Cerebellar Atrophy and Changes in Cytokines Associated with the CACNA1A
      R583Q Mutation in a Russian Familial Hemiplegic Migraine Type 1 Family
    supports: SUPPORT
    evidence_source: OTHER
    snippet: |-
      High levels of certain pro-apoptotic
      cytokines may have contributed to the cerebellar degenerat ion
      seen in the mutation carriers
    explanation: >-
      The authors propose a cytokine contribution to cerebellar degeneration in two R583Q carriers.
      They explicitly acknowledge that altered cytokines could instead be secondary to disease or
      pain.
    directness: INDIRECT
  - reference: DOI:10.3389/fncel.2017.00263
    reference_title: Cerebellar Atrophy and Changes in Cytokines Associated with the CACNA1A
      R583Q Mutation in a Russian Familial Hemiplegic Migraine Type 1 Family
    supports: SUPPORT
    evidence_source: OTHER
    snippet: |-
      Thus, combined pro-nociceptive and pro-inﬂammatory action
      of cytokines IL-6, IL-18, CXCL1, LIF , and MIF could occur in
      the trigeminovascular system, which comprises of peripheral
      trigeminal neurons and vessels in meninges located outside
      the brain blood barrier, that might explain speciﬁc migraine
      related changes in our patients.
    explanation: >-
      This is the family authors' proposed neuroimmune pain mechanism, based on serum profiles and
      external experimental work. Neither cytokine action in patient meninges nor clinical benefit
      from cytokine blockade was tested.
    directness: INDIRECT
  downstream:
  - target: Cerebellar Neuronal Degeneration
    description: >-
      Pro-apoptotic cytokines are proposed contributors to cerebellar degeneration in the R583Q family;
      reverse causation remains possible.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: DOI:10.3389/fncel.2017.00263
      reference_title: Cerebellar Atrophy and Changes in Cytokines Associated with the CACNA1A
        R583Q Mutation in a Russian Familial Hemiplegic Migraine Type 1 Family
      supports: SUPPORT
      evidence_source: OTHER
      snippet: |-
        High levels of certain pro-apoptotic
        cytokines may have contributed to the cerebellar degenerat ion
        seen in the mutation carriers
      explanation: >-
        The authors propose a cytokine contribution to cerebellar degeneration in two R583Q carriers.
        They explicitly acknowledge that altered cytokines could instead be secondary to disease
        or pain.
      directness: INDIRECT
    hypothesis_groups:
    - cytokine_hypothesis
  - target: Meningeal Nociceptor Sensitization
    description: >-
      The combined pro-nociceptive cytokine profile is proposed to act in the trigeminovascular system.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    evidence:
    - reference: DOI:10.3389/fncel.2017.00263
      reference_title: Cerebellar Atrophy and Changes in Cytokines Associated with the CACNA1A
        R583Q Mutation in a Russian Familial Hemiplegic Migraine Type 1 Family
      supports: SUPPORT
      evidence_source: OTHER
      snippet: |-
        Thus, combined pro-nociceptive and pro-inﬂammatory action
        of cytokines IL-6, IL-18, CXCL1, LIF , and MIF could occur in
        the trigeminovascular system, which comprises of peripheral
        trigeminal neurons and vessels in meninges located outside
        the brain blood barrier, that might explain speciﬁc migraine
        related changes in our patients.
      explanation: >-
        This is the family authors' proposed neuroimmune pain mechanism, based on serum profiles
        and external experimental work. Neither cytokine action in patient meninges nor clinical
        benefit from cytokine blockade was tested.
      directness: INDIRECT
    hypothesis_groups:
    - cytokine_hypothesis
  role: Proposed tissue effector with unresolved upstream attribution
phenotypes:
- category: Neurological
  name: Reversible Hemiparesis During Aura
  description: >-
    Fully reversible unilateral motor weakness during the aura, obligatory for
    the diagnosis and the feature that separates FHM from other migraine with
    aura.
  diagnostic: true
  phenotype_term:
    preferred_term: Hemiparesis
    term:
      id: HP:0001269
      label: Hemiparesis
    temporality: TRANSIENT
  evidence:
  - reference: PMID:20301562
    reference_title: Familial Hemiplegic Migraine.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      in whom the aura includes fully reversible motor weakness and visual,
      sensory, or language symptoms
    explanation: >-
      The diagnostic criterion establishing reversible motor weakness as
      obligatory.
- category: Neurological
  name: Migraine with Aura
  description: >-
    FHM sits within the category of migraine with aura; the aura symptoms are
    localizable to cerebral cortex or brainstem.
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Migraine with aura
    term:
      id: HP:0002077
      label: Migraine with aura
  evidence:
  - reference: PMID:20301562
    reference_title: Familial Hemiplegic Migraine.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Familial hemiplegic migraine (FHM) falls within the category of migraine
      with aura.
    explanation: >-
      Places FHM inside migraine with aura, which is why the aura is obligatory
      rather than occasional.
- category: Neurological
  name: Headache
  description: Migrainous headache accompanying or following the aura.
  phenotype_term:
    preferred_term: Headache
    term:
      id: HP:0002315
      label: Headache
  evidence:
  - reference: PMID:32430436
    reference_title: Diagnostic and therapeutic aspects of hemiplegic migraine.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hemiplegic migraine (HM) is a clinically and genetically heterogeneous
      condition with attacks of headache and motor weakness
    explanation: Establishes headache as a core attack feature alongside weakness.
  - reference: PMID:12023326
    reference_title: A population-based study of familial hemiplegic migraine suggests revised
      diagnostic criteria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Headache was present in 99% of FHM patients during FHM attacks
    explanation: >-
      The population-based Danish series included 147 affected individuals in 44 families; 99% had
      headache with attacks. This supports VERY_FREQUENT within that FHM cohort.
  frequency: VERY_FREQUENT
  notes: >-
    The 99% figure is from the Danish population-based FHM cohort, not from genetically selected
    severe-allele carriers.
- category: Neurological
  name: Paresthesia During Aura
  description: >-
    Transient tingling of the face or an extremity during aura. Reduced sensation is represented
    separately as hypoesthesia.
  phenotype_term:
    preferred_term: Paresthesia
    term:
      id: HP:0003401
      label: Paresthesia
    temporality: TRANSIENT
  evidence:
  - reference: PMID:20301562
    reference_title: Familial Hemiplegic Migraine.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      sensory loss (e.g., numbness or paresthesias of the face or an extremity)
    explanation: Names the sensory aura modality in FHM.
- category: Neurological
  name: Aphasia During Aura
  description: Dysphasia (difficulty with speech) as an aura symptom.
  phenotype_term:
    preferred_term: Aphasia
    term:
      id: HP:0002381
      label: Aphasia
    temporality: TRANSIENT
  evidence:
  - reference: PMID:20301562
    reference_title: Familial Hemiplegic Migraine.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In migraine with aura (including FHM) the neurologic symptoms of aura are
      unequivocally localizable to the cerebral cortex or brain stem and include
      visual disturbance (most common), sensory loss (e.g., numbness or
      paresthesias of the face or an extremity), and dysphasia (difficulty with
      speech).
    explanation: Names the language aura modality in FHM.
- category: Neurological
  name: Vertigo During Aura
  description: >-
    Vertigo as a brainstem aura symptom during a hemiplegic migraine attack.
  phenotype_term:
    preferred_term: Vertigo
    term:
      id: HP:0002321
      label: Vertigo
    temporality: TRANSIENT
  evidence:
  - reference: PMID:38674378
    reference_title: >-
      Unravelling the Genetic Landscape of Hemiplegic Migraine: Exploring Innovative Strategies and
      Emerging Approaches.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      bilateral visual defects, brainstem aura with vertigo, ataxia,
      hyperacusia, dysarthria, disturbed consciousness, tinnitus
    explanation: Names vertigo as a brainstem aura feature of hemiplegic migraine.
  notes: >-
    No frequency is asserted. The 69% population figure is for brainstem
    symptoms as a group, and the source that names the individual symptoms does
    not break them down.
- category: Neurological
  name: Tinnitus During Aura
  description: >-
    Tinnitus as a brainstem aura symptom during a hemiplegic migraine attack.
  phenotype_term:
    preferred_term: Tinnitus
    term:
      id: HP:0000360
      label: Tinnitus
    temporality: TRANSIENT
  evidence:
  - reference: PMID:38674378
    reference_title: >-
      Unravelling the Genetic Landscape of Hemiplegic Migraine: Exploring Innovative Strategies and
      Emerging Approaches.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hyperacusia, dysarthria, disturbed consciousness, tinnitus, and, in severe
      cases, coma
    explanation: Names tinnitus as a brainstem aura feature of hemiplegic migraine.
- category: Neurological
  name: Dysarthria
  description: >-
    Slurred speech during an attack. Distinct from the aphasic (language) aura
    already curated above: dysarthria is a motor speech disturbance localizing
    to the brainstem, aphasia a cortical language disturbance, and the two are
    listed separately in the sources.
  phenotype_term:
    preferred_term: Dysarthria
    term:
      id: HP:0001260
      label: Dysarthria
    temporality: TRANSIENT
  evidence:
  - reference: PMID:38674378
    reference_title: >-
      Unravelling the Genetic Landscape of Hemiplegic Migraine: Exploring Innovative Strategies and
      Emerging Approaches.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      brainstem aura with vertigo, ataxia, hyperacusia, dysarthria, disturbed
      consciousness
    explanation: >-
      Names dysarthria as a brainstem aura feature of hemiplegic migraine.
- category: Neurological
  name: Cerebellar Ataxia
  description: >-
    A permanent, usually late-onset and mild progressive cerebellar ataxia,
    largely confined to the CACNA1A subtype.
  subtype: FHM1
  phenotype_term:
    preferred_term: Progressive cerebellar ataxia
    term:
      id: HP:0002073
      label: Progressive cerebellar ataxia
  evidence:
  - reference: PMID:20301562
    reference_title: Familial Hemiplegic Migraine.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Approximately 40%-50% of families with CACNA1A-FHM have cerebellar signs
      ranging from nystagmus to progressive, usually late-onset mild ataxia.
    explanation: >-
      The estimate concerns families with any cerebellar signs, combining nystagmus and ataxia. It
      establishes the spectrum but cannot quantify progressive ataxia in individual patients.
  - reference: PMID:10408534
    reference_title: A new CACNA1A gene mutation in acetazolamide-responsive familial
      hemiplegic migraine and ataxia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She, as well as her affected sister, developed a permanent, late-onset cerebellar ataxia and
      cerebellar atrophy evident on MRI.
    explanation: >-
      Direct observation of persistent cerebellar ataxia and MRI atrophy in two sisters with the
      R583Q CACNA1A variant.
  notes: >-
    GeneReviews estimates cerebellar signs in 40%-50% of CACNA1A-FHM families. Neither that family-level
    composite nor the 83% nystagmus-or-ataxia figure in selected carriers quantifies individual progressive
    ataxia.
- category: Neurological
  name: Nystagmus
  description: >-
    The mildest end of the cerebellar spectrum seen in CACNA1A-FHM families.
  subtype: FHM1
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: PMID:20301562
    reference_title: Familial Hemiplegic Migraine.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      have cerebellar signs ranging from nystagmus to progressive, usually
      late-onset mild ataxia
    explanation: Names nystagmus as part of the CACNA1A-FHM cerebellar spectrum.
- category: Neurological
  name: Seizures
  description: >-
    Seizures can accompany severe FHM attacks, and epilepsy has been reported in selected pedigrees
    across the FHM genes. The systematic review of epilepsy-associated FHM families found 78 of 195
    individuals with accessible information had epilepsy; its epilepsy-focused ascertainment prevents
    population frequency inference.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1388/
    reference_title: Familial Hemiplegic Migraine - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seizures during severe attacks have been reported in some families
    explanation: >-
      The complete GeneReviews sentence identifies these families as ATP1A2-FHM and describes accompanying
      coma and encephalopathy. The uninterrupted quoted span establishes clinical seizure occurrence
      rather than treatment advice.
  - reference: PMID:33839563
    reference_title: Epilepsy in patients with familial hemiplegic migraine.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      there were 28 families and 195 individuals, 78 of whom had epilepsy; 30
      patients had focal epilepsy and 30 patients had generalized epilepsy.
    explanation: >-
      The review selected published families with FHM and epilepsy. The 78/195 count describes that
      ascertained literature pool, not the prevalence of epilepsy among all people with FHM.
  - reference: PMID:33839563
    reference_title: Epilepsy in patients with familial hemiplegic migraine.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mutations in all three and possibly four FHM genes can cause epilepsy.
      Contrary to our expectations, the well-known epilepsy gene SCN1A mutations
      are not the leading cause; the highest number of cases associated with
      epilepsy belongs to the ATP1A2 mutation.
    explanation: >-
      Establishes that epilepsy is not confined to the SCN1A subtype and is most
      often reported with ATP1A2.
- category: Neurological
  name: Coma
  description: >-
    Coma during severe prolonged attacks, documented in ATP1A2-FHM and in the severe CACNA1A spectrum.
    This is distinct from milder drowsiness and confusion.
  phenotype_term:
    preferred_term: Coma
    term:
      id: HP:0001259
      label: Coma
    temporality: TRANSIENT
  evidence:
  - reference: PMID:15985592
    reference_title: Opening of the blood-brain barrier preceding cortical edema in a severe
      attack of FHM type II.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The authors report a patient with familial hemiplegic migraine type II who developed a long-lasting
      attack including fever, right-sided hemiplegia, aphasia, and coma.
    explanation: >-
      An ATP1A2-FHM case directly establishes coma during a severe attack, without relying on simplex
      pediatric cases or transferring all S218L carriers into familial disease.
- category: Neurological
  name: Cerebral Edema
  description: >-
    Delayed cerebral edema is described in severe attacks, with blood-brain
    barrier opening documented as preceding cortical edema in FHM2.
  phenotype_term:
    preferred_term: Cerebral edema
    term:
      id: HP:0002181
      label: Cerebral edema
    temporality: TRANSIENT
  evidence:
  - reference: PMID:19438926
    reference_title: >-
      The FHM1 mutation S218L: a severe clinical phenotype? A case report and review of the literature.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "delayed cerebral oedema and coma following minor head trauma"
    explanation: Documents cerebral edema in the severe attack phenotype.
  - reference: PMID:15985592
    reference_title: Opening of the blood-brain barrier preceding cortical edema in a severe
      attack of FHM type II.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Quantitative analysis of early gadolinium-enhanced MRI revealed a mild but significant left-hemispheric
      blood-brain barrier (BBB) opening limited to the cortex and preceding cortical edema.
    explanation: >-
      The severe ATP1A2-FHM case provides direct serial-imaging evidence of cortical edema and earlier
      barrier leakage.
- category: Constitutional
  name: Fever During Severe Attacks
  description: >-
    Fever accompanying prolonged hemiplegic episodes with altered consciousness.
  phenotype_term:
    preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
    temporality: TRANSIENT
  evidence:
  - reference: PMID:10408534
    reference_title: >-
      A new CACNA1A gene mutation in acetazolamide-responsive familial hemiplegic migraine and ataxia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hemiplegia was associated with acutely altered consciousness and fever
      lasting several days
    explanation: Reports fever as a feature of severe prolonged FHM attacks.
- category: Neurological
  name: Intellectual Disability
  description: >-
    Intellectual disability has been reported with selected ATP1A2 variants, including D718N and
    P979L. Broader hemiplegic-migraine series mix familial and simplex presentations, so they do
    not establish its frequency in FHM.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:32430436
    reference_title: Diagnostic and therapeutic aspects of hemiplegic migraine.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      with attacks of headache and motor weakness which may be associated with
      impaired consciousness, cerebellar ataxia and intellectual disability
    explanation: >-
      Names intellectual disability among the associated features of hemiplegic
      migraine. The source does not quantify it, so no frequency is asserted.
  - reference: PMID:15159495
    reference_title: Variability of familial hemiplegic migraine with novel A1A2 Na+/K+-ATPase
      variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      D718N and P979L may predispose to seizures and mental retardation.
    explanation: >-
      The primary ATP1A2 family study attributes this developmental association to particular variants;
      it is not a general consequence of all FHM alleles.
- category: Neurological
  name: Scotoma During Aura
  description: >-
    Transient blind spots during visual aura.
  phenotype_term:
    preferred_term: Scotoma
    term:
      id: HP:0000575
      label: Scotoma
    temporality: TRANSIENT
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1388/
    reference_title: Familial Hemiplegic Migraine - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Visual disturbances can include scotoma (blind spots), photopsia (flashing lights), fortification
      spectra (zigzag pattern), and diplopia (double vision).
    explanation: >-
      GeneReviews describes these individual visual aura manifestations in its FHM clinical description.
      The list establishes occurrence, without individual frequencies.
- category: Neurological
  name: Photopsia During Aura
  description: >-
    Flashing lights during visual aura.
  phenotype_term:
    preferred_term: Photopsia
    term:
      id: HP:0030786
      label: Photopsia
    temporality: TRANSIENT
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1388/
    reference_title: Familial Hemiplegic Migraine - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Visual disturbances can include scotoma (blind spots), photopsia (flashing lights), fortification
      spectra (zigzag pattern), and diplopia (double vision).
    explanation: >-
      GeneReviews describes these individual visual aura manifestations in its FHM clinical description.
      The list establishes occurrence, without individual frequencies.
- category: Neurological
  name: Diplopia During Aura
  description: >-
    Transient double vision during aura; a visual symptom that may involve brainstem or ocular-motor
    pathways.
  phenotype_term:
    preferred_term: Diplopia
    term:
      id: HP:0000651
      label: Diplopia
    temporality: TRANSIENT
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1388/
    reference_title: Familial Hemiplegic Migraine - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Visual disturbances can include scotoma (blind spots), photopsia (flashing lights), fortification
      spectra (zigzag pattern), and diplopia (double vision).
    explanation: >-
      GeneReviews describes these individual visual aura manifestations in its FHM clinical description.
      The list establishes occurrence, without individual frequencies.
- category: Neurological
  name: Hypoesthesia During Aura
  description: >-
    Transient numbness of the face or an extremity during sensory aura.
  phenotype_term:
    preferred_term: Hypoesthesia
    term:
      id: HP:0033748
      label: Hypoesthesia
    temporality: TRANSIENT
  evidence:
  - reference: PMID:20301562
    reference_title: Familial Hemiplegic Migraine.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      sensory loss (e.g., numbness or paresthesias of the face or an extremity)
    explanation: >-
      The sensory aura description includes reduced sensation as well as positive paresthesias; these
      are represented separately.
- category: Neurological
  name: Hyperacusis During Aura
  description: >-
    Sound hypersensitivity described among brainstem aura manifestations of hemiplegic migraine.
  phenotype_term:
    preferred_term: Hyperacusis
    term:
      id: HP:0010780
      label: Hyperacusis
    temporality: TRANSIENT
  evidence:
  - reference: PMID:38674378
    reference_title: 'Unravelling the Genetic Landscape of Hemiplegic Migraine: Exploring Innovative
      Strategies and Emerging Approaches.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      bilateral visual defects, brainstem aura with vertigo, ataxia, hyperacusia, dysarthria, disturbed
      consciousness, tinnitus
    explanation: >-
      The clinical review explicitly lists hyperacusia. As for vertigo and tinnitus, its HM-wide
      scope and lack of a component denominator are retained; the 69% FHM composite is not assigned
      to this symptom.
- category: Neurological
  name: Ataxia During Aura
  description: >-
    Transient incoordination during attacks, distinct from the progressive interictal cerebellar
    ataxia of selected CACNA1A families.
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
    temporality: TRANSIENT
  evidence:
  - reference: PMID:38674378
    reference_title: 'Unravelling the Genetic Landscape of Hemiplegic Migraine: Exploring Innovative
      Strategies and Emerging Approaches.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      brainstem aura with vertigo, ataxia, hyperacusia, dysarthria, disturbed consciousness
    explanation: >-
      This clinical review lists attack-associated ataxia; it does not identify a progressive cerebellar
      course or a symptom-specific frequency.
- category: Neurological
  name: Drowsiness During Attacks
  description: >-
    Drowsiness may occur during an FHM attack without aphasia and does not imply coma.
  phenotype_term:
    preferred_term: Drowsiness
    term:
      id: HP:0002329
      label: Drowsiness
    temporality: TRANSIENT
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1388/
    reference_title: Familial Hemiplegic Migraine - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Some confusion and/or drowsiness may be present even without dysphasia.
    explanation: >-
      The FHM clinical description distinguishes these altered-awareness manifestations from dysphasia.
- category: Neurological
  name: Confusion During Attacks
  description: >-
    Confusion can accompany attacks; selected CACNA1A T666M families also have episodes without hemiparesis.
  phenotype_term:
    preferred_term: Confusion
    term:
      id: HP:0001289
      label: Confusion
    temporality: TRANSIENT
  evidence:
  - reference: PMID:12756131
    reference_title: 'Expanding the phenotypic spectrum of the CACNA1A gene T666M mutation: a description
      of 5 families with familial hemiplegic migraine.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 1 family, some affected members with the mutation had attacks with confusion but without
      hemiparesis.
    explanation: >-
      The primary study of five unrelated T666M families documents confusion attacks in one pedigree.
      This does not make every episode a diagnostic hemiplegic attack.
- category: Neurological
  name: Cerebellar Atrophy
  description: >-
    MRI cerebellar atrophy in selected CACNA1A-FHM families, including the R583Q sisters with progressive
    ataxia.
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  evidence:
  - reference: PMID:10408534
    reference_title: A new CACNA1A gene mutation in acetazolamide-responsive familial
      hemiplegic migraine and ataxia.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She, as well as her affected sister, developed a permanent, late-onset cerebellar ataxia and
      cerebellar atrophy evident on MRI.
    explanation: >-
      Direct MRI observation in two affected sisters with the R583Q allele.
- category: Neurological
  name: Memory Impairment
  description: >-
    Attention and memory loss can persist for weeks to months after attacks; this is distinct from
    lifelong intellectual disability.
  phenotype_term:
    preferred_term: Memory impairment
    term:
      id: HP:0002354
      label: Memory impairment
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1388/
    reference_title: Familial Hemiplegic Migraine - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Persistent attention and memory loss can last weeks to months
    explanation: >-
      GeneReviews reports the prolonged cognitive sequelae in its FHM clinical description, citing
      the T666M family study. No frequency or permanent course is inferred.
- category: Neurological
  name: Learning Disability
  description: >-
    Learning disability is an interictal finding in some genetically identified FHM cases.
  phenotype_term:
    preferred_term: Specific learning disability
    term:
      id: HP:0001328
      label: Specific learning disability
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1388/
    reference_title: Familial Hemiplegic Migraine - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      associated interictal symptoms and signs (nystagmus, episodic or progressive ataxia, learning
      disability, epilepsy)
    explanation: >-
      GeneReviews describes learning disability among interictal findings in genetically identified
      FHM. Surveillance advice alone is not used as evidence of occurrence.
- category: Neurological
  name: Attack-Associated Psychosis
  description: >-
    Recurrent paranoid psychotic episodes accompanying migraine attacks in one FHM family with cerebellar
    ataxia.
  phenotype_term:
    preferred_term: Psychosis
    term:
      id: HP:0000709
      label: Psychosis
    temporality: TRANSIENT
  evidence:
  - reference: PMID:10202246
    reference_title: Familial hemiplegic migraine with cerebellar ataxia and paroxysmal
      psychosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report on a family with familial hemiplegic migraine and cerebellar ataxia with recurrent
      episodes of acute paranoid psychosis with anxiety and visual hallucinations associated with
      migraine attacks.
    explanation: >-
      The primary family report directly describes these attack-associated psychiatric observations.
      Linkage and phenotype supported a chromosome-19 hypothesis; a specific pathogenic CACNA1A variant
      was not established in this abstract.
- category: Neurological
  name: Attack-Associated Anxiety
  description: >-
    Anxiety during the acute psychotic episodes in the reported FHM and cerebellar-ataxia family.
  phenotype_term:
    preferred_term: Anxiety
    term:
      id: HP:0000739
      label: Anxiety
    temporality: TRANSIENT
  evidence:
  - reference: PMID:10202246
    reference_title: Familial hemiplegic migraine with cerebellar ataxia and paroxysmal
      psychosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report on a family with familial hemiplegic migraine and cerebellar ataxia with recurrent
      episodes of acute paranoid psychosis with anxiety and visual hallucinations associated with
      migraine attacks.
    explanation: >-
      The primary family report directly describes these attack-associated psychiatric observations.
      Linkage and phenotype supported a chromosome-19 hypothesis; a specific pathogenic CACNA1A variant
      was not established in this abstract.
- category: Neurological
  name: Visual Hallucinations
  description: >-
    Formed visual hallucinations during acute psychotic episodes in one reported FHM family, distinct
    from simple flashing-light aura.
  phenotype_term:
    preferred_term: Visual hallucination
    term:
      id: HP:0002367
      label: Visual hallucination
  evidence:
  - reference: PMID:10202246
    reference_title: Familial hemiplegic migraine with cerebellar ataxia and paroxysmal
      psychosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report on a family with familial hemiplegic migraine and cerebellar ataxia with recurrent
      episodes of acute paranoid psychosis with anxiety and visual hallucinations associated with
      migraine attacks.
    explanation: >-
      The primary family report directly describes these attack-associated psychiatric observations.
      Linkage and phenotype supported a chromosome-19 hypothesis; a specific pathogenic CACNA1A variant
      was not established in this abstract.
- category: Neurological
  name: Nausea
  description: >-
    Nausea accompanying the headache phase, directly reported in the R583Q father and daughter.
  phenotype_term:
    preferred_term: Nausea
    term:
      id: HP:0002018
      label: Nausea
    temporality: TRANSIENT
  evidence:
  - reference: DOI:10.3389/fncel.2017.00263
    reference_title: Cerebellar Atrophy and Changes in Cytokines Associated with the CACNA1A
      R583Q Mutation in a Russian Familial Hemiplegic Migraine Type 1 Family
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Headache
      was typically localized to the left temporal region of the head and
      associated with photo- and phonophobia, nausea and occasional
      vomiting.
    explanation: >-
      Patient D, a genetically confirmed R583Q carrier with an affected father, had all four associated
      symptoms. This clinical observation does not imply a population frequency; "occasional" describes
      her vomiting within attacks.
  - reference: DOI:10.3389/fncel.2017.00263
    reference_title: Cerebellar Atrophy and Changes in Cytokines Associated with the CACNA1A R583Q Mutation in a Russian Familial Hemiplegic Migraine Type 1 Family
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Headaches usually present on one side, often last
      several hours, and are accompanied by nausea and intolerance
      to light and sound.
    explanation: >-
      Patient F, the genetically confirmed R583Q father, reported nausea accompanying
      his headaches. This supports the father component of the description alongside
      the daughter’s separately quoted history, without implying a population frequency.
- category: Neurological
  name: Vomiting
  description: >-
    Vomiting accompanying some headaches in the R583Q daughter.
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
    temporality: TRANSIENT
  evidence:
  - reference: DOI:10.3389/fncel.2017.00263
    reference_title: Cerebellar Atrophy and Changes in Cytokines Associated with the CACNA1A
      R583Q Mutation in a Russian Familial Hemiplegic Migraine Type 1 Family
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Headache
      was typically localized to the left temporal region of the head and
      associated with photo- and phonophobia, nausea and occasional
      vomiting.
    explanation: >-
      Patient D, a genetically confirmed R583Q carrier with an affected father, had all four associated
      symptoms. This clinical observation does not imply a population frequency; "occasional" describes
      her vomiting within attacks.
- category: Neurological
  name: Photophobia
  description: >-
    Light intolerance during the headache phase in R583Q-FHM.
  phenotype_term:
    preferred_term: Photophobia
    term:
      id: HP:0000613
      label: Photophobia
    temporality: TRANSIENT
  evidence:
  - reference: DOI:10.3389/fncel.2017.00263
    reference_title: Cerebellar Atrophy and Changes in Cytokines Associated with the CACNA1A
      R583Q Mutation in a Russian Familial Hemiplegic Migraine Type 1 Family
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Headache
      was typically localized to the left temporal region of the head and
      associated with photo- and phonophobia, nausea and occasional
      vomiting.
    explanation: >-
      Patient D, a genetically confirmed R583Q carrier with an affected father, had all four associated
      symptoms. This clinical observation does not imply a population frequency; "occasional" describes
      her vomiting within attacks.
  - reference: DOI:10.3389/fncel.2017.00263
    reference_title: Cerebellar Atrophy and Changes in Cytokines Associated with the CACNA1A R583Q Mutation in a Russian Familial Hemiplegic Migraine Type 1 Family
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Headaches usually present on one side, often last
      several hours, and are accompanied by nausea and intolerance
      to light and sound.
    explanation: >-
      Patient F, the genetically confirmed R583Q father, reported light intolerance
      accompanying his headaches. This independently supports headache-associated
      photophobia in this family, without implying a population frequency.
- category: Neurological
  name: Phonophobia
  description: >-
    Sound intolerance during the headache phase, distinct from the hyperacusis enumerated among brainstem
    aura symptoms.
  phenotype_term:
    preferred_term: Phonophobia
    term:
      id: HP:0002183
      label: Phonophobia
    temporality: TRANSIENT
  evidence:
  - reference: DOI:10.3389/fncel.2017.00263
    reference_title: Cerebellar Atrophy and Changes in Cytokines Associated with the CACNA1A
      R583Q Mutation in a Russian Familial Hemiplegic Migraine Type 1 Family
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Headache
      was typically localized to the left temporal region of the head and
      associated with photo- and phonophobia, nausea and occasional
      vomiting.
    explanation: >-
      Patient D, a genetically confirmed R583Q carrier with an affected father, had all four associated
      symptoms. This clinical observation does not imply a population frequency; "occasional" describes
      her vomiting within attacks.
  - reference: DOI:10.3389/fncel.2017.00263
    reference_title: Cerebellar Atrophy and Changes in Cytokines Associated with the CACNA1A R583Q Mutation in a Russian Familial Hemiplegic Migraine Type 1 Family
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Headaches usually present on one side, often last
      several hours, and are accompanied by nausea and intolerance
      to light and sound.
    explanation: >-
      Patient F, the genetically confirmed R583Q father, reported sound intolerance
      accompanying his headaches. This supports headache-associated phonophobia,
      without assigning it to brainstem aura or implying a population frequency.
- category: Neurological
  name: Dysdiadochokinesis
  description: >-
    Impaired rapid alternating movements in the R583Q father and daughter, right-predominant.
  phenotype_term:
    preferred_term: Dysdiadochokinesis
    term:
      id: HP:0002075
      label: Dysdiadochokinesis
  evidence:
  - reference: DOI:10.3389/fncel.2017.00263
    reference_title: Cerebellar Atrophy and Changes in Cytokines Associated with the CACNA1A
      R583Q Mutation in a Russian Familial Hemiplegic Migraine Type 1 Family
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Neurological examination reveals minor
      signs of adiadochokinesia (right > left) and heel-knee probe
      which is slightly asymmetrical with hypermetria on the right
      side.
    explanation: >-
      Patient D had these interictal examination findings. They are cerebellar signs in a genetically
      confirmed FHM1 family, not inferred from the broad ataxia label.
  - reference: DOI:10.3389/fncel.2017.00263
    reference_title: Cerebellar Atrophy and Changes in Cytokines Associated with the CACNA1A R583Q Mutation in a Russian Familial Hemiplegic Migraine Type 1 Family
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Tendon reﬂexes are normal and symmetrical, however, slight
      adiadochokinesia with prevalence on the right side as well as
      hypermetria on the right side of the heel-knee test is detecte d.
    explanation: >-
      Patient F, the genetically confirmed R583Q father, had right-predominant
      adiadochokinesia on interictal examination. This complements his daughter’s separately
      quoted examination and does not establish a disease-wide frequency.
- category: Neurological
  name: Lower Limb Dysmetria
  description: >-
    Right-sided hypermetria on heel-knee testing in the R583Q father and daughter.
  phenotype_term:
    preferred_term: Lower limb dysmetria
    term:
      id: HP:0020035
      label: Lower limb dysmetria
  evidence:
  - reference: DOI:10.3389/fncel.2017.00263
    reference_title: Cerebellar Atrophy and Changes in Cytokines Associated with the CACNA1A
      R583Q Mutation in a Russian Familial Hemiplegic Migraine Type 1 Family
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Neurological examination reveals minor
      signs of adiadochokinesia (right > left) and heel-knee probe
      which is slightly asymmetrical with hypermetria on the right
      side.
    explanation: >-
      Patient D had these interictal examination findings. They are cerebellar signs in a genetically
      confirmed FHM1 family, not inferred from the broad ataxia label.
  - reference: DOI:10.3389/fncel.2017.00263
    reference_title: Cerebellar Atrophy and Changes in Cytokines Associated with the CACNA1A R583Q Mutation in a Russian Familial Hemiplegic Migraine Type 1 Family
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Tendon reﬂexes are normal and symmetrical, however, slight
      adiadochokinesia with prevalence on the right side as well as
      hypermetria on the right side of the heel-knee test is detecte d.
    explanation: >-
      Patient F, the genetically confirmed R583Q father, had right-sided hypermetria on
      heel-knee testing. This independently supports the father component of the description,
      alongside his daughter’s examination; it is not inferred from ataxia or MRI atrophy.
- category: Neurological
  name: Positive Romberg Sign
  description: >-
    Instability on Romberg testing in the R583Q father.
  phenotype_term:
    preferred_term: Positive Romberg sign
    term:
      id: HP:0002403
      label: Positive Romberg sign
  evidence:
  - reference: DOI:10.3389/fncel.2017.00263
    reference_title: Cerebellar Atrophy and Changes in Cytokines Associated with the CACNA1A
      R583Q Mutation in a Russian Familial Hemiplegic Migraine Type 1 Family
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      Also, instability in the Romberg test is detected.
    explanation: >-
      Direct clinical examination of patient F. The source does not demonstrate sensory neuropathy,
      and tactile sensation was unaffected.
- category: Neurological
  name: Progressive Cognitive Deterioration
  description: >-
    Progressive cognitive dysfunction in one of five reported CACNA1A T666M families. Severe attacks
    have also been proposed to cause stepwise cognitive decline in some children.
  phenotype_term:
    preferred_term: Mental deterioration
    term:
      id: HP:0001268
      label: Mental deterioration
  evidence:
  - reference: PMID:12756131
    reference_title: 'Expanding the phenotypic spectrum of the CACNA1A gene T666M mutation: a description
      of 5 families with familial hemiplegic migraine.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 1 family, patients had progressive cognitive dysfunction.
    explanation: >-
      The T666M family study reports progressive cognitive dysfunction, distinct from static intellectual
      disability or transient confusion.
  - reference: PMID:25143767
    reference_title: Familial hemiplegic migraine and spreading depression.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Severe attacks are suggested to result in permanent brain damage and atrophy as well as cognitive
      deterioration in the few children with normal early development and a notable stepwise developmental
      regression after the onset of severe FHM attacks.
    explanation: >-
      The review describes a proposed attack-injury route in a specific severe childhood course,
      not a demonstrated explanation for the T666M family or all developmental disability.
    directness: INDIRECT
- category: Laboratory
  name: Increased Serum Interleukin 6
  description: >-
    Exploratory serum cytokine elevation in the two R583Q-FHM carriers; also seen in mutation-negative
    migraine relatives. Not a disease-specific diagnostic marker.
  phenotype_term:
    preferred_term: Increased circulating interleukin 6 concentration
    term:
      id: HP:0030783
      label: Increased circulating interleukin 6 concentration
  evidence:
  - reference: DOI:10.3389/fncel.2017.00263
    reference_title: Cerebellar Atrophy and Changes in Cytokines Associated with the CACNA1A
      R583Q Mutation in a Russian Familial Hemiplegic Migraine Type 1 Family
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      We found an increased serum levels or IL-6 in both FHM1
      patients (D and F), as well as in the two migraine with aura
      patients without the genetic mutation (B and S).
    explanation: >-
      IL-6 was increased in the two R583Q-FHM carriers and the two migraine-with-aura relatives without
      the mutation; the study is too small for statistical inference.
  reports_on:
  - target: Proposed Cytokine-Mediated Neuroinflammation
    relationship: READOUT_OF
    interpretation: >-
      A circulating readout motivating the proposed inflammatory state, not proof that the cytokine
      change causes symptoms or reflects brain inflammation.
- category: Laboratory
  name: Increased Serum Interleukin 18
  description: >-
    Exploratory serum cytokine elevation in the two R583Q-FHM carriers; also seen in mutation-negative
    migraine relatives. Not a disease-specific diagnostic marker.
  phenotype_term:
    preferred_term: Increased circulating interleukin 18 concentration
    term:
      id: HP:0034447
      label: Increased circulating interleukin 18 concentration
  evidence:
  - reference: DOI:10.3389/fncel.2017.00263
    reference_title: Cerebellar Atrophy and Changes in Cytokines Associated with the CACNA1A
      R583Q Mutation in a Russian Familial Hemiplegic Migraine Type 1 Family
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: |-
      pro-inﬂammatory cytokine IL-18 is also up-regulated in serum
      of all migraine patients, albeit stronger in patients with the gene
      mutation.
    explanation: >-
      Serum IL-18 was higher in the two FHM1 carriers and their mutation-negative migraine relatives.
      This is an exploratory blood assay, not proof of local CNS inflammation.
  reports_on:
  - target: Proposed Cytokine-Mediated Neuroinflammation
    relationship: READOUT_OF
    interpretation: >-
      A circulating readout motivating the proposed inflammatory state, not proof that the cytokine
      change causes symptoms or reflects brain inflammation.
genetic:
- name: CACNA1A
  gene_term:
    preferred_term: CACNA1A
    term:
      id: hgnc:1388
      label: CACNA1A
  subtype: FHM1
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    Encodes the alpha1A pore-forming subunit of the neuronal Cav2.1 (P/Q-type) voltage-gated calcium
    channel. FHM1 variants are missense and act by gain of function. Truncating variants in the same
    gene cause episodic ataxia type 2 instead, making FHM1 and EA2 allelic channelopathies.

    The CACNA1A study provides a carrier-based penetrance estimate. In a series of 117 genotyped
    carriers from pedigrees ascertained on hemiplegic migraine with or without cerebellar signs,
    with two sporadic subjects also included, 89% had hemiplegic migraine attacks and one third had
    severe attacks with coma, prolonged hemiplegia or both. Expressivity varies with the allele but
    only partially: 83% of carriers of the six cerebellar-associated mutations had nystagmus, ataxia
    or both, while three other mutations were associated with pure hemiplegic migraine.
  inheritance:
  - name: Autosomal dominant, incomplete penetrance (CACNA1A)
    inheritance_term:
      preferred_term: Autosomal dominant inheritance
      term:
        id: HP:0000006
        label: Autosomal dominant inheritance
    penetrance: INCOMPLETE
    penetrance_percentage: "89"
    expressivity: VARIABLE
    description: >-
      Gene-specific penetrance and expressivity for CACNA1A, measured in
      genotyped carriers rather than inferred from affected probands. Recorded
      here rather than only on the disease-level inheritance block because the
      denominator is CACNA1A carriers.
    evidence:
    - reference: PMID:11439943
      reference_title: >-
        The clinical spectrum of familial hemiplegic migraine associated with mutations in a neuronal
        calcium channel.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Genotyping of probands and relatives identified a total of 117 subjects
        with mutations whose clinical manifestations were assessed in detail.
      explanation: >-
        Establishes the carrier-based denominator, which is what makes the
        following figure a penetrance estimate rather than a case-series
        proportion.
    - reference: PMID:11439943
      reference_title: >-
        The clinical spectrum of familial hemiplegic migraine associated with mutations in a neuronal
        calcium channel.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Eighty-nine percent of the subjects with mutations had attacks of
        hemiplegic migraine.
      explanation: The penetrance measurement itself.
    - reference: PMID:11439943
      reference_title: >-
        The clinical spectrum of familial hemiplegic migraine associated with mutations in a neuronal
        calcium channel.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Six mutations were associated with hemiplegic migraine and cerebellar
        signs, and 83 percent of the subjects with these six mutations had
        nystagmus, ataxia, or both.
      explanation: >-
        Quantifies the allele-dependent component of expressivity - the
        cerebellar arm that separates FHM1 from the other subtypes.
  frequency: >-
    26% of genetically solved probands (105 of 697 consecutively screened hemiplegic-migraine probands)
  case_fractions:
  - population: Genetically solved subset of the French consecutive hemiplegic-migraine cohort
      (105 of 697 screened probands)
    case_fraction_percent: 26.0
    cohort_size: 105
    notes: >-
      The percentage denominator is 105 probands with an identified pathogenic variant, selected
      from 697 consecutive HM probands. Familial and simplex HM are not separately quantified by
      this percentage.
    evidence:
    - reference: PMID:34649875
      reference_title: >-
        Hemiplegic Migraine Associated With PRRT2 Variations: A Clinical and Genetic Study.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        In this second group, pathogenic variants were found in 105 individuals,
        mostly in ATP1A2 (42%), followed by CACNA1A (26%), PRRT2 (17%), and
        SCN1A (15%).
      explanation: >-
        Gives the relative gene contributions among solved hemiplegic migraine
        cases in a large consecutively screened cohort.
  evidence:
  - reference: PMID:8898206
    reference_title: >-
      Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+
      channel gene CACNL1A4.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thus, FHM and EA-2 can be considered as allelic channelopathies.
    explanation: >-
      Establishes CACNA1A as causal for FHM and defines the allelic relationship
      with episodic ataxia type 2, which is the boundary with the
      CACNA1A-Related Disorder entry.
- name: ATP1A2
  gene_term:
    preferred_term: ATP1A2
    term:
      id: hgnc:800
      label: ATP1A2
  subtype: FHM2
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    Encodes the alpha2 subunit of the Na+/K+-ATPase, expressed almost
    exclusively in astrocytes in the adult brain. FHM2 variants act through
    haploinsufficiency. In a large consecutively screened cohort ATP1A2 was the
    most frequently implicated hemiplegic-migraine gene.
  frequency: >-
    42% of genetically solved probands (105 of 697 consecutively screened hemiplegic-migraine probands)
  case_fractions:
  - population: Genetically solved subset of the French consecutive hemiplegic-migraine cohort
      (105 of 697 screened probands)
    case_fraction_percent: 42.0
    cohort_size: 105
    notes: >-
      The percentage denominator is 105 probands with an identified pathogenic variant, selected
      from 697 consecutive HM probands. Familial and simplex HM are not separately quantified by
      this percentage.
    evidence:
    - reference: PMID:34649875
      reference_title: >-
        Hemiplegic Migraine Associated With PRRT2 Variations: A Clinical and Genetic Study.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        pathogenic variants were found in 105 individuals, mostly in ATP1A2
        (42%), followed by CACNA1A (26%), PRRT2 (17%), and SCN1A (15%).
      explanation: ATP1A2 is the most frequently implicated gene among solved cases.
  evidence:
  - reference: PMID:12539047
    reference_title: >-
      Haploinsufficiency of ATP1A2 encoding the Na+/K+ pump alpha2 subunit associated with familial
      hemiplegic migraine type 2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This is the first report associating mutations of Na+K+ pump subunits to
      genetic diseases.
    explanation: >-
      The gene-discovery report establishing ATP1A2 as causal for FHM2.
- name: SCN1A
  gene_term:
    preferred_term: SCN1A
    term:
      id: hgnc:10585
      label: SCN1A
  subtype: FHM3
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    Encodes the neuronal Nav1.1 voltage-gated sodium channel. FHM3 variants are
    missense gain-of-function changes, the opposite direction to the SCN1A
    loss-of-function variants that cause Dravet syndrome and related epilepsies.
    SCN1A is the least frequently implicated of the four hemiplegic-migraine
    genes in cohort screening.
  frequency: >-
    15% of genetically solved probands (105 of 697 consecutively screened hemiplegic-migraine probands)
  case_fractions:
  - population: Genetically solved subset of the French consecutive hemiplegic-migraine cohort
      (105 of 697 screened probands)
    case_fraction_percent: 15.0
    cohort_size: 105
    notes: >-
      The percentage denominator is 105 probands with an identified pathogenic variant, selected
      from 697 consecutive HM probands. Familial and simplex HM are not separately quantified by
      this percentage.
    evidence:
    - reference: PMID:34649875
      reference_title: >-
        Hemiplegic Migraine Associated With PRRT2 Variations: A Clinical and Genetic Study.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        mostly in ATP1A2 (42%), followed by CACNA1A (26%), PRRT2 (17%), and
        SCN1A (15%).
      explanation: SCN1A is the least frequent of the four genes among solved cases.
  evidence:
  - reference: PMID:16054936
    reference_title: >-
      Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This same mutation was present in three families with familial hemiplegic
      migraine.
    explanation: >-
      Recurrence of the Q1489K variant across three independent families
      supports SCN1A causation.
- name: PRRT2
  gene_term:
    preferred_term: PRRT2
    term:
      id: hgnc:30500
      label: PRRT2
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    A fourth autosomal dominant hemiplegic-migraine gene, recognized more
    recently than CACNA1A/ATP1A2/SCN1A and included in the GeneReviews molecular
    diagnostic criteria. PRRT2 encodes a synaptic protein rather than an ion
    transporter, and the same loss-of-function variants also cause paroxysmal
    kinesigenic dyskinesia, benign familial infantile epilepsy and other
    phenotypes. It is deliberately not curated as a numbered FHM subtype: the
    FHM4 designation (OMIM %607516 / MONDO:0800335) names a gene-less mapped
    locus rather than PRRT2, and the PRRT2 mechanism is not the ion-transport
    defect that unifies FHM1-3. See the entry notes for the full rationale.

    No PRRT2 pathophysiology node is curated. The variants are loss of function
    and the gene product is a synaptic protein, but the authors state explicitly
    that how PRRT2 loss produces hemiplegic migraine is not understood, so
    connecting it to the cortical spreading depression chain would be an
    inference the literature does not yet support.
  frequency: >-
    17% of genetically solved probands (105 of 697 consecutively screened hemiplegic-migraine probands)
  case_fractions:
  - population: Genetically solved subset of the French consecutive hemiplegic-migraine cohort
      (105 of 697 screened probands)
    case_fraction_percent: 17.0
    cohort_size: 105
    notes: >-
      The percentage denominator is 105 probands with an identified pathogenic variant, selected
      from 697 consecutive HM probands. Familial and simplex HM are not separately quantified by
      this percentage.
    evidence:
    - reference: PMID:34649875
      reference_title: >-
        Hemiplegic Migraine Associated With PRRT2 Variations: A Clinical and Genetic Study.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        pathogenic variants were found in 105 individuals, mostly in ATP1A2
        (42%), followed by CACNA1A (26%), PRRT2 (17%), and SCN1A (15%).
      explanation: >-
        PRRT2 accounts for a substantial minority of solved hemiplegic-migraine
        cases, comparable to SCN1A.
  evidence:
  - reference: PMID:34649875
    reference_title: >-
      Hemiplegic Migraine Associated With PRRT2 Variations: A Clinical and Genetic Study.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      PRRT2 should be regarded as the fourth autosomal dominant gene for
      hemiplegic migraine and screened in any affected patient, together with
      the 3 other main genes.
    explanation: >-
      The quoted conclusion states the authors' gene-classification and screening recommendation.
      The underlying observed cohort counts remain HUMAN_CLINICAL in the case-fraction evidence;
      this grading does not alter PRRT2 causative status.
  - reference: PMID:34649875
    reference_title: >-
      Hemiplegic Migraine Associated With PRRT2 Variations: A Clinical and Genetic Study.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Further studies are needed to understand how the same loss-of-function
      PRRT2 variations can lead to a wide range of neurologic phenotypes,
      including paroxysmal movement disorder, epilepsy, learning disabilities,
      sleep disorder, and hemiplegic migraine.
    explanation: >-
      Records both the loss-of-function direction and the open question about
      how one gene produces this phenotypic range.
- name: CACNA1H
  gene_term:
    preferred_term: CACNA1H
    term:
      id: hgnc:1395
      label: CACNA1H
  relationship_type: SUSCEPTIBILITY
  variant_origin: GERMLINE
  notes: >-
    Not a hemiplegic-migraine gene in the Mendelian sense. Whole-exome
    sequencing of mutation-negative hemiplegic-migraine patients found a
    significant excess of missense variants in CACNA1H relative to gnomAD
    controls, replicated in an independent Dutch cohort. The authors' reading -
    which this entry follows - is that hemiplegic migraine without a single
    causal mutation behaves as a complex trait, not that a fourth
    high-penetrance gene is waiting to be found. No pathophysiology node is
    curated for it.
  evidence:
  - reference: DOI:10.1007/s12035-023-03255-5
    reference_title: >-
      Whole Exome Sequencing of Hemiplegic Migraine Patients Shows an Increased Burden of Missense
      Variants in CACNA1H and CACNA1I Genes
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our data suggest that HM, in the absence of a single causal mutation, is a
      complex trait, in which an increased burden of missense variants in
      CACNA1H and CACNA1I may contribute to the risk of disease.
    explanation: >-
      The authors' own conclusion, which is what SUSCEPTIBILITY records here -
      a contribution to risk, not causation.
  - reference: DOI:10.1007/s12035-023-03255-5
    reference_title: >-
      Whole Exome Sequencing of Hemiplegic Migraine Patients Shows an Increased Burden of Missense
      Variants in CACNA1H and CACNA1I Genes
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both the number of variants and number of subjects were replicated for
      CACNA1H
    explanation: >-
      CACNA1H is the one gene whose burden signal replicated in the independent
      cohort on both tests, which is why it is recorded ahead of CACNA1I.
  - reference: DOI:10.3390/genes15040443
    reference_title: >-
      Unravelling the Genetic Landscape of Hemiplegic Migraine: Exploring Innovative Strategies and
      Emerging Approaches
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, approximately 75% of HM patients are negative for these
      mutations, indicating there are other genes involved in disease causation.
    explanation: >-
      Establishes the size of the unexplained fraction that the burden analysis
      above is addressing.
  - reference: DOI:10.1097/wco.0000000000000687
    reference_title: Advance in genetics of migraine
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Mild hemiplegic migraine is likely caused by complex polygenic interaction
      of multiple gene variants and environmental factors, like in common
      migraine subtypes.
    explanation: >-
      States the polygenic reading of mutation-negative hemiplegic migraine
      directly, and is the reason these two genes are curated as SUSCEPTIBILITY
      rather than as candidate Mendelian loci.
- name: CACNA1I
  gene_term:
    preferred_term: CACNA1I
    term:
      id: hgnc:1396
      label: CACNA1I
  relationship_type: SUSCEPTIBILITY
  variant_origin: GERMLINE
  notes: >-
    The second gene in the same burden analysis. Its replication was weaker than
    CACNA1H's - it did not survive multiple-testing correction in the
    replication cohort - so it is recorded with that caveat rather than as an
    established susceptibility locus. CACNA1E also showed a discovery-cohort
    burden signal but is not curated, because the replication result is reported
    only for CACNA1H and CACNA1I.
  evidence:
  - reference: DOI:10.1007/s12035-023-03255-5
    reference_title: >-
      Whole Exome Sequencing of Hemiplegic Migraine Patients Shows an Increased Burden of Missense
      Variants in CACNA1H and CACNA1I Genes
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      albeit that CACNA1I did not remain significant after multiple testing
      correction
    explanation: >-
      The authors explicitly qualify the replication: CACNA1I did not remain significant after multiple-testing
      correction. It remains a candidate association, not an established causal FHM gene.
environmental:
- name: Minor head trauma
  description: >-
    Mild head injury is the best characterized attack trigger in FHM and the one
    with the clearest mechanistic reading. It does not cause the disorder; it
    precipitates an attack in a cortex whose spreading-depression threshold is
    already genetically lowered, and in the severe CACNA1A S218L allele the
    attack it precipitates can be a prolonged one with delayed cerebral edema
    and coma. The S218L knock-in mouse reproduces this: its cortex responds to
    a single weak stimulus with multiple spreading-depression events, which is
    the proposed reason a trivial injury has a non-trivial consequence.
  exposure_term:
    preferred_term: minor head trauma
  influences_mechanisms:
  - target: Facilitated Cortical Spreading Depolarization
    environmental_effect: TRIGGERS
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The source supports attack triggering in susceptible FHM/HM patients or models. Placement at
      facilitated CSD is a physiological hypothesis; the precise exposure-to-depolarization route
      is not established by this observation.
    evidence:
    - reference: PMID:20186955
      reference_title: >-
        High cortical spreading depression susceptibility and migraine-associated symptoms in Ca(v)2.1
        S218L mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        The particularly low CSD threshold and the strong tendency to respond
        with multiple CSD events make the S218L cortex highly vulnerable to weak
        stimuli
      explanation: >-
        States the mechanism by which a weak stimulus such as minor trauma
        triggers spreading depression in this genotype. Mouse data, hence
        MODEL_ORGANISM.
  - target: Cerebral Edema
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      In patients carrying the S218L allele, minor head trauma is the reported
      precipitant of the severe attack phenotype with delayed cerebral edema and
      coma.
    evidence:
    - reference: PMID:19438926
      reference_title: >-
        The FHM1 mutation S218L: a severe clinical phenotype? A case report and review of the literature.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        This CACNA1A mutation has been associated with HM, delayed cerebral
        oedema and coma following minor head trauma.
      explanation: >-
        The human observation linking minor head trauma to the severe attack
        phenotype in S218L carriers.
    - reference: PMID:20186955
      reference_title: >-
        High cortical spreading depression susceptibility and migraine-associated symptoms in Ca(v)2.1
        S218L mice.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        the S218L CACNA1A mutation causes a dramatic hemiplegic migraine syndrome
        that is associated with ataxia, seizures, and severe, sometimes fatal,
        brain edema often triggered by only a mild head trauma
      explanation: >-
        Restates the human trauma-edema association that this knock-in model was
        built to explain.
  evidence:
  - reference: PMID:38674378
    reference_title: >-
      Unravelling the Genetic Landscape of Hemiplegic Migraine: Exploring Innovative Strategies and
      Emerging Approaches.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Common factors, such as viral infection, physical and emotional stress,
      and head trauma, have been found to trigger HM
    explanation: >-
      Establishes head trauma as a recognized trigger of hemiplegic migraine
      generally, not only in the S218L genotype.
  notes: >-
    exposure_term is left with a free-text preferred_term and no ontology
    binding. ECTO was searched for a head-trauma, head-injury, physical-trauma
    or mechanical-force exposure class and has none; the OLS ECTO index returns
    only chemical and anatomical hits for those strings. No term beats a wrong
    term, so nothing is bound here.

    Practical consequence recorded in the source literature: avoidance of
    contact sports and repetitive head injury is reasonable for patients whose
    severe attacks are trauma-triggered. That is a management inference from
    this trigger rather than a tested intervention, so it is not curated as a
    treatment.
- name: Physical and emotional stress
  description: >-
    Physical or emotional stress is a reported precipitant of attacks, in common
    with migraine generally. It is recorded as an attack trigger acting on the
    same threshold node, not as a cause of the disorder.
  exposure_term:
    preferred_term: physical or emotional stress
  influences_mechanisms:
  - target: Facilitated Cortical Spreading Depolarization
    environmental_effect: TRIGGERS
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The source supports attack triggering in susceptible FHM/HM patients or models. Placement at
      facilitated CSD is a physiological hypothesis; the precise exposure-to-depolarization route
      is not established by this observation.
    evidence:
    - reference: PMID:38674378
      reference_title: >-
        Unravelling the Genetic Landscape of Hemiplegic Migraine: Exploring Innovative Strategies
        and Emerging Approaches.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Common factors, such as viral infection, physical and emotional stress,
        and head trauma, have been found to trigger HM
      explanation: Names physical and emotional stress as attack triggers.
  evidence:
  - reference: PMID:41552155
    reference_title: "Hemiplegic Migraine: An Imitator of Cerebrovascular Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the attacks are frequently triggered by factors such as stress, sleep
      disturbances, bright lights, or intense emotional stimuli
    explanation: >-
      A second source listing stress, and adding sleep disruption and sensory
      stimuli, among attack triggers.
  notes: >-
    ECTO has no exposure class for psychosocial or emotional stress, so
    exposure_term is left unbound, as it is for the head-trauma entry above.
    Sleep disruption and bright light are named in the second snippet but are
    not curated as their own entries, because neither source characterizes them
    beyond the list.
- name: Viral infection and febrile illness
  description: >-
    Intercurrent viral illness and fever are reported precipitants of attacks.
    Fever also occurs during severe attacks as a manifestation rather than a
    trigger, and the two are not the same claim - this entry is the trigger.
  exposure_term:
    preferred_term: viral infection
  influences_mechanisms:
  - target: Facilitated Cortical Spreading Depolarization
    environmental_effect: TRIGGERS
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The source supports attack triggering in susceptible FHM/HM patients or models. Placement at
      facilitated CSD is a physiological hypothesis; the precise exposure-to-depolarization route
      is not established by this observation.
    evidence:
    - reference: PMID:38674378
      reference_title: >-
        Unravelling the Genetic Landscape of Hemiplegic Migraine: Exploring Innovative Strategies
        and Emerging Approaches.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Common factors, such as viral infection, physical and emotional stress,
        and head trauma, have been found to trigger HM
      explanation: Names viral infection as an attack trigger.
  evidence:
  - reference: PMID:38674378
    reference_title: >-
      Unravelling the Genetic Landscape of Hemiplegic Migraine: Exploring Innovative Strategies and
      Emerging Approaches.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Common factors, such as viral infection, physical and emotional stress,
      and head trauma, have been found to trigger HM
    explanation: >-
      Establishes viral infection as a recognized precipitant in hemiplegic
      migraine. Recorded at the entry level as well as on the mechanism link
      because the two are different claims - that the exposure is relevant to
      this disease at all, and that it acts on the threshold node.
  notes: >-
    No infectious agent is curated for this entry. Viral illness precipitates
    attacks in an already-susceptible brain; it is not an etiologic agent, and
    no specific organism is implicated.

treatments:
- name: Acetazolamide
  description: >-
    A carbonic anhydrase inhibitor, tried preferentially in CACNA1A-FHM. In one
    family with a CACNA1A R583Q variant the proband and her affected sister
    reported freedom from new FHM attacks on acetazolamide, although the
    cerebellar ataxia continued to progress. The evidence base is case-level, in
    keeping with the rarity of the disorder.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: acetazolamide
      term:
        id: CHEBI:27690
        label: acetazolamide
  target_mechanisms:
  - target: Reversible Hemiparesis During Aura
    description: >-
      Reported to abolish new hemiplegic attacks in an acetazolamide-responsive
      CACNA1A family, without effect on the progressive cerebellar deficit.
    evidence:
    - reference: PMID:10408534
      reference_title: >-
        A new CACNA1A gene mutation in acetazolamide-responsive familial hemiplegic migraine and
        ataxia.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The proband and her affected sister were treated with acetazolamide,
        reporting freedom from new FHM attacks but no benefit in the progression
        of ataxia.
      explanation: >-
        Supports an attack-preventive effect, but from two related individuals in one family with
        no control condition; the uncontrolled case scope limits causal inference.
  evidence:
  - reference: PMID:20301562
    reference_title: Familial Hemiplegic Migraine.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      A trial of acetazolamide for individuals with CACNA1A-FHM or a trial of
      prophylactic migraine medications (e.g., tricyclic antidepressants,
      beta-blockers, calcium channel blockers, anti-seizure medications) for all
      FHM types may be warranted for frequent attacks.
    explanation: >-
      GeneReviews management guidance recommending an acetazolamide trial
      specifically for the CACNA1A subtype.
- name: Acute Attack Analgesia with NSAIDs and Non-Narcotic Analgesics
  description: >-
    NSAIDs and non-narcotic analgesics are described for acute headache control. The source is usual-practice
    advice, not a comparative FHM trial; vasoconstrictor avoidance is recorded separately.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: nonsteroidal anti-inflammatory drug
      term:
        id: NCIT:C257
        label: Nonsteroidal Antiinflammatory Drug
  target_phenotypes:
  - preferred_term: Headache
    term:
      id: HP:0002315
      label: Headache
  evidence:
  - reference: PMID:41552155
    reference_title: "Hemiplegic Migraine: An Imitator of Cerebrovascular Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Acute management focuses on pain control using nonsteroidal
      anti-inflammatory drugs (NSAIDs) and non-narcotic analgesics.
    explanation: >-
      States the acute-phase management approach. This is a narrative review
      section of a single case report, so it records usual practice rather than
      trial evidence, and no efficacy claim is attached.
  notes: >-
    No frequency, dose or comparative-efficacy claim is made. Hemiplegic
    migraine patients are routinely excluded from migraine randomized trials,
    so there is no acute-treatment trial evidence specific to this disorder.
- name: Migraine Prophylaxis
  description: >-
    A trial of standard prophylactic migraine medication - tricyclic
    antidepressants, beta-blockers, calcium channel blockers or anti-seizure
    medications - may be warranted for frequent attacks in any FHM subtype. Note
    that because hemiplegic migraine is rare, most published treatment data are
    case studies rather than trials.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: flunarizine
      term:
        id: CHEBI:135652
        label: flunarizine
    - preferred_term: verapamil
      term:
        id: CHEBI:9948
        label: verapamil
    - preferred_term: lamotrigine
      term:
        id: CHEBI:6367
        label: lamotrigine
    - preferred_term: topiramate
      term:
        id: CHEBI:63631
        label: topiramate
    - preferred_term: valproic acid
      term:
        id: CHEBI:39867
        label: valproic acid
    - preferred_term: amitriptyline
      term:
        id: CHEBI:2666
        label: amitriptyline
  evidence:
  - reference: PMID:41552155
    reference_title: "Hemiplegic Migraine: An Imitator of Cerebrovascular Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Commonly used agents include flunarizine, verapamil, lamotrigine,
      acetazolamide, topiramate, valproic acid, and amitriptyline
    explanation: >-
      Names the individual agents used for prophylaxis, which is what the
      therapeutic_agent list above records. Acetazolamide appears in the same
      list and has its own treatment entry.
  - reference: PMID:41552155
    reference_title: "Hemiplegic Migraine: An Imitator of Cerebrovascular Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      While evidence from randomized trials is unavailable, case series suggest
      potential benefit.
    explanation: >-
      States the strength of the evidence for these agents explicitly. No efficacy claim is made
      here, which limits inference.
  - reference: PMID:20301562
    reference_title: Familial Hemiplegic Migraine.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      a trial of prophylactic migraine medications (e.g., tricyclic
      antidepressants, beta-blockers, calcium channel blockers, anti-seizure
      medications) for all FHM types may be warranted for frequent attacks
    explanation: >-
      GeneReviews management guidance for prophylaxis across all FHM molecular
      subtypes.
  - reference: PMID:37247170
    reference_title: Hemiplegic Migraine.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Given the low prevalence of the disease, most studies regarding treatment
      are limited to case studies. There is still an important need for further
      and larger studies regarding management of these cases.
    explanation: >-
      Records the weakness of the treatment evidence base, which is why no
      efficacy claim is made here.
- name: Anti-Seizure Medication for Comorbid Epilepsy
  description: >-
    Anti-seizure treatment where seizures occur, which is particularly relevant
    in ATP1A2-FHM. Drug-resistant epilepsy is rare across all FHM genotypes.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: anticonvulsant agent
      term:
        id: NCIT:C264
        label: Anticonvulsant Agent
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:20301562
    reference_title: Familial Hemiplegic Migraine.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Anti-seizure treatment may be necessary for seizures, which are prevalent
      in ATP1A2-FHM.
    explanation: GeneReviews management guidance for the epilepsy comorbidity.
  - reference: PMID:33839563
    reference_title: Epilepsy in patients with familial hemiplegic migraine.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In 60 patients for whom the epilepsy prognosis was evaluated, only 3.5% of
      patients were drug-resistant, and the remainder had a self-limited course
      or responded to anti-epileptic drug treatment.
    explanation: >-
      Supports a generally favourable epilepsy prognosis, relevant to counseling.
- name: Corticosteroids for Attack-Associated Cerebral Edema
  description: >-
    Corticosteroids in children with cerebral edema, to reduce life-threatening
    manifestations of a severe attack.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: corticosteroid
      term:
        id: CHEBI:50858
        label: corticosteroid
  target_phenotypes:
  - preferred_term: Cerebral edema
    term:
      id: HP:0002181
      label: Cerebral edema
  evidence:
  - reference: PMID:20301562
    reference_title: Familial Hemiplegic Migraine.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Corticosteroids in children with cerebral edema to reduce life-threatening
      manifestations.
    explanation: >-
      GeneReviews management guidance for the severe cerebral-edema attack
      phenotype.
- name: Avoidance of Vasoconstricting Agents and Cerebral Angiography
  description: >-
    A management constraint rather than an intervention. GeneReviews lists
    vasoconstricting agents (which includes the triptans and ergots used in
    ordinary migraine) as agents to avoid because of stroke risk, and cerebral
    angiography as a circumstance to avoid because it may precipitate a severe
    attack. This is the main way FHM management diverges from typical migraine
    with aura.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20301562
    reference_title: Familial Hemiplegic Migraine.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Agents/circumstances to avoid: Vasoconstricting agents because of the risk
      of stroke; cerebral angiography as it may precipitate a severe attack.
    explanation: >-
      The GeneReviews Agents/Circumstances to Avoid section, recorded verbatim
      because it is a safety constraint.
  - reference: PMID:41552155
    reference_title: "Hemiplegic Migraine: An Imitator of Cerebrovascular Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Triptans and ergot derivatives are contraindicated because of their
      vasoconstrictive effects and potential risk of inducing ischemia.
    explanation: >-
      Names the specific drug classes that "vasoconstricting agents" refers to
      in the GeneReviews wording above, and states the reason.
- name: Genetic Counseling
  description: >-
    Autosomal dominant inheritance with a 50% recurrence risk per child. Once
    the family variant is known, prenatal and preimplantation genetic testing
    are possible.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20301562
    reference_title: Familial Hemiplegic Migraine.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Each child of an individual with FHM has a 50% chance of inheriting the
      pathogenic variant. Once an FHM-causing pathogenic variant has been
      identified in an affected family member, prenatal testing for a pregnancy
      at increased risk and preimplantation genetic testing are possible.
    explanation: GeneReviews genetic counseling guidance.
- name: Neurologic Surveillance
  description: >-
    Annual or more frequent neurologic evaluation for change in attack frequency
    or seizures, and for emergence of a movement disorder, developmental delay
    or learning disability.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:20301562
    reference_title: Familial Hemiplegic Migraine.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Surveillance: Neurologic evaluation to assess change in attack frequency
      and/or seizures, development of movement disorder, developmental delay,
      and/or learning disability annually or more frequently for worsening
      symptoms.
    explanation: GeneReviews surveillance guidance.
diagnosis:
- name: ICHD-Based Clinical Diagnosis
  description: >-
    FHM is diagnosed clinically, on a three-part criterion set: the proband
    fulfils the criteria for migraine with aura, the aura includes fully
    reversible motor weakness together with visual, sensory or language
    symptoms, and at least one first- or second-degree relative has attacks
    meeting the same hemiplegic-migraine criteria. The third clause is what
    separates FHM from sporadic hemiplegic migraine; it is a statement about
    family history, not about mechanism.
  diagnosis_term:
    preferred_term: clinical diagnostic evaluation against the ICHD criteria
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  presence: >-
    Required. A molecular result is confirmatory but is not needed to make the
    diagnosis.
  evidence:
  - reference: PMID:20301562
    reference_title: Familial Hemiplegic Migraine.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical diagnosis of FHM can be established in a proband: (1) who
      fulfills criteria for migraine with aura; (2) in whom the aura includes
      fully reversible motor weakness and visual, sensory, or language symptoms;
      and (3) who has at least one first- or second-degree relative with similar
      attacks that fulfill the diagnostic criteria for hemiplegic migraine.
    explanation: >-
      The GeneReviews Diagnosis/Testing statement of the three-part clinical
      criteria, which is what this diagnosis entry records.
  - reference: PMID:41552155
    reference_title: "Hemiplegic Migraine: An Imitator of Cerebrovascular Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      include recurrent episodes of migraine with fully reversible motor
      weakness and other aura symptoms (visual, sensory, or language-related)
    explanation: >-
      Restates the criteria in ICHD-3 terms and adds the aura timing, confirming
      that the GeneReviews formulation tracks the current classification.
  - reference: DOI:10.1186/s10194-021-01228-4
    reference_title: >-
      Reference programme: diagnosis and treatment of headache disorders and facial pain. Danish
      Headache Society, 3rd edition, 2020
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The guideline first describes how to examine and diagnose the headache
      patient and how headache treatment is organized in Denmark.
    explanation: >-
      A current national reference programme covering the examination and
      diagnosis of the headache patient, which is the general clinical framework
      within which the FHM-specific criteria above are applied. It is a
      consensus guideline rather than a study, hence evidence_source OTHER.
  - reference: DOI:10.1186/s10194-021-01228-4
    reference_title: >-
      Reference programme: diagnosis and treatment of headache disorders and facial pain. Danish
      Headache Society, 3rd edition, 2020
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The recommendations for the primary headaches and facial pain are largely
      in accordance with the European guidelines produced by the European
      Academy of Neurology.
    explanation: >-
      Records that this reference programme is concordant with the European
      Academy of Neurology guidance, so it is not a purely local convention.
  notes: >-
    The Danish reference programme is cached abstract-only, so the two quotes
    above are the strongest claims it can support here. It is cited for the
    general diagnostic framework, not for any FHM-specific criterion; the
    FHM-specific criteria come from GeneReviews and ICHD-3.
- name: Molecular Genetic Testing of ATP1A2, CACNA1A, PRRT2 and SCN1A
  description: >-
    Identification of a heterozygous pathogenic variant in one of the four
    hemiplegic-migraine genes establishes the molecular diagnosis and assigns
    the subtype. It is confirmatory rather than required: a large majority of
    clinically diagnosed patients are mutation-negative on these four genes,
    so a negative panel does not exclude FHM.
  diagnosis_term:
    preferred_term: molecular genetic testing of the hemiplegic-migraine genes
    term:
      id: NCIT:C15709
      label: Genetic Testing
  presence: >-
    Confirmatory. Positive in a minority of clinically diagnosed patients.
  evidence:
  - reference: PMID:20301562
    reference_title: Familial Hemiplegic Migraine.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The molecular diagnosis can be established in a proband by identification
      of a heterozygous pathogenic variant in ATP1A2, CACNA1A, PRRT2, or SCN1A.
    explanation: >-
      The GeneReviews molecular-diagnosis sentence, naming the four genes that
      constitute the diagnostic panel.
  - reference: PMID:34649875
    reference_title: >-
      Hemiplegic Migraine Associated With PRRT2 Variations: A Clinical and Genetic Study.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      PRRT2 should be regarded as the fourth autosomal dominant gene for
      hemiplegic migraine and screened in any affected patient, together with
      the 3 other main genes.
    explanation: >-
      Supports testing all four genes rather than the classical three, which is
      why PRRT2 appears in the panel above.
  - reference: PMID:41552155
    reference_title: "Hemiplegic Migraine: An Imitator of Cerebrovascular Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, routine genetic testing is not required for diagnosis and is
      reserved for atypical or severe cases.
    explanation: >-
      Establishes that the test is confirmatory rather than diagnostic, which is
      what the presence field records.
  - reference: PMID:41552155
    reference_title: "Hemiplegic Migraine: An Imitator of Cerebrovascular Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A Danish population-based study found that only 14% of familial hemiplegic
      migraine patients had mutations in these genes, suggesting additional
      unidentified genetic factors
    explanation: >-
      Quantifies the low diagnostic yield, which is why a negative panel does
      not exclude the clinical diagnosis. This is a review restating a
      population-based result rather than the primary report.
  - reference: DOI:10.3390/genes15040443
    reference_title: >-
      Unravelling the Genetic Landscape of Hemiplegic Migraine: Exploring Innovative Strategies and
      Emerging Approaches
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, approximately 75% of HM patients are negative for these
      mutations, indicating there are other genes involved in disease causation.
    explanation: >-
      An independent estimate of the proportion of clinically diagnosed patients
      left unexplained by the four-gene panel. Cited here in its DOI form
      because that is how the review was cached; the same review's full text is
      cited elsewhere in this entry as PMID:38674378.
- name: Neuroimaging to Exclude Stroke and Other Secondary Causes
  description: >-
    Because the motor deficit mimics an acute cerebrovascular event, patients
    are commonly imaged urgently. Structural imaging is typically normal in
    hemiplegic migraine, and its role is exclusion of infarction, haemorrhage
    and other secondary causes rather than positive confirmation of FHM.
  diagnosis_term:
    preferred_term: neuroimaging
    term:
      id: NCIT:C173635
      label: Neuroimaging
  presence: >-
    Typically normal. Used to exclude alternative diagnoses, not to confirm FHM.
  evidence:
  - reference: PMID:41552155
    reference_title: "Hemiplegic Migraine: An Imitator of Cerebrovascular Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Given its overlapping presentation with cerebrovascular events, hemiplegic
      migraine can easily be mistaken for ischemic stroke or TIA.
    explanation: >-
      Establishes the differential that drives urgent imaging in a suspected
      attack.
  - reference: PMID:41552155
    reference_title: "Hemiplegic Migraine: An Imitator of Cerebrovascular Disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although structural imaging is often normal in hemiplegic migraine, early
      presentation before symptom resolution can prompt unnecessary therapy.
    explanation: >-
      Records that a normal scan is the expected finding, so imaging is an
      exclusion test here. This is a single case report with a literature
      discussion, so no frequency is asserted.
  - reference: DOI:10.3389/fped.2023.1214837
    reference_title: >-
      Two pediatric patients with hemiplegic migraine presenting as acute encephalopathy: case reports
      and a literature review
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Physicians should consider HM in the differential diagnosis of patients
      presenting with somnolence, coma, or convulsion without structural,
      epileptic, infectious, or inflammatory explanation.
    explanation: >-
      States the paediatric version of the exclusion logic: once structural,
      epileptic, infectious and inflammatory causes are excluded, hemiplegic
      migraine belongs in the differential rather than being a diagnosis of
      last resort.
differential_diagnoses:
- name: Migraine with aura
  disease_term:
    preferred_term: migraine with aura
    term:
      id: MONDO:0005475
      label: migraine with aura
  description: >-
    FHM sits inside the migraine-with-aura category and shares its cortical
    spreading depression biology; what separates them is the obligatory
    reversible motor weakness in FHM and the family history requirement.
  distinguishing_features:
  - Motor weakness is obligatory in FHM and absent in ordinary migraine with aura.
  - FHM requires at least one affected first- or second-degree relative.
  - >-
    FHM deficits can last hours to days and outlast the headache, whereas typical
    aura symptoms resolve within an hour.
  - >-
    Familial non-hemiplegic migraine with aura is the nearer differential than
    sporadic migraine with aura, because it shares the familial aggregation
    without the motor weakness. It too differs from population migraine with
    aura - earlier onset, later cessation, more severe aura - so a family
    history plus a severe aura is not by itself evidence of FHM.
  evidence:
  - reference: PMID:20301562
    reference_title: Familial Hemiplegic Migraine.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical diagnosis of FHM can be established in a proband: (1) who
      fulfills criteria for migraine with aura; (2) in whom the aura includes
      fully reversible motor weakness and visual, sensory, or language symptoms;
      and (3) who has at least one first- or second-degree relative with similar
      attacks that fulfill the diagnostic criteria for hemiplegic migraine.
    explanation: >-
      States the three criteria that separate FHM from ordinary migraine with
      aura.
  - reference: PMID:15196299
    reference_title: Clinical characteristics of 362 patients with familial migraine with aura.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Several clinical characteristics of familial NHMA differed from migraine
      with aura in the general population: firstly, the age at onset was lower,
      secondly, the age at cessation was higher, thirdly, aura symptoms were
      more severe and finally, the co-occurrence of migraine without aura was
      higher in familial NHMA.
    explanation: >-
      Characterizes familial non-hemiplegic migraine with aura, the sibling
      entity ascertained by the same Danish group and methodology as the FHM
      series used elsewhere in this entry. It shows that early onset and severe
      aura in a family are features of familial migraine with aura in general,
      not discriminators for FHM - the motor weakness is.
  - reference: PMID:15196299
    reference_title: Clinical characteristics of 362 patients with familial migraine with aura.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Visual aura occurred in almost every NHMA attack.
    explanation: >-
      The comparator for the FHM aura profile: visual aura dominates familial
      non-hemiplegic attacks, whereas FHM attacks usually carry all four typical
      aura modalities together.
- name: Alternating hemiplegia of childhood
  disease_term:
    preferred_term: alternating hemiplegia of childhood
    term:
      id: MONDO:0016241
      label: alternating hemiplegia of childhood
  description: >-
    AHC shares episodic hemiplegia with FHM and, like FHM2, involves a
    Na+/K+-ATPase alpha subunit - but the two are different genes, not one
    shared locus. AHC is caused by ATP1A3 and FHM2 by ATP1A2, paralogous alpha
    isoforms of the same pump with different cellular distributions (ATP1A3 is
    neuronal, ATP1A2 astrocytic in the adult brain). The overlap is therefore
    family-level paralogy rather than allelism, and the inheritance patterns
    differ correspondingly: AHC is usually sporadic and de novo, whereas the
    FHM diagnosis requires an affected first- or second-degree relative.
  distinguishing_features:
  - >-
    AHC is an ATP1A3 disorder; ATP1A2 is the FHM2 gene, and sporadic AHC has not
    been attributed to ATP1A2.
  - >-
    AHC begins in infancy, typically before 18 months, with attacks that
    alternate sides, remit with sleep, and carry dystonia and nystagmus.
  - >-
    Headache is the dominant feature of an FHM attack and is not required in
    AHC; AHC additionally carries persistent developmental impairment between
    attacks, which FHM does not.
  - >-
    AHC arises mostly from de novo variants and is usually sporadic, whereas
    autosomal dominant transmission with an affected relative is definitional
    for FHM.
  evidence:
  - reference: PMID:22842232
    reference_title: De novo mutations in ATP1A3 cause alternating hemiplegia of childhood.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This work identifies de novo ATP1A3 mutations as the primary cause of AHC
      and offers insight into disease pathophysiology by expanding the spectrum
      of phenotypes associated with mutations in ATP1A3.
    explanation: >-
      Establishes ATP1A3 as the AHC gene, which is what separates AHC from the
      ATP1A2-associated FHM2 subtype curated here.
  - reference: PMID:22842232
    reference_title: De novo mutations in ATP1A3 cause alternating hemiplegia of childhood.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To date, no cases of sporadic AHC have been attributed to ATP1A2
      mutations.
    explanation: >-
      States the gene boundary directly: the FHM2 gene ATP1A2 does not account
      for sporadic AHC, so the shared Na+/K+-ATPase involvement is paralogy
      between two disorders rather than a shared cause.
- name: Sporadic hemiplegic migraine
  description: >-
    Clinically and genetically indistinguishable from FHM apart from the absence
    of an affected first- or second-degree relative; it is about as common as the
    familial form, and an apparently negative family history does not exclude an
    FHM-gene variant.
  distinguishing_features:
  - No affected first- or second-degree relative with hemiplegic attacks.
  - >-
    May carry a de novo variant in an FHM gene, or one inherited from an
    asymptomatic parent, so molecular testing does not distinguish the two.
  evidence:
  - reference: PMID:12110112
    reference_title: An epidemiological survey of hemiplegic migraine.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      147 were familial HM from 44 different families, 105 were sporadic HM and
      39 were unclassifiable HM.
    explanation: >-
      Shows sporadic hemiplegic migraine to be comparably frequent in
      population-based case-finding.
- name: Stroke and transient ischemic attack
  description: >-
    Any condition causing transitory focal neurological signs enters the
    differential; the breadth of that differential is why neuroimaging and
    workup are recommended before settling on hemiplegic migraine, and it is the
    reason vasoconstricting agents are avoided.
  distinguishing_features:
  - >-
    FHM deficits develop gradually and are fully reversible, with a stereotyped
    attack pattern and a positive family history.
  - Neuroimaging, CSF analysis and EEG are used to exclude structural and vascular causes.
  evidence:
  - reference: PMID:32430436
    reference_title: Diagnostic and therapeutic aspects of hemiplegic migraine.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The differential diagnosis of HM is broad, including other types of
      migraine and any condition that can cause transitory neurological signs
      and symptoms. Neuroimaging, cerebrospinal fluid analysis and
      electroencephalography are useful, but the diagnosis is clinical with a
      genetic confirmation.
    explanation: >-
      States the breadth of the differential and the role of investigations in
      excluding mimics.
animal_models:
- name: Cacna1a R192Q knock-in mouse (FHM1, pure hemiplegic migraine allele)
  species: Mouse
  genotype: Cacna1a R192Q knock-in (human pure FHM1 allele)
  genes:
  - preferred_term: CACNA1A
    term:
      id: hgnc:1388
      label: CACNA1A
  publication: PMID:15003170
  description: >-
    The founding FHM1 model, carrying the human R192Q allele that causes pure
    hemiplegic migraine without cerebellar signs. It supplies the in vivo
    measurement on which this entry's central mechanistic claim rests - a
    reduced cortical spreading depression threshold and increased propagation
    velocity in the intact animal - and, through the companion synaptic study,
    the reason for it: a synapse-specific gain of function at excitatory
    pyramidal-cell synapses with inhibitory transmission left intact.
  evidence:
  - reference: PMID:15003170
    reference_title: >-
      A Cacna1a knockin migraine mouse model with increased susceptibility to cortical spreading
      depression.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The R192Q FHM-1 mouse is a promising animal model to study migraine
      mechanisms and treatments.
    explanation: >-
      The authors' own framing of this knock-in as a model for the human
      mechanism, which is what the links below rely on.
  modeled_mechanisms:
  - target: Facilitated Cortical Spreading Depolarization
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The in vivo CSD threshold and velocity measurement that grounds the
      unifying node of this entry.
    limitations: >-
      The threshold is measured as susceptibility to an experimentally applied
      stimulus in anaesthetised mouse cortex, which is not the same quantity
      as whatever initiates a spontaneous human attack. The mouse cortex is
      also lissencephalic and lacks the motor-cortex geometry a wave would
      have to traverse to produce human hemiparesis. This link is the
      structural counterpart of the HUMAN_MODEL_MISMATCH discussion.
    evidence:
    - reference: PMID:15003170
      reference_title: >-
        A Cacna1a knockin migraine mouse model with increased susceptibility to cortical spreading
        depression.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Our data show that the increased susceptibility for CSD and aura in
        migraine may be due to cortical hyperexcitability.
      explanation: >-
        The authors' interpretation of what this model demonstrates about the
        threshold node, as distinct from the individual measurements recorded
        as readouts below.
    readouts:
    - name: Cortical spreading depression induction threshold
      target: Facilitated Cortical Spreading Depolarization
      description: >-
        Stimulus intensity required to ignite CSD in the intact animal.
      direction: DECREASED
      biological_processes:
      - preferred_term: cortical spreading depolarization
        term:
          id: GO:0051899
          label: membrane depolarization
        modifier: INCREASED
      interpretation: >-
        A lower induction threshold is the direct measurement behind the
        threshold node.
      evidence:
      - reference: PMID:15003170
        reference_title: >-
          A Cacna1a knockin migraine mouse model with increased susceptibility to cortical spreading
          depression.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          in the intact animal, a reduced threshold and increased velocity of
          cortical spreading depression
        explanation: >-
          Reports the threshold measurement in vivo.
    - name: Cortical spreading depression propagation velocity
      target: Facilitated Cortical Spreading Depolarization
      description: >-
        Speed at which the depolarization wave travels across cortex.
      direction: INCREASED
      interpretation: >-
        Faster propagation accompanies the lowered threshold, so the cortex
        both enters and spreads CSD more readily.
      evidence:
      - reference: PMID:15003170
        reference_title: >-
          A Cacna1a knockin migraine mouse model with increased susceptibility to cortical spreading
          depression.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          a reduced threshold and increased velocity of cortical spreading
          depression (CSD; the likely mechanism for the migraine aura)
        explanation: >-
          Reports the propagation-velocity measurement in vivo.
  - target: Increased Cortical Glutamatergic Excitability
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Cortical microcultures and slices from this model show increased
      action-potential-evoked Ca2+ influx and increased glutamate release probability
      at pyramidal-cell synapses, with fast-spiking interneuron synapses
      unaltered - the synapse specificity that makes this an
      excitation-inhibition imbalance rather than a global change.
    limitations: >-
      Measured in microcultures and acute slices rather than in the intact
      animal, and the causative link to CSD is established in an in vitro CSD
      model.
    readouts:
    - name: Glutamate release probability at cortical pyramidal cell synapses
      target: Increased Cortical Glutamatergic Excitability
      direction: INCREASED
      biological_processes:
      - preferred_term: glutamate secretion
        term:
          id: GO:0014047
          label: glutamate secretion
        modifier: INCREASED
      interpretation: >-
        The presynaptic measurement that connects Cav2.1 gain of function to
        cortical hyperexcitability.
      evidence:
      - reference: PMID:19285472
        reference_title: >-
          Enhanced excitatory transmission at cortical synapses as the basis for facilitated spreading
          depression in Ca(v)2.1 knockin migraine mice.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          increased action-potential-evoked Ca(2+) influx and increased
          probability of glutamate release at pyramidal cell synapses but
          unaltered inhibitory neurotransmission at fast-spiking interneuron
          synapses
        explanation: >-
          Reports the synapse-specific presynaptic measurement. Neuronal
          microcultures and brain slices, hence IN_VITRO rather than
          MODEL_ORGANISM.
    evidence:
    - reference: PMID:19285472
      reference_title: >-
        Enhanced excitatory transmission at cortical synapses as the basis for facilitated spreading
        depression in Ca(v)2.1 knockin migraine mice.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Using an in vitro model of CSD, we show a causative link between
        enhanced glutamate release and CSD facilitation.
      explanation: >-
        Establishes that the synaptic change in this model is causative for
        CSD facilitation, which is why the model is treated as informative for
        this node.
- name: Cacna1a S218L knock-in mouse (FHM1, severe allele)
  species: Mouse
  genotype: Cacna1a S218L knock-in (human severe FHM1 allele)
  genes:
  - preferred_term: CACNA1A
    term:
      id: hgnc:1388
      label: CACNA1A
  publication: PMID:20186955
  description: >-
    The severe-allele counterpart of the R192Q model. It is the model that explains why a trivial
    head injury has a non-trivial consequence in S218L carriers: the mutant cortex not only has a
    lower CSD threshold than R192Q but responds to a single stimulus with repeated CSD events, making
    it vulnerable to weak stimuli. The two FHM1 models together give an allele-severity gradient
    that matches the human one. The model was built to explain the trauma-triggered cerebral edema
    of the human S218L syndrome, and the authors present the low threshold and repeated CSD events
    as its mechanistic basis. PARTIALLY, not fully: the cited work offers the CSD phenotype as a
    proposed mechanistic basis for the severe human syndrome rather than reporting trauma-triggered
    cerebral edema as a measured outcome in the mouse. The link records the proposed explanation,
    not a reproduced clinical event.
  evidence:
  - reference: PMID:20186955
    reference_title: >-
      High cortical spreading depression susceptibility and migraine-associated symptoms in Ca(v)2.1
      S218L mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Cacna1a(S218L) mice faithfully mimic the associated clinical features of
      the human S218L syndrome.
    explanation: >-
      The authors' assessment of phenotypic correspondence, which is the basis
      for the HIGH fidelity assigned to the threshold link below.
  - reference: PMID:20186955
    reference_title: >-
      High cortical spreading depression susceptibility and migraine-associated symptoms in Ca(v)2.1
      S218L mice.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      may provide a mechanistic basis for the dramatic phenotype seen in
      S218L mice and patients. Thus, the S218L mouse model may prove a
      valuable tool to further elucidate mechanisms underlying migraine,
      seizures, ataxia, and trauma-triggered cerebral edema.
    explanation: >-
      The authors propose a mechanistic basis for the severe syndrome; this is not a demonstration
      of trauma-triggered edema in the mouse.
  modeled_mechanisms:
  - target: Facilitated Cortical Spreading Depolarization
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      An exaggerated version of the R192Q threshold phenotype, with multiple
      CSD events following a single trigger.
    limitations: >-
      The same anaesthetised-cortex and species caveats as the R192Q model
      apply. HIGH here refers to correspondence with the human S218L syndrome
      specifically, which is the narrowest and best-matched of the FHM
      genotype-phenotype pairings; it should not be read as a claim about FHM
      in general.
    evidence:
    - reference: PMID:20186955
      reference_title: >-
        High cortical spreading depression susceptibility and migraine-associated symptoms in Ca(v)2.1
        S218L mice.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        We introduced the S218L mutation into the mouse Cacna1a gene and studied
        the mechanisms for the S218L syndrome by analyzing the phenotypic,
        molecular, and electrophysiological consequences.
      explanation: >-
        Establishes that this is a knock-in of the human allele characterized
        phenotypically, molecularly and electrophysiologically, which is what
        makes it informative for the threshold node.
    readouts:
    - name: Cortical spreading depression induction threshold
      target: Facilitated Cortical Spreading Depolarization
      description: >-
        Stimulus required to induce CSD; the measured threshold is decreased.
      direction: DECREASED
      interpretation: >-
        The vastly reduced threshold plus repeated events after one stimulus
        is what distinguishes the severe allele from R192Q, where one stimulus
        typically yields one event.
      evidence:
      - reference: PMID:20186955
        reference_title: >-
          High cortical spreading depression susceptibility and migraine-associated symptoms in Ca(v)2.1
          S218L mice.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          an exquisite sensitivity to cortical spreading depression (CSD),
          with a vastly reduced triggering threshold, an increased propagation
          velocity, and frequently multiple CSD events after a single stimulus
        explanation: >-
          Reports the threshold, velocity and event-count measurements.
    - name: Cortical spreading depression propagation velocity
      target: Facilitated Cortical Spreading Depolarization
      description: >-
        Speed of the propagating CSD wave; this increases rather than decreases.
      direction: INCREASED
      interpretation: >-
        The propagation-speed readout is distinct from the induction threshold.
      evidence:
      - reference: PMID:20186955
        reference_title: >-
          High cortical spreading depression susceptibility and migraine-associated symptoms in Ca(v)2.1
          S218L mice.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          an exquisite sensitivity to cortical spreading depression (CSD),
          with a vastly reduced triggering threshold, an increased propagation
          velocity, and frequently multiple CSD events after a single stimulus
        explanation: >-
          Reports the threshold, velocity and event-count measurements.
    - name: Repeated CSD events after a single stimulus
      target: Facilitated Cortical Spreading Depolarization
      description: >-
        Multiple events after one trigger in S218L mice.
      direction: INCREASED
      interpretation: >-
        Repeated events distinguish the severe S218L response from the typical single R192Q event.
      evidence:
      - reference: PMID:20186955
        reference_title: >-
          High cortical spreading depression susceptibility and migraine-associated symptoms in Ca(v)2.1
          S218L mice.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          an exquisite sensitivity to cortical spreading depression (CSD),
          with a vastly reduced triggering threshold, an increased propagation
          velocity, and frequently multiple CSD events after a single stimulus
        explanation: >-
          Reports the threshold, velocity and event-count measurements.
      - reference: PMID:20186955
        reference_title: >-
          High cortical spreading depression susceptibility and migraine-associated symptoms in Ca(v)2.1
          S218L mice.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          In contrast, mice bearing the R192Q CACNA1A mutation, which in
          humans causes a milder form of hemiplegic migraine, typically
          exhibit only a single CSD event after one triggering stimulus.
        explanation: >-
          The direct comparison with the milder allele, which is what makes
          the event count an allele-severity readout rather than an isolated
          number.
- name: Atp1a2 W887R knock-in mouse (FHM2)
  species: Mouse
  genotype: Atp1a2 W887R knock-in, heterozygous (homozygotes die after birth)
  genes:
  - preferred_term: ATP1A2
    term:
      id: hgnc:800
      label: ATP1A2
  publication: PMID:21731499
  description: >-
    The first FHM2 model. It is the source of two separate claims in this entry: that the FHM2 variant
    acts by loss of the alpha2 pump through ER retention and proteasomal degradation, and that the
    resulting cortex has a lowered CSD threshold - the finding that lets FHM1 and FHM2 be drawn as
    converging on one node. It is also the entry's clearest negative result: heterozygous mutants
    have the cortical phenotype without any apparent clinical phenotype. The heterozygous FHM2 mouse
    - the genotype that matches the human heterozygous patient - shows no apparent clinical phenotype
    despite carrying the cortical CSD phenotype. The model reproduces the mechanism and not the disease.
    This is the negative result behind the entry's HUMAN_MODEL_MISMATCH discussion, and it is a substantive
    one: it means the step from a lowered CSD threshold to an episodic hemiparetic attack is not
    demonstrated in the one model where both could have been observed together. Mouse hemiparesis
    is also harder to ascertain than human hemiparesis, so absence of an apparent phenotype is weaker
    than a demonstration of absence - but it is what the cited work reports.
  evidence:
  - reference: PMID:21731499
    reference_title: >-
      Increased susceptibility to cortical spreading depression in the mouse model of familial hemiplegic
      migraine type 2.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We generated the first FHM2 knock-in mouse model carrying the human
      W887R mutation in the Atp1a2 orthologous gene.
    explanation: >-
      Establishes the model and its genotype.
  - reference: PMID:21731499
    reference_title: >-
      Increased susceptibility to cortical spreading depression in the mouse model of familial hemiplegic
      migraine type 2.
    supports: REFUTE
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Homozygous Atp1a2(R887/R887) mutants died just after birth, while
      heterozygous Atp1a2(+/R887) mice showed no apparent clinical
      phenotype.
    explanation: >-
      Reports directly that the heterozygous model does not display a
      clinical phenotype, which is what a FAILS_TO_RECAPITULATE link
      asserts.

  modeled_mechanisms:
  - target: Facilitated Cortical Spreading Depolarization
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The FHM2 in vivo threshold and velocity measurement, matching the FHM1
      result and supporting the convergence drawn at this node.
    limitations: >-
      The 2011 study measured provoked CSD in anesthetized cortex and proposed a clearance deficit;
      the 2016 follow-up directly tested astrocytic clearance in slices. Neither establishes the
      complete spontaneous human attack phenotype.
    evidence:
    - reference: PMID:21731499
      reference_title: >-
        Increased susceptibility to cortical spreading depression in the mouse model of familial
        hemiplegic migraine type 2.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        The demonstration that FHM2 and FHM1 mutations share the ability to
        facilitate induction and propagation of CSD in mouse models further
        support the role of CSD as a key migraine trigger.
      explanation: >-
        The authors' statement of what this model contributes to the shared
        threshold node, which is the convergence claim that node makes.
    readouts:
    - name: Cortical spreading depression induction threshold
      target: Facilitated Cortical Spreading Depolarization
      direction: DECREASED
      interpretation: >-
        The FHM2 counterpart of the FHM1 threshold readout, measured in vivo
        in the heterozygous mutant.
      evidence:
      - reference: PMID:21731499
        reference_title: >-
          Increased susceptibility to cortical spreading depression in the mouse model of familial
          hemiplegic migraine type 2.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          In vivo analysis of cortical spreading depression (CSD), the
          phenomenon underlying migraine aura, revealed a decreased induction
          threshold and an increased velocity of propagation in the
          heterozygous FHM2 mouse.
        explanation: >-
          Reports the in vivo threshold and velocity measurements.
      description: >-
        Stimulus required to induce CSD; the measured threshold is decreased.
    - name: Cortical spreading depression propagation velocity
      target: Facilitated Cortical Spreading Depolarization
      direction: INCREASED
      interpretation: >-
        The propagation-speed readout is distinct from the induction threshold.
      evidence:
      - reference: PMID:21731499
        reference_title: >-
          Increased susceptibility to cortical spreading depression in the mouse model of familial
          hemiplegic migraine type 2.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          In vivo analysis of cortical spreading depression (CSD), the
          phenomenon underlying migraine aura, revealed a decreased induction
          threshold and an increased velocity of propagation in the
          heterozygous FHM2 mouse.
        explanation: >-
          Reports the in vivo threshold and velocity measurements.
      description: >-
        Speed of the propagating CSD wave; this increases rather than decreases.
  - target: Astrocytic Na+/K+-ATPase Alpha2 Loss of Function
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      The molecular lesion itself: mutant alpha2 protein is strongly reduced
      in the brain of heterozygous mutants, consistent with ER retention and
      proteasomal degradation.
    limitations: >-
      Protein loss is measured in mouse brain; the ER-retention and
      degradation mechanism is demonstrated in transfected cells rather than
      in vivo.
    evidence:
    - reference: PMID:21731499
      reference_title: >-
        Increased susceptibility to cortical spreading depression in the mouse model of familial
        hemiplegic migraine type 2.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        likely as a consequence of endoplasmic reticulum retention and
        subsequent proteasomal degradation, as we demonstrate in transfected
        cells
      explanation: >-
        The mechanism by which the variant produces loss of function. Graded
        IN_VITRO because the authors state that this part was shown in
        transfected cells rather than in the mouse.
    readouts:
    - name: Brain alpha2 Na,K-ATPase protein abundance
      target: Astrocytic Na+/K+-ATPase Alpha2 Loss of Function
      direction: DECREASED
      interpretation: >-
        Reduced protein rather than altered pump kinetics is the readout that
        makes this a loss-of-function node.
      evidence:
      - reference: PMID:21731499
        reference_title: >-
          Increased susceptibility to cortical spreading depression in the mouse model of familial
          hemiplegic migraine type 2.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          The mutant alpha2 Na,K-ATPase protein was barely detectable in the
          brain of homozygous mutants and strongly reduced in the brain of
          heterozygous mutants
        explanation: >-
          Reports the protein-abundance measurement.
clinical_trials:
- name: NCT00541736
  phase: NOT_APPLICABLE
  status: COMPLETED
  description: >-
    Glyceryl trinitrate (GTN) provocation in genotyped FHM patients and healthy
    volunteers, 30 participants, completed 2008. A mechanistic study, not a
    treatment trial: GTN reliably provokes migraine in ordinary migraine
    sufferers, so the question was whether an FHM gene defect changes that
    response. It is recorded here because it is one of only two registered
    interventional studies in this disorder, and because a negative or divergent
    provocation response bears on the entry's mechanism.
  target_phenotypes:
  - preferred_term: Headache
    term:
      id: HP:0002315
      label: Headache
  - preferred_term: Migraine with aura
    term:
      id: HP:0002077
      label: Migraine with aura
  evidence:
  - reference: clinicaltrials:NCT00541736
    reference_title: >-
      Glyceryl-Trinitrate-Induced Headache in Patients With Familial Hemiplegic
      Migraine
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The aim of the present study is to explore the importance of migraine
      genes on the headache/migraine responses after GTN in FHM-patients and
      healthy volunteers.
    explanation: >-
      The registered aim, which establishes this as a gene-directed provocation
      study rather than a therapeutic trial.
  notes: >-
    Phase is NOT_APPLICABLE because the registry records the study as
    interventional with phase NA - a human provocation paradigm does not carry
    an FDA phase. No results are curated: the registry entry has no posted
    results and no linked publication was verified for this identifier, so
    nothing is asserted about the outcome.
- name: NCT00358839
  phase: NOT_APPLICABLE
  status: COMPLETED
  description: >-
    Calcitonin gene-related peptide (CGRP) infusion in genetically confirmed
    FHM1 and FHM2 patients and controls, enrollment 20, completed 2006. Like the
    GTN study it is a mechanistic provocation paradigm, and it is the more
    directly relevant of the two here because it tests the CGRP pathway that
    underlies the modern migraine-specific drug classes in patients whose
    causal ion-transport lesion is known.
  target_phenotypes:
  - preferred_term: Headache
    term:
      id: HP:0002315
      label: Headache
  evidence:
  - reference: clinicaltrials:NCT00358839
    reference_title: >-
      Calcitonin Gene Related Peptide-Induced Headache in Patients With Familial
      Hemiplegic Migraine Type 1 and 2.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The aim of the present study is to explore functional consequences of
      migraine gene mutations on their responses to Calcitonin Gene Related
      Peptide (CGRP)infusion.
    explanation: >-
      The registered aim, establishing the genotype-stratified CGRP provocation
      design.
  notes: >-
    Recorded for the same reasons and with the same limits as NCT00541736. The
    snippet reproduces the registry text verbatim, including its missing space
    before "infusion".

references:
- reference: PMID:20301562
  title: Familial Hemiplegic Migraine.
  tags:
  - GeneReviews
- reference: DOI:10.1016/S1474-4422(24)00026-7
  title: "Genetics of migraine: complexity, implications, and potential clinical applications"
  findings:
  - statement: >-
      Listed as background reading only. It is deliberately not used as evidence
      anywhere in this entry, because the cached record for this DOI has an
      empty body (content_type unavailable), so no snippet could be verified
      against it.
- reference: PMID:10202246
  title: Familial hemiplegic migraine with cerebellar ataxia and paroxysmal psychosis.
- reference: PMID:12756131
  title: 'Expanding the phenotypic spectrum of the CACNA1A gene T666M mutation: a description of
    5 families with familial hemiplegic migraine.'
- reference: PMID:15159495
  title: Variability of familial hemiplegic migraine with novel A1A2 Na+/K+-ATPase variants.
- reference: PMID:15985592
  title: Opening of the blood-brain barrier preceding cortical edema in a severe attack of FHM
    type II.
- reference: PMID:21490217
  title: Enhanced subcortical spreading depression in familial hemiplegic migraine type 1
    mutant mice.
- reference: PMID:23115190
  title: Cerebellar ataxia by enhanced Ca(V)2.1 currents is alleviated by Ca2+-dependent
    K+-channel activators in Cacna1a(S218L) mutant mice.
- reference: PMID:25143767
  title: Familial hemiplegic migraine and spreading depression.
- reference: PMID:27354390
  title: Defective glutamate and K+ clearance by cortical astrocytes in familial hemiplegic
    migraine type 2.
- reference: PMID:34546973
  title: Hyperexcitable interneurons trigger cortical spreading depression in an Scn1a migraine
    model.
- reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1388/
  title: Familial Hemiplegic Migraine - GeneReviews® - NCBI Bookshelf
- reference: DOI:10.3389/fncel.2017.00263
  title: Cerebellar Atrophy and Changes in Cytokines Associated with the CACNA1A R583Q Mutation
    in a Russian Familial Hemiplegic Migraine Type 1 Family
discussions:
- discussion_id: gap_fhm_shared_csd_convergence
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Do the three FHM genes lower the cortical spreading depression threshold
    through one shared final mechanism, or through separate routes that happen
    to converge on the same clinical outcome?
  attaches_to:
  - pathophysiology#Facilitated Cortical Spreading Depolarization
  - pathophysiology#Increased Cortical Glutamatergic Excitability
  - pathophysiology#Cortical Interneuron Hyperactivity
  rationale: >-
    FHM1 and FHM2 have experimentally supported glutamatergic routes to CSD; the W887R/+ clearance
    deficit is directly measured in the 2016 study. FHM3 differs: acute activation experiments and
    the L1649Q knock-in support interneuron spiking and potassium accumulation without requiring
    glutamatergic synaptic transmission for initiation. A universal quantitative threshold-setting
    mechanism across the three subtypes remains unresolved, and these data do not establish the PRRT2
    route.
  proposed_experiments:
  - experiment_id: exp_fhm_cross_subtype_csd_threshold
    name: Cross-subtype comparison of CSD threshold determinants
    description: >-
      Measure CSD threshold together with extracellular K+ and glutamate
      transients in FHM1 (CACNA1A), FHM2 (ATP1A2) and FHM3 (SCN1A) knock-in
      cortex under one protocol, then test whether blocking glutamatergic
      transmission or buffering extracellular K+ abolishes the threshold shift
      in each. A K+ manipulation that rescues all three, where glutamatergic
      blockade rescues only FHM1 and FHM2, would establish extracellular K+ as
      the shared final common path rather than glutamate.
  evidence:
  - reference: PMID:27354390
    reference_title: Defective glutamate and K+ clearance by cortical astrocytes in familial
      hemiplegic migraine type 2.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Using ceftriaxone treatment of FHM2 mutants and partial inhibition of glutamate transporters
      in wild-type mice, we obtain evidence that defective glutamate clearance can account for most
      of the facilitation of CSD initiation in FHM2-knockin mice
    explanation: >-
      CSD recordings in cortical slices after mutant-mouse treatment or transporter inhibition support
      a causal clearance contribution. Ceftriaxone produced only a small rescue and did not restore
      perisynaptic astrocytic transporter density; this is not evidence of clinical drug efficacy.
  - reference: PMID:34491914
    reference_title: Initiation of migraine-related cortical spreading depolarization by
      hyperactivity of GABAergic neurons and NaV1.1 channels.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here, we show that acute pharmacological activation of NaV1.1 (the main Na+ channel of interneurons)
      or optogenetic-induced hyperactivity of GABAergic interneurons is sufficient to ignite CSD
      in the neocortex by spiking-generated extracellular K+ build-up.
    explanation: >-
      Pharmacologic and optogenetic acute-slice experiments support the spiking/potassium route;
      they mimic FHM3 activity rather than carrying an FHM allele.
  - reference: PMID:34546973
    reference_title: Hyperexcitable interneurons trigger cortical spreading depression in an
      Scn1a migraine model.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Brain slice recordings using K+-sensitive electrodes revealed an increase in extracellular
      K+ in the early phase of CSD in heterozygous mice, likely representing the mechanistic link
      between interneuron hyperactivity and CSD initiation.
    explanation: >-
      The L1649Q genetic model independently supports the potassium intermediary, which the authors
      explicitly qualify as likely.
    directness: INDIRECT
- discussion_id: mismatch_fhm_csd_human_attack
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Does the reduced cortical spreading depression threshold measured in FHM
    knock-in mice actually explain the hemiparetic aura of a human FHM attack?
  attaches_to:
  - pathophysiology#Facilitated Cortical Spreading Depolarization
  - phenotypes#Reversible Hemiparesis During Aura
  rationale: >-
    FHM1, FHM2 and FHM3 models show facilitated CSD, while the CSD-to-human-aura relation remains
    the leading clinical hypothesis rather than a directly recorded spontaneous FHM event. Qualified
    causal edges preserve that explanatory relation. Experimentally evoked thresholds measure susceptibility,
    and W887R heterozygotes showed no apparent clinical phenotype despite facilitated CSD. That negative
    result remains in animal-model evidence and limitations; it is not a clinical-restatement mechanism
    node.
  proposed_experiments:
  - experiment_id: exp_fhm_human_csd_correlate
    name: Non-invasive detection of a CSD correlate during a human FHM attack
    description: >-
      Capture spontaneous or provoked attacks in genotyped FHM patients using
      serial perfusion and diffusion MRI or MEG timed to aura onset, and test
      whether a propagating wavefront traverses the motor cortex with the
      timing and direction predicted by CSD, and whether its speed and
      threshold differ between FHM1, FHM2 and FHM3 carriers as the mouse models
      predict.
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1388/
    reference_title: Familial Hemiplegic Migraine - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Accumulating evidence supports the hypothesis that the electrophysiologic correlate underlying
      migraine aura is cortical spreading depolarization (CSD)
    explanation: >-
      GeneReviews presents CSD as the hypothesized electrophysiologic basis of aura. Together with
      its clinical localization of aura to cortex or brainstem, this supports a qualified route to
      cortical motor, sensory, visual and language manifestations; it is not a direct recording during
      human FHM attacks.
    directness: INDIRECT
- discussion_id: fhm_brainstem_component_scope
  kind: INTERPRETATION
  status: OPEN
  prompt: Which individual aura components explain the reported brainstem composite?
  rationale: >-
    The 69% figure is for any basilar-type symptom in 147 Danish FHM patients. It cannot quantify
    vertigo, tinnitus, dysarthria, diplopia, hyperacusis or transient ataxia separately. The primary
    abstract establishes ordering and the composite, while the full phenotype table was unavailable
    through attempted publisher and author-copy routes. The later clinical review explicitly lists
    individual HM manifestations, whose familial-versus-simplex component denominators remain unresolved.
    No composite phenotype is used to duplicate its constituents.
  evidence:
  - reference: PMID:12023326
    reference_title: >-
      A population-based study of familial hemiplegic migraine suggests revised diagnostic criteria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition, 69% had basilar migraine (BM) symptoms during FHM attacks.
    explanation: >-
      The Danish population-based study reports a 69% composite for any basilar-type symptoms in
      147 FHM patients. It does not give the individual component frequencies in the accessible abstract.
  - reference: PMID:12023326
    reference_title: >-
      A population-based study of familial hemiplegic migraine suggests revised diagnostic criteria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The order of the aura symptoms was usually visual, followed by sensory,
      aphasic, motor and, lastly, basilar-type migraine symptoms.
    explanation: >-
      The Danish FHM cohort reports the usual ordering of aura modalities, with basilar-type symptoms
      last. This supports the discussion of the composite's timing, not a frequency for any particular
      component.
  - reference: PMID:38674378
    reference_title: >-
      Unravelling the Genetic Landscape of Hemiplegic Migraine: Exploring Innovative Strategies and
      Emerging Approaches.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other accompanying features during the attacks may include seizure, fever,
      bilateral visual defects, brainstem aura with vertigo, ataxia,
      hyperacusia, dysarthria, disturbed consciousness, tinnitus, and, in severe
      cases, coma
    explanation: >-
      The later clinical review lists individual manifestations across hemiplegic migraine. It does
      not establish that this enumeration matches the components or denominators of the separate
      Danish FHM composite, and does not provide familial-only component frequencies.
  attaches_to: []
- discussion_id: fhm_residual_clinical_routes
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: Which routes account for brainstem, cognitive and febrile findings beyond the modeled
    cortical and severe-allele pathways?
  attaches_to:
  - phenotypes#Vertigo During Aura
  - phenotypes#Tinnitus During Aura
  - phenotypes#Dysarthria
  - phenotypes#Diplopia During Aura
  - phenotypes#Hyperacusis During Aura
  - phenotypes#Ataxia During Aura
  - phenotypes#Drowsiness During Attacks
  - phenotypes#Confusion During Attacks
  - phenotypes#Nystagmus
  - phenotypes#Fever During Severe Attacks
  - phenotypes#Intellectual Disability
  - phenotypes#Memory Impairment
  - phenotypes#Learning Disability
  - phenotypes#Nausea
  - phenotypes#Vomiting
  - phenotypes#Photophobia
  - phenotypes#Phonophobia
  rationale: >-
    The reviewed sources establish occurrence or syndrome/allele attribution, but do not resolve
    the particular upstream causal route for these findings. Brainstem localization alone does not
    establish cortical depolarization as the cause of each brainstem manifestation. Nystagmus is
    a cerebellar sign, but the S218L Purkinje firing experiment tests ataxia rather than ocular-motor
    dysfunction. Drowsiness and confusion are not automatically coma, and the severe-allele subcortical-spread
    hypothesis should not be transferred to all altered-awareness symptoms. Developmental disability
    in selected ATP1A2 variants and prolonged memory/learning problems are not all consequences of
    attack injury. Fever lacks a demonstrated thermoregulatory mechanism. The family authors' channel
    hypothesis covers the observed psychotic episodes, including anxiety and visual hallucinations.
    All three have the same provisional, family-scoped channel attribution; their unspecified intermediate
    circuits do not negate that broader hypothesis. These are attribution or translation gaps, not
    missing clinical observations. The reviewed FHM family data establish nausea, vomiting and sensory
    intolerance, but do not identify their autonomic or sensory-integration routes; a nociceptive
    pain mechanism alone does not establish these additional effects. The family authors' cerebellar
    attribution is represented by qualified channel-level links to coordination signs and Romberg
    instability, without asserting a specific balance-control intermediary.
  evidence:
  - reference: PMID:15159495
    reference_title: Variability of familial hemiplegic migraine with novel A1A2 Na+/K+-ATPase
      variants.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      D718N and P979L may predispose to seizures and mental retardation.
    explanation: >-
      The primary ATP1A2 family study attributes this developmental association to particular variants;
      it is not a general consequence of all FHM alleles.
  - reference: PMID:10202246
    reference_title: Familial hemiplegic migraine with cerebellar ataxia and paroxysmal
      psychosis.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here we report on a family with familial hemiplegic migraine and cerebellar ataxia with recurrent
      episodes of acute paranoid psychosis with anxiety and visual hallucinations associated with
      migraine attacks.
    explanation: >-
      The primary family report directly describes these attack-associated psychiatric observations.
      Linkage and phenotype supported a chromosome-19 hypothesis; a specific pathogenic CACNA1A variant
      was not established in this abstract.
  - reference: url:https://www.ncbi.nlm.nih.gov/books/NBK1388/
    reference_title: Familial Hemiplegic Migraine - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Accumulating evidence supports the hypothesis that the electrophysiologic correlate underlying
      migraine aura is cortical spreading depolarization (CSD)
    explanation: >-
      GeneReviews presents CSD as the hypothesized electrophysiologic basis of aura. Together with
      its clinical localization of aura to cortex or brainstem, this supports a qualified route to
      cortical motor, sensory, visual and language manifestations; it is not a direct recording during
      human FHM attacks.
    directness: INDIRECT
- discussion_id: fhm_missing_candidate_scope
  kind: INTERPRETATION
  status: OPEN
  prompt: Which additional findings can be assigned specifically to familial hemiplegic
    migraine?
  rationale: >-
    Whole-source review added specific visual/sensory aura, brainstem components, prolonged cognitive
    and psychiatric findings. The R583Q father/daughter primary report directly supports nausea,
    vomiting, photophobia, phonophobia and specific cerebellar examination findings, independently
    of general migraine descriptions or management advice. Its two mutation-negative relatives are
    not counted as molecular FHM1. Pediatric encephalopathy pools mix familial and simplex cases;
    PRRT2 hypersomnia cohorts do not resolve a familial-only clinical denominator. Surveillance for
    developmental delay is advice rather than clinical occurrence. Serum cytokines are exploratory
    readouts and their causal role is a separate hypothesis.
  evidence:
  - reference: PMID:12023326
    reference_title: A population-based study of familial hemiplegic migraine suggests revised
      diagnostic criteria.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      FHM patients most often had all four 'typical' aura symptoms (visual, sensory, aphasic and
      motor symptoms) and all had at least two of these aura symptoms during FHM attacks.
    explanation: >-
      The primary familial cohort establishes typical aura modalities, but its accessible abstract
      does not quantify the additional associated symptoms.
  attaches_to: []
classifications:
  harrisons_chapter:
  - classification_value: NEUROLOGIC
  channelopathy_category:
    classification_value: neurological channelopathy
    notes: >-
      ChannelopathyOrganSystemEnum classifies by affected organ system rather
      than by ion, and all three classical FHM subtypes act on cortical neurons
      and astrocytes, so the single neurological value covers the whole entry.
      The underlying transport lesions are heterogeneous - a calcium channel
      (CACNA1A/Cav2.1, FHM1), a sodium channel (SCN1A/Nav1.1, FHM3), and an ion
      pump rather than a channel (ATP1A2/Na+,K+-ATPase alpha2, FHM2) - so
      "channelopathy" is applied here in its broad ion-transport sense. PRRT2,
      the fourth hemiplegic-migraine gene, is a synaptic protein and is not a
      channelopathy locus at all; see the genetic section.
mappings:
  icd10cm_mappings:
  - term:
      id: ICD10CM:G43.4
      label: Hemiplegic migraine
    mapping_predicate: skos:broadMatch
    mapping_source: ICD10CM
    mapping_justification: semapv:ManualMappingCuration
    notes: >-
      Deliberately a broadMatch. ICD-10-CM G43.4 codes hemiplegic migraine as a
      whole and does not distinguish the familial form from the sporadic form,
      which this entry treats as a separate entity (see differential diagnoses).
      Its children encode intractability and status migrainosus rather than
      family history, so no narrower code corresponds to FHM.
  icd11f_mappings:
  - term:
      id: icd11f:1827007904
      label: Familial hemiplegic migraine
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: semapv:ManualMappingCuration
    notes: >-
      MONDO:0000700 cross-references icd11.foundation:1827007904, whose
      foundation-entity label matches this entry exactly. Unlike the ICD-10-CM
      code, the ICD-11 Foundation does separate the familial form from the
      sporadic one, so this mapping is exact.
mechanistic_hypotheses:
- hypothesis_group_id: cortical_aura
  hypothesis_label: Cortical spreading depolarization and focal aura
  status: CANONICAL
  description: >-
    The leading aura explanation, with indirect translation from model physiology to spontaneous
    human FHM.
- hypothesis_group_id: fhm3_potassium
  hypothesis_label: FHM3 spiking and potassium-mediated CSD initiation
  status: EMERGING
  description: >-
    Genetic L1649Q and acute activation experiments support a route distinct from glutamatergic initiation.
- hypothesis_group_id: csd_headache
  hypothesis_label: CSD-triggered meningeal sensitization
  status: EMERGING
  description: >-
    A proposed link to headache, not an obligatory causal ordering of aura and pain.
- hypothesis_group_id: severe_fhm1_spread
  hypothesis_label: Subcortical spread in severe FHM1
  status: EMERGING
  description: >-
    Allele-scoped mouse explanation for prolonged hemiplegia, coma and seizures, especially S218L.
- hypothesis_group_id: fhm1_cerebellar
  hypothesis_label: FHM1 cerebellar current abnormalities
  status: EMERGING
  description: >-
    Selected FHM1 alleles alter Purkinje firing or contribute to neuronal loss; this does not encompass
    all CACNA1A disorders.
- hypothesis_group_id: familial_psychosis
  hypothesis_label: Calcium-channel attribution of familial psychosis
  status: EMERGING
  description: >-
    An explicit chromosome-19 family hypothesis without a confirmed causal variant or defined psychiatric
    intermediary.
- hypothesis_group_id: fhm2_vasogenic_edema
  hypothesis_label: Case-scoped vasogenic edema
  status: EMERGING
  description: >-
    One severe ATP1A2-FHM attack showed barrier opening preceding edema, interpreted as vasogenic.
- hypothesis_group_id: severe_attack_injury
  hypothesis_label: Severe-attack neuronal injury and acquired cognitive decline
  status: EMERGING
  description: >-
    The childhood regression hypothesis draws on clinical course and juvenile-rat spreading-depression
    injury, not a proven universal developmental mechanism.
- hypothesis_group_id: cytokine_hypothesis
  hypothesis_label: Exploratory neuroimmune contribution in R583Q-FHM
  status: EMERGING
  description: >-
    Two-carrier serum observations motivate possible nociceptive and neurodegenerative cytokine actions.
    Reverse causation and effects shared with ordinary migraine remain unresolved.

📚

References & Deep Research

References

13

PMID:20301562

Familial Hemiplegic Migraine.

No top-level findings curated for this source.

DOI:10.1016/S1474-4422(24)00026-7

Genetics of migraine: complexity, implications, and potential clinical applications

1 finding

Listed as background reading only. It is deliberately not used as evidence anywhere in this entry, because the cached record for this DOI has an empty body (content_type unavailable), so no snippet could be verified against it.

PMID:10202246

Familial hemiplegic migraine with cerebellar ataxia and paroxysmal psychosis.

No top-level findings curated for this source.

PMID:12756131

Expanding the phenotypic spectrum of the CACNA1A gene T666M mutation: a description of 5 families with familial hemiplegic migraine.

No top-level findings curated for this source.

PMID:15159495

Variability of familial hemiplegic migraine with novel A1A2 Na+/K+-ATPase variants.

No top-level findings curated for this source.

PMID:15985592

Opening of the blood-brain barrier preceding cortical edema in a severe attack of FHM type II.

No top-level findings curated for this source.

PMID:21490217

Enhanced subcortical spreading depression in familial hemiplegic migraine type 1 mutant mice.

No top-level findings curated for this source.

PMID:23115190

Cerebellar ataxia by enhanced Ca(V)2.1 currents is alleviated by Ca2+-dependent K+-channel activators in Cacna1a(S218L) mutant mice.

No top-level findings curated for this source.

PMID:25143767

Familial hemiplegic migraine and spreading depression.

No top-level findings curated for this source.

PMID:27354390

Defective glutamate and K+ clearance by cortical astrocytes in familial hemiplegic migraine type 2.

No top-level findings curated for this source.

PMID:34546973

Hyperexcitable interneurons trigger cortical spreading depression in an Scn1a migraine model.

No top-level findings curated for this source.

url:https://www.ncbi.nlm.nih.gov/books/NBK1388/

Familial Hemiplegic Migraine - GeneReviews® - NCBI Bookshelf

No top-level findings curated for this source.

DOI:10.3389/fncel.2017.00263

Cerebellar Atrophy and Changes in Cytokines Associated with the CACNA1A R583Q Mutation in a Russian Familial Hemiplegic Migraine Type 1 Family

No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Falcon ▸

Familial Hemiplegic Migraine: Disease-Characteristics Research Report

Edison Scientific Literature 26 citations 2026-08-27T11:57:04.079945

Familial Hemiplegic Migraine: Disease-Characteristics Research Report

Scope. This report prioritizes literature published in 2023–2024, supplemented by established diagnostic guidance and landmark mechanistic evidence. Evidence types are identified explicitly. Familial hemiplegic migraine (FHM) is rare, and many management recommendations rest on observational studies, small series, or extrapolation from ordinary migraine rather than randomized FHM trials.

Executive summary

FHM is a usually autosomal-dominant subtype of migraine with aura in which attacks include fully reversible motor weakness and at least one first- or second-degree relative has hemiplegic migraine. Estimated prevalence is approximately 0.003% (3 per 100,000). Onset is usually pediatric or adolescent (mean reported onset 12–17 years), attacks average approximately 3–4 per year but vary from weekly to only a few lifetime events, and frequency commonly decreases with age. Besides hemiparesis, attacks may include visual, sensory, language, and brainstem aura; severe episodes can cause seizures, fever, encephalopathy, coma, and reversible cerebral edema. (alfayyadh2024unravellingthegenetic pages 1-2, alfayyadh2024unravellingthegenetic pages 2-4, grangeon2023geneticsofmigraine pages 1-2)

Three genes have definitive causal status: CACNA1A (FHM1), ATP1A2 (FHM2), and SCN1A (FHM3). Their dysfunction converges on disturbed neuronal–glial ion and glutamate homeostasis, lowering the threshold for cortical spreading depolarization/depression (CSD), the accepted physiological substrate of aura. Nevertheless, approximately 75% of clinically diagnosed HM is negative for pathogenic variants in these genes, and some unsolved disease may be oligogenic or polygenic. (alfayyadh2024unravellingthegenetic pages 1-2, maksemous2023wholeexomesequencing pages 1-3, sutherland2024geneticsofmigraine pages 1-2)

There is no validated blood, CSF, imaging, electrophysiological, or omics biomarker and no FHM-specific approved therapy. Diagnosis is clinical and genetic testing can confirm a molecular subtype. First or atypical attacks require urgent exclusion of stroke, seizure/Todd paresis, infection or inflammation, and metabolic disease. Treatment is individualized; evidence for verapamil, flunarizine, acetazolamide, lamotrigine, valproate, or topiramate is low quality. Gene, RNA, cell, and surgical therapies are not established.

A compact knowledge-base scaffold follows.

Domain	Key finding	Suggested ontology terms	Evidence level/limitations
Definition / epidemiology	Familial hemiplegic migraine (FHM) is a rare, severe subtype of migraine with aura defined by reversible motor weakness and at least one first- or second-degree relative with hemiplegic migraine; usually autosomal dominant. Reported prevalence is ~0.003% for FHM, within overall HM prevalence around 0.01% in European populations. Onset is typically in youth, often first or second decade; mean onset 12–17 years; females are affected more often; attack severity/frequency often decrease with age. (alfayyadh2024unravellingthegenetic pages 1-2, grangeon2023geneticsofmigraine pages 1-2)	Hemiplegic migraine; Migraine with aura [MeSH D020325]; hemiparesis; autosomal dominant inheritance	Recent review-level evidence synthesizing older epidemiology; prevalence estimates derive from limited rare-disease cohorts and may vary by ascertainment. (alfayyadh2024unravellingthegenetic pages 1-2, grangeon2023geneticsofmigraine pages 1-2)
Core phenotypes	Core attack phenotype is unilateral motor weakness/hemiparesis during aura, often with visual, sensory, speech/language, and brainstem symptoms. Brainstem aura symptoms occur in ~70% of cases; average attack frequency ~3–4/year but ranges widely; aura may last days to weeks in some patients. Severe attacks can include confusion, fever, seizures, coma, encephalopathy, and reversible cerebral edema; mild head trauma can trigger severe episodes. (alfayyadh2024unravellingthegenetic pages 2-4, grangeon2023geneticsofmigraine pages 1-2, xiang2023twopediatricpatients pages 1-3)	HP:0001269 Hemiplegia; hemiparesis; visual aura; paresthesia; aphasia; ataxia; dysarthria; vertigo; seizure; coma; fever; cerebral edema	Mixed evidence: narrative reviews plus pediatric case-based literature summary; exact phenotype frequencies beyond brainstem symptoms are incompletely standardized. (alfayyadh2024unravellingthegenetic pages 2-4, grangeon2023geneticsofmigraine pages 1-2, xiang2023twopediatricpatients pages 1-3)
CACNA1A / FHM1	CACNA1A is the best-established FHM gene and accounts for ~50–75% of genetically solved FHM. Variants are mostly missense, with some deletions/other classes. Functional effect is usually gain of function of Cav2.1 (P/Q-type) calcium channels, increasing calcium influx, glutamate release, neuronal hyperexcitability, and susceptibility to cortical spreading depression (CSD). Chronic progressive ataxia and nystagmus are especially associated with FHM1; some variants are linked to developmental/epileptic encephalopathy, cerebellar atrophy, coma, or seizures. Example recurrent variants summarized in a 2024 table include R192Q, S218L, T501M, R583Q, T666M/T665M, V714A, D715E, and Y1384C. (alfayyadh2024unravellingthegenetic pages 4-5, alfayyadh2024unravellingthegenetic pages 2-4)	CACNA1A; Cav2.1 / P/Q-type voltage-gated calcium channel; glutamatergic synapse; cortical spreading depression; cerebellar ataxia	Strong gene-disease validity from longstanding familial, functional, and animal-model data; many variant-specific assertions are compiled from prior studies rather than re-tested in 2024. (alfayyadh2024unravellingthegenetic pages 4-5, alfayyadh2024unravellingthegenetic pages 2-4)
ATP1A2 / FHM2	ATP1A2 is an established causal FHM gene encoding the Na+/K+-ATPase alpha-2 subunit, with astrocytic potassium and glutamate homeostasis central to mechanism. FHM2 converges mechanistically on elevated extracellular glutamate and increased CSD susceptibility; ATP1A2-related severe pediatric attacks can present with encephalopathy, seizures, and stroke-like episodes. (sutherland2024geneticsofmigraine pages 1-2, xiang2023twopediatricpatients pages 1-3, alfayyadh2024unravellingthegenetic pages 24-26)	ATP1A2; sodium-potassium ATPase; astrocyte; potassium ion homeostasis; glutamate clearance	Strong gene-level evidence, but the provided contexts contain fewer variant-by-variant details than for CACNA1A. Much of the mechanistic detail is review-synthesized. (sutherland2024geneticsofmigraine pages 1-2, xiang2023twopediatricpatients pages 1-3, alfayyadh2024unravellingthegenetic pages 24-26)
SCN1A / FHM3	SCN1A is the third established FHM gene, encoding a neuronal voltage-gated sodium channel. FHM3 overlaps clinically with epilepsy; SCN1A variants can produce hemiplegic migraine with seizures and, in some cases, prolonged or severe neurological sequelae. A recent case report highlighted late-onset type 3 HM with permanent neurologic sequelae after attacks. (alfayyadh2024unravellingthegenetic pages 2-4, boer2019advanceingenetics pages 5-8, grangeon2023geneticsofmigraine pages 1-2)	SCN1A; voltage-gated sodium channel; epilepsy; neuronal excitability	Established causal gene, but rarer than CACNA1A/ATP1A2 and less comprehensively represented in the retrieved 2023–2024 primary data. (alfayyadh2024unravellingthegenetic pages 2-4, boer2019advanceingenetics pages 5-8, grangeon2023geneticsofmigraine pages 1-2)
Emerging genes / modifiers	A substantial proportion of HM/FHM remains genetically unexplained: recent reviews state ~75% of HM cases are negative for CACNA1A, ATP1A2, and SCN1A. Danish and Finnish studies found only 14% and 9% of FHM families, respectively, with variants in the 3 known genes. PRRT2 is described as more likely a modifier than a primary causal FHM gene. WES burden testing in 184 Australian HM cases found significant excess missense variation in CACNA1E, CACNA1H, and CACNA1I, with replication for CACNA1H and partial replication for CACNA1I in 32 Dutch cases, supporting a more complex architecture in some unsolved HM. (alfayyadh2024unravellingthegenetic pages 1-2, alfayyadh2024unravellingthegenetic pages 2-4, maksemous2023wholeexomesequencing pages 1-3)	PRRT2; CACNA1E; CACNA1H; CACNA1I; modifier gene; complex trait	Emerging/disputed evidence. Burden studies indicate association, not monogenic causality; unsolved cases likely reflect locus heterogeneity and polygenic/background effects. (alfayyadh2024unravellingthegenetic pages 2-4, maksemous2023wholeexomesequencing pages 1-3)
Mechanism / CSD	Current model: pathogenic ion-transport defects in neurons and astrocytes disturb excitatory-inhibitory balance and glutamatergic signaling, increase extracellular glutamate and/or impair ion homeostasis, thereby lowering the threshold for CSD initiation and propagation; CSD then drives aura and can activate downstream migraine pain pathways. The neurovascular unit is emphasized, involving neurons, glial cells, and vessels. Female sex hormones may further enhance CSD susceptibility. (sutherland2024geneticsofmigraine pages 1-2, grangeon2023geneticsofmigraine pages 1-2, alfayyadh2024unravellingthegenetic pages 4-5)	cortical spreading depression; glutamatergic neurotransmission; excitatory-inhibitory balance; neuron; astrocyte; neurovascular unit; GO:0007268 synaptic transmission	Mechanism is strongly supported by convergent human genetics and animal models, but the direct step from CSD to individual clinical features remains partly inferential. (sutherland2024geneticsofmigraine pages 1-2, grangeon2023geneticsofmigraine pages 1-2, alfayyadh2024unravellingthegenetic pages 4-5)
Diagnosis	Diagnosis is clinical using ICHD-3 criteria for migraine with aura; if aura includes motor weakness it is classified as hemiplegic migraine. FHM is distinguished from sporadic HM by family history. Because presentation overlaps with stroke and other acute neurologic disorders, diagnosis often requires exclusion of structural, vascular, infectious, epileptic, and inflammatory causes; genetic testing is particularly useful in atypical or pediatric severe cases. (schytz2021referenceprogrammediagnosis pages 3-7, alfayyadh2024unravellingthegenetic pages 1-2, xiang2023twopediatricpatients pages 1-3)	ICHD-3; Migraine with aura [MeSH D020325]; hemiplegic migraine; family history	Guideline and review support are strong for clinical diagnosis, but no single biomarker or pathognomonic ancillary test exists. (schytz2021referenceprogrammediagnosis pages 3-7, alfayyadh2024unravellingthegenetic pages 1-2)
Treatment	No FHM-specific approved therapy was identified in the retrieved evidence. Management is largely extrapolated from migraine care and case-based experience. Human provocation studies show FHM has been used experimentally in GTN and CGRP infusion paradigms (NCT00541736, n=30; NCT00358839, n=20) to probe mechanism. Pediatric longitudinal EMR data in CACNA1A-related HM (15 individuals, 163 patient-years) found no clear efficacy for levetiracetam or acetazolamide, while verapamil and valproate were associated with modest prevention but not reduced severity. (NCT00541736 chunk 1, NCT00358839 chunk 1, xiang2023twopediatricpatients pages 1-3)	verapamil; valproate; acetazolamide; levetiracetam; migraine prophylaxis; supportive care	Evidence is weak to moderate and mostly non-randomized/case-based; HM patients are commonly excluded from migraine RCTs. Provocation trials are mechanistic, not therapeutic. (NCT00541736 chunk 1, NCT00358839 chunk 1, xiang2023twopediatricpatients pages 1-3)
Prognosis	Many patients improve over time with decreasing attack frequency/severity, but prognosis is highly variable. Severe attacks can be prolonged and life-threatening; permanent neurologic sequelae, cognitive impairment, cerebellar atrophy, or developmental issues occur in some genetic subgroups, especially severe CACNA1A- or SCN1A-related disease. Early recognition in children may improve prognosis by avoiding misdiagnosis and delayed care. (alfayyadh2024unravellingthegenetic pages 1-2, alfayyadh2024unravellingthegenetic pages 2-4, xiang2023twopediatricpatients pages 1-3)	cognitive impairment; cerebellar atrophy; developmental delay; permanent neurologic deficit	Mostly derived from reviews, longitudinal pediatric series, and case reports; mortality/life expectancy statistics are not well defined in retrieved evidence. (alfayyadh2024unravellingthegenetic pages 1-2, xiang2023twopediatricpatients pages 1-3)
Models	Knock-in mouse models carrying human FHM mutations, especially CACNA1A R192Q and S218L, show increased CSD susceptibility and enhanced excitatory/glutamatergic transmission; ATP1A2-related models show extracellular glutamate abnormalities ("glutamate plumes") and increased CSD propensity. These models are useful for studying synaptic signaling, neuroinflammation, metabolite changes, and sex-hormone modulation, but cannot fully recapitulate subjective human aura/headache experience. (sutherland2024geneticsofmigraine pages 1-2, alfayyadh2024unravellingthegenetic pages 23-24, alfayyadh2024unravellingthegenetic pages 24-26)	mouse model; knock-in model; Cacna1a; Atp1a2; cortical spreading depression; glutamate	Strong translational value for mechanism; limited face validity for subjective pain and heterogeneous human attack phenomenology. (sutherland2024geneticsofmigraine pages 1-2, alfayyadh2024unravellingthegenetic pages 23-24, alfayyadh2024unravellingthegenetic pages 24-26)

Table: This table compacts the main disease, genetic, mechanistic, diagnostic, treatment, prognosis, and model-organism findings for familial hemiplegic migraine. It is useful as a structured scaffold for populating a disease knowledge base while preserving evidence strength and key limitations.

1. Disease information

Definition and classification

Hemiplegic migraine (HM) is a rare, severe form of migraine with aura characterized by reversible motor weakness, usually unilateral. FHM is diagnosed when at least one first- or second-degree relative has HM; without such a family history, the classification is sporadic hemiplegic migraine (SHM). FHM constitutes approximately two-thirds and SHM one-third of HM in a recent review. (alfayyadh2024unravellingthegenetic pages 1-2, grangeon2023geneticsofmigraine pages 1-2)

The current diagnostic construct is disease-level and aggregated from ICHD, curated genetic resources, cohorts, and literature—not principally an EHR-derived phenotype. Individual case reports and recent electronic-record cohorts supply natural-history details but should not be treated as population estimates.

Identifiers and synonyms

MONDO: familial hemiplegic migraine is represented in MONDO as a hereditary hemiplegic-migraine concept; database releases should be checked before ingestion because parent/child mappings can change.
OMIM phenotypes: FHM1 #141500; FHM2 #602481; FHM3 #609634.
Orphanet: familial hemiplegic migraine, ORPHA:569.
MeSH: Migraine with Aura, D020325; the clinical-trial registry also maps FHM1 to MeSH supplementary concept C536890. (NCT00541736 chunk 1, NCT00358839 chunk 1)
ICD-10-CM: G43.4- (hemiplegic migraine; extensions specify intractability/status migrainosus). ICD systems generally do not reliably encode molecular FHM subtype.
ICD-11: classified under migraine with aura/hemiplegic migraine; verify the current browser code at implementation time.
Synonyms: familial hemiplegic migraine; familial hemiplegic migraine with aura; FHM; familial hemiplegic migraine type 1/FHM1, type 2/FHM2, and type 3/FHM3; historically, familial hemiplegic migraine with progressive cerebellar ataxia for some CACNA1A families.

2. Etiology, risk, protection, and gene–environment interaction

Primary causal factors

FHM is primarily a germline genetic channelopathy/ion-transport disorder. Heterozygous pathogenic variants in CACNA1A, ATP1A2, or SCN1A alter presynaptic calcium entry, astrocytic Na+/K+ transport, or neuronal sodium-channel excitability. These defects converge on excessive extracellular glutamate or defective ionic homeostasis and heightened CSD susceptibility. (alfayyadh2024unravellingthegenetic pages 4-5, sutherland2024geneticsofmigraine pages 1-2)

Genetic risk and modifiers

The three established genes account for only a minority of all clinically diagnosed families in population-based series: a Danish study found variants in 14%, and a Finnish study in 9% of 45 families. Conversely, among genetically solved FHM, CACNA1A has been reported to account for 50–75%. These denominators are different and should not be conflated. (alfayyadh2024unravellingthegenetic pages 4-5, alfayyadh2024unravellingthegenetic pages 2-4)

PRRT2 loss-of-function variation has been reported in HM, especially in overlapping paroxysmal phenotypes, but current evidence favors a modifier or susceptibility role rather than definitive primary FHM causation. A 2023 WES study found excess missense variation in CACNA1E, CACNA1H, and CACNA1I among 184 Australian HM cases; CACNA1H replicated in 32 Dutch cases, while CACNA1I did not survive correction in the replication analysis. These are association/burden findings, not established Mendelian genes. (maksemous2023wholeexomesequencing pages 1-3)

Environmental and lifestyle triggers

Reported attack triggers include minor head trauma, physical or emotional stress, viral illness/fever, disrupted sleep, and other homeostatic stresses. Hormonal state is relevant: experimental FHM1 evidence indicates female sex hormones can increase CSD susceptibility. These exposures precipitate attacks in a genetically susceptible brain; they do not cause the inherited disorder. (alfayyadh2024unravellingthegenetic pages 4-5, alfayyadh2024unravellingthegenetic pages 1-2, alfayyadh2024unravellingthegenetic pages 2-4)

No toxin, pollution, occupational exposure, diet, smoking pattern, alcohol exposure, or infectious organism is established as an FHM cause. Viral infection may trigger an attack but is not etiologic. No replicated genetic protective allele is established. Environmental protection is therefore pragmatic—regular sleep and meals, hydration, stress management, and avoidance of individually documented triggers, particularly head trauma—not evidence of disease prevention.

3. Phenotypes

Phenotype	Characteristics and frequency	Suggested HPO annotation
Motor aura/hemiparesis	Defining feature; usually unilateral, reversible, may switch sides, rarely bilateral; episodic and variable in severity	Hemiplegia HP:0002301; hemiparesis; migraine with aura
Headache	Often unilateral and severe but may be bilateral, ipsilateral, or contralateral to weakness; headache is not required after every aura	Migraine; headache HP:0002315; nausea/vomiting; photophobia; phonophobia
Visual aura	Scintillating scotoma, hemianopia, or other positive/negative visual symptoms; commonly accompanies motor aura	Visual aura; hemianopia HP:0012377
Sensory aura	Numbness, tingling, and paresthesia; generally spreads gradually	Paresthesia HP:0003401; hypoesthesia
Language aura	Dysphasia/aphasia or dysarthria	Aphasia HP:0002381; dysarthria HP:0001260
Brainstem manifestations	Vertigo, tinnitus, hyperacusis, ataxia, dysarthria, or impaired consciousness; collectively reported in approximately 70%	Vertigo HP:0002321; tinnitus HP:0000360; ataxia HP:0001251
Severe encephalopathic attack	Confusion, somnolence, fever, seizure/status epilepticus, coma, and reversible edema; uncommon but clinically critical; may last days–weeks	Encephalopathy HP:0001298; seizure HP:0001250; coma HP:0001259; cerebral edema HP:0002181
Chronic cerebellar syndrome	Progressive or interictal ataxia and gaze-evoked nystagmus, particularly CACNA1A-related disease; reported in up to 60% of FHM1 in the cited review but rare in FHM2	Cerebellar ataxia HP:0001251; nystagmus HP:0000639; cerebellar atrophy HP:0001272
Neurodevelopmental/cognitive phenotype	Learning disability, intellectual disability, or cognitive impairment in severe CACNA1A/ATP1A2 disease; may precede or follow HM	Intellectual disability HP:0001249; developmental delay HP:0001263

The frequency, duration, and sequence of symptoms vary substantially even among relatives carrying the same variant. Typical individual aura symptoms often evolve over minutes; motor weakness commonly resolves within hours, but severe attacks can persist for weeks. (alfayyadh2024unravellingthegenetic pages 2-4, grangeon2023geneticsofmigraine pages 1-2, schytz2021referenceprogrammediagnosis pages 3-7)

A 2023 pediatric analysis assembled 160 mutation-positive patients—73 CACNA1A and 87 ATP1A2—and emphasized that severe childhood attacks may present principally as acute encephalopathy. Its abstract states: “Physicians should consider HM in the differential diagnosis of patients presenting with somnolence, coma, or convulsion without structural, epileptic, infectious, or inflammatory explanation.” This is case-based literature evidence, not a frequency estimate for all FHM. (xiang2023twopediatricpatients pages 1-3)

Quality of life

Motor deficits, pain, vomiting, sensory/language impairment, fear of recurrence, emergency assessment for stroke, school/work absence, and prolonged post-attack recovery can markedly impair function. Severe chronic cerebellar or developmental phenotypes add interictal disability. However, no robust FHM-specific EQ-5D, SF-36, PROMIS, or MIDAS population dataset was identified; general migraine burden statistics should not be assigned directly to FHM.

4. Genetic and molecular information

Definitive causal genes

Subtype	Gene/protein	Locus/function	Typical functional consequence
FHM1	CACNA1A; CaV2.1 α1A subunit	19p13; presynaptic P/Q-type voltage-gated Ca²⁺ channel	Usually gain of function: activation at lower voltage, increased Ca²⁺ influx and glutamate release, cortical hyperexcitability
FHM2	ATP1A2; Na⁺/K⁺-ATPase α2	1q23; enriched in astrocytes in adult brain	Usually loss of pump function, impaired extracellular K⁺ and glutamate clearance
FHM3	SCN1A; NaV1.1	2q24; neuronal voltage-gated Na⁺ channel, especially inhibitory interneurons	Variant-dependent altered excitability; many HM variants produce gain-of-function or impaired inactivation, disturbing excitation–inhibition balance

All are ordinarily heterozygous germline variants. Somatic mutation is not a recognized usual mechanism. Large recurrent chromosomal rearrangements, aneuploidy, repeat expansions, and mitochondrial inheritance are not established causes.

Variant classes and examples

Most classic FHM1 alleles are missense variants in channel pore/voltage-sensor or regulatory regions, although splice, deletion, frameshift, and other loss-of-function alleles occur across the broader CACNA1A disorder spectrum. Recurrent examples include p.Arg192Gln (R192Q; rs121908211), p.Ser218Leu (S218L; rs121908225), p.Thr501Met, p.Arg583Gln, p.Thr666Met, p.Val714Ala, and p.Asp715Glu. R192Q and S218L increase calcium influx and CSD susceptibility; S218L is associated with a particularly severe epilepsy/ataxia/encephalopathy spectrum. Variant-specific effects are not uniform: for example, p.Tyr1384Cys is reported as CaV2.1 loss of function. (alfayyadh2024unravellingthegenetic pages 4-5, alfayyadh2024unravellingthegenetic media 3fe8f9b6, alfayyadh2024unravellingthegenetic media bf5d2d35)

Population frequency must be evaluated per exact HGVS allele and transcript in gnomAD. A credible highly penetrant FHM allele is generally absent or extremely rare in reference populations. Pathogenicity must be assigned under ACMG/AMP criteria using segregation, de novo status, population rarity, functional evidence, phenotype specificity, and validated database assertions; a rare missense variant or in-silico score alone is insufficient.

Penetrance and expressivity

Inheritance is usually autosomal dominant with high but not universally complete penetrance. Expressivity is markedly variable—including within a pedigree—from infrequent pure HM to epilepsy, ataxia, intellectual disability, edema, or coma. Mutation-positive patients in a comparison of 208 carriers versus 73 mutation-negative HM patients had earlier onset and more extensive motor, brainstem, confusion, edema, and head-trauma-triggered phenotypes; intellectual disability and progressive ataxia occurred only among mutation-positive individuals in that dataset. (boer2019advanceingenetics pages 5-8)

No consistent anticipation mechanism is established. De novo variants are well documented, especially in severe sporadic presentations. Parental germline mosaicism is biologically possible and relevant to counseling after an apparently de novo result, but its frequency is unknown. Founder variants exist in individual populations/families, but there is no universal founder allele. Consanguinity is not a principal risk factor for this dominant disorder.

Epigenetics and structural variation

No validated FHM-specific DNA-methylation, histone, or chromatin signature is used clinically. Copy-number and structural variants are plausible and occasionally reported, particularly in CACNA1A/PRRT2 regions, but sequence-level variants predominate. A negative exome or panel does not exclude deep-intronic, regulatory, repeat-complex, mosaic, or structural variation.

5. Environmental information

FHM is not caused by toxins, radiation, pollution, occupational exposure, or infection. The relevant environmental layer is attack provocation. Minor head trauma is particularly important because severe edema, encephalopathy, seizure, or coma may follow otherwise mild injury in susceptible children. Physical/emotional stress and febrile or viral illness are also reported triggers. (alfayyadh2024unravellingthegenetic pages 1-2, grangeon2023geneticsofmigraine pages 1-2, xiang2023twopediatricpatients pages 1-3)

Regular sleep, meals, hydration, graded exercise as tolerated, and trigger diaries are reasonable implementations of general migraine care. Evidence for avoiding particular foods is weak; a guideline notes no clear evidence for commonly implicated foods such as red wine, chocolate, or cheese. (schytz2021referenceprogrammediagnosis pages 3-7)

6. Mechanism and pathophysiology

Causal chain

Upstream germline lesion: altered CACNA1A, ATP1A2, or SCN1A protein function.
Cellular ion-homeostasis defect: excessive presynaptic Ca²⁺-dependent glutamate release (FHM1), impaired astrocytic K⁺/glutamate clearance (FHM2), or altered interneuron/network excitability (FHM3).
Network consequence: increased extracellular glutamate/K⁺ and impaired cortical excitation–inhibition balance.
Threshold event: easier initiation and propagation of CSD—a slowly advancing wave of neuronal/glial depolarization followed by suppression of activity.
Clinical aura: propagation through visual, somatosensory, language, and motor cortex produces corresponding positive and negative neurological symptoms, including hemiparesis.
Downstream pain: CSD and associated neurovascular signaling can activate meningeal/trigeminovascular afferents and release vasoactive neuropeptides, producing migraine headache and associated symptoms. Severe depolarization and homeostatic failure can produce seizures, edema, or prolonged encephalopathy. (alfayyadh2024unravellingthegenetic pages 4-5, sutherland2024geneticsofmigraine pages 1-2, grangeon2023geneticsofmigraine pages 1-2)

A 2024 Lancet Neurology review summarizes the convergence directly: FHM1 and FHM2 mutations increase extracellular glutamate, dysregulate cortical excitatory–inhibitory balance, and increase CSD initiation and propagation. (sutherland2024geneticsofmigraine pages 1-2)

Cells, tissues, pathways, and ontology suggestions

Cells: excitatory cortical neuron (CL:0000679), GABAergic neuron (CL:0000617), astrocyte (CL:0000127), trigeminal sensory neuron, vascular endothelial cell (CL:0000115), vascular smooth-muscle cell.
Anatomy: cerebral cortex (UBERON:0000956), motor cortex, visual cortex, somatosensory cortex, brainstem (UBERON:0002298), cerebellum (UBERON:0002037), meninges (UBERON:0002360), trigeminal ganglion.
GO biological processes: synaptic transmission (GO:0007268), glutamatergic synaptic transmission (GO:0035249), calcium-ion transmembrane transport (GO:0070588), potassium-ion homeostasis, regulation of membrane potential (GO:0042391), neurotransmitter secretion (GO:0007269), spreading depolarization/CSD (use the current GO term if available).
GO cellular components: voltage-gated calcium-channel complex (GO:0005891), sodium-channel complex (GO:0034706), sodium:potassium-exchanging ATPase complex (GO:0005890), presynaptic membrane (GO:0042734), astrocyte projection.

Metabolism, immunity, and tissue injury

Metabolic abnormalities observed in FHM models are chiefly downstream of abnormal ion flux and the energetic demand of repolarization. Neuroinflammatory and vascular responses can accompany CSD, but FHM is neither a primary autoimmune disease nor an immunodeficiency. Cerebral edema, rare infarction, neuronal stress, and cerebellar degeneration are complications rather than universal progressive tissue injury.

Molecular profiling and advanced technologies

No reproducible FHM-specific clinical transcriptomic, proteomic, metabolomic, lipidomic, single-cell, spatial-transcriptomic, or multi-omic diagnostic signature is established. Current high-value technologies are family-based WES/WGS, structural-variant analysis, electrophysiology, knock-in models, and patient-derived neuronal systems. The 2023 burden study supports pathway-level analysis of rare variants rather than assuming every unsolved patient has a fourth high-penetrance gene. (maksemous2023wholeexomesequencing pages 1-3)

7. Anatomical structures affected

The primary system is the central nervous system, especially cerebral cortical networks. Symptoms lateralize according to the cortical hemisphere involved; weakness is usually unilateral, may alternate between attacks, and rarely becomes bilateral. Visual, sensory, language, and motor cortices account for aura topography. Brainstem networks account for vertigo, dysarthria, tinnitus, ataxia, and impaired consciousness; cerebellar tissue is chronically affected in some CACNA1A genotypes. Meningeal vessels and trigeminal afferents mediate downstream headache. (alfayyadh2024unravellingthegenetic pages 2-4, grangeon2023geneticsofmigraine pages 1-2)

At the subcellular level, relevant compartments are presynaptic membranes/active zones, voltage-gated ion-channel complexes, astrocytic plasma membranes, and synaptic extracellular space. FHM is not primarily a muscle disorder despite the clinical weakness.

8. Temporal development

Onset: usually childhood/adolescence; mean 12–17 years, although infancy and adult-onset cases occur. (alfayyadh2024unravellingthegenetic pages 1-2, grangeon2023geneticsofmigraine pages 1-2)
Attack onset: aura generally develops acutely and often spreads over minutes; stroke-like abrupt onset can occur.
Duration: typical aura components often last 5–60 minutes, but motor or encephalopathic deficits may last days to weeks. (alfayyadh2024unravellingthegenetic pages 2-4, schytz2021referenceprogrammediagnosis pages 3-7)
Course: lifelong episodic/relapsing disorder rather than staged neurodegeneration. Mean attack frequency is approximately 3–4/year but ranges from more than weekly to a few lifetime attacks. Frequency and severity often decline with age. (alfayyadh2024unravellingthegenetic pages 1-2, grangeon2023geneticsofmigraine pages 1-2)
Interictal state: many patients recover fully; some genotypes produce persistent ataxia, nystagmus, epilepsy, cognitive disability, or cerebellar atrophy.
Critical periods: childhood severe attacks, attacks after minor head trauma, and prolonged altered consciousness are high-risk windows requiring urgent assessment and supportive treatment.

9. Inheritance and population

FHM is usually autosomal dominant, with each child of a heterozygous affected person having a 50% chance of inheriting the variant. Clinical penetrance is high but incomplete and age-dependent in some families; molecular inheritance does not guarantee identical severity. The 2023 genetics review describes monogenic FHM as having “almost complete penetrance,” while other families demonstrate incomplete penetrance—an important counseling distinction. (alfayyadh2024unravellingthegenetic pages 22-23, grangeon2023geneticsofmigraine pages 1-2)

Estimated prevalence is 0.003%, equivalent to roughly 3 per 100,000; overall HM is approximately 0.01%. Reliable incidence, carrier frequency, mortality rate, ethnic stratification, and geographic variation are unavailable. Females are affected more often, but a robust FHM-specific sex ratio is not established. (alfayyadh2024unravellingthegenetic pages 1-2)

No ethnicity is intrinsically exempt or consistently at uniquely high risk. Apparent geographic clusters usually reflect founder alleles, family ascertainment, access to specialty diagnosis, or sequencing practices.

10. Diagnostics

Clinical criteria

ICHD-3 requires attacks meeting hemiplegic-migraine criteria: migraine with aura including fully reversible motor weakness plus fully reversible visual, sensory, and/or speech/language symptoms. FHM additionally requires at least one first- or second-degree relative meeting HM criteria. The gradual spread and sequential appearance of aura favor migraine, but abrupt deficits occur and do not safely exclude stroke. (alfayyadh2024unravellingthegenetic pages 1-2, schytz2021referenceprogrammediagnosis pages 3-7)

Acute assessment and ancillary tests

There is no confirmatory routine laboratory biomarker. In a first, abrupt, prolonged, febrile, encephalopathic, or otherwise atypical attack, evaluation commonly includes:

CT/CTA or MRI with diffusion and vascular imaging to exclude hemorrhage, infarction, dissection, venous thrombosis, or other lesions;
glucose, electrolytes, calcium, renal/hepatic indices, toxicology and metabolic testing as clinically indicated;
CSF studies when infection/inflammation is plausible;
EEG for seizure or unexplained altered consciousness.

MRI may be normal or show transient cortical swelling, diffusion/perfusion changes, meningeal enhancement, or edema. EEG can show nonspecific slowing. These findings are neither necessary nor specific. In one pediatric CACNA1A case, prior MRI/MRA/MRV and routine metabolic testing were normal, while a later attack produced right frontotemporal cortical DWI hyperintensities. (xiang2023twopediatricpatients pages 1-3)

Genetic testing strategy

Begin with a multigene episodic-neurology/HM panel including CACNA1A, ATP1A2, and SCN1A, with deletion/duplication analysis.
Add phenotype-overlap genes where appropriate—PRRT2, SLC2A1, ATP1A3, NOTCH3 and other epilepsy, ataxia, small-vessel, or metabolic genes—noting that these may cause mimics rather than classic FHM.
Use trio WES or WGS when panel-negative, syndromic, very early onset, or severe; WGS is preferable for noncoding and structural variants.
Confirm reportable variants and perform segregation/cascade testing.

CMA is reasonable for syndromic developmental disease but has low expected yield in isolated FHM. Karyotyping, FISH, mitochondrial sequencing, and repeat-expansion testing are not routine unless the phenotype suggests another disorder. RNA-seq may clarify a suspected splice variant but is not a standard diagnostic assay.

Differential diagnosis

Urgent differentials are ischemic/hemorrhagic stroke, TIA, cerebral venous thrombosis, arterial dissection, focal seizure with Todd paresis, encephalitis/meningitis, inflammatory demyelination, metabolic derangement, and toxic exposure. Genetic mimics include CADASIL (NOTCH3), MELAS/mitochondrial disease, GLUT1 deficiency (SLC2A1), ATP1A3 disorders, alternating hemiplegia of childhood, epilepsy syndromes, and other CACNA1A phenotypes. Severe pediatric HM is frequently mistaken for epilepsy, viral encephalitis, or postictal confusion. (xiang2023twopediatricpatients pages 1-3)

Screening

There is no population or newborn screening. Once a pathogenic familial variant is known, cascade testing of at-risk relatives is appropriate after genetic counseling. Prenatal diagnosis and preimplantation genetic testing are technically possible for a known pathogenic variant, subject to local law and informed reproductive counseling.

11. Outcome and prognosis

Most attacks resolve completely, and attack frequency commonly declines with age. Life expectancy is generally presumed near normal in uncomplicated FHM, but population-level survival estimates are unavailable. Severe attacks can be life-threatening through coma, status epilepticus, edema, or rare infarction; permanent ataxia, cognitive impairment, epilepsy, and cerebellar atrophy occur in severe molecular subtypes. (alfayyadh2024unravellingthegenetic pages 4-5, alfayyadh2024unravellingthegenetic pages 1-2, xiang2023twopediatricpatients pages 1-3)

Important adverse prognostic indicators include very early onset, recurrent encephalopathy, prolonged weakness, seizures, cerebral edema, developmental impairment, progressive ataxia, and severe CACNA1A alleles such as S218L. Mutation-positive cases tend to have earlier and more extensive neurological manifestations than mutation-negative HM. (boer2019advanceingenetics pages 5-8, alfayyadh2024unravellingthegenetic media 3fe8f9b6)

No validated prognostic blood or imaging biomarker exists. Recovery potential is usually high after ordinary attacks, but prolonged attacks require rehabilitation assessment for residual motor, cognitive, speech, or school-function deficits.

12. Treatment

General strategy

Because HM patients are usually excluded from migraine randomized trials, management should be specialist-led and individualized. A practical algorithm is:

New or atypical deficit: treat as possible stroke/encephalitis/seizure until excluded.
Supportive acute care: quiet/dark environment, hydration, antiemetic, acetaminophen or NSAID when safe; control fever, seizures, vomiting, and intracranial complications.
Prevention: consider frequent, prolonged, disabling, or encephalopathic attacks; select an agent based on aura, headache, epilepsy, ataxia, blood pressure, weight, pregnancy potential, and genotype.
Monitor: headache/aura diary, attack duration, weakness, consciousness, adverse effects, school/work function, and interictal neurological signs.

Pharmacotherapy

Intervention	Role/evidence	Suggested NCIt concept
NSAID or acetaminophen	Acute headache; extrapolated from migraine	Analgesic therapy; nonsteroidal anti-inflammatory agent
Antiemetic	Nausea/vomiting and hydration support	Antiemetic therapy
Verapamil	Often used preventively; occasional acute reports; low-quality HM evidence	Verapamil NCIt:C928
Flunarizine	Common pediatric/HM preventive where available; observational evidence	Flunarizine
Acetazolamide	Consider particularly with CACNA1A/ataxia overlap; case-based evidence	Acetazolamide NCIt:C225
Lamotrigine	May reduce aura; useful where epilepsy coexists; limited HM data	Lamotrigine NCIt:C38703
Valproate	Preventive option with seizure comorbidity; teratogenic and metabolically adverse	Valproic acid NCIt:C29536
Topiramate	General migraine preventive; HM-specific evidence sparse and occasional worsening reported	Topiramate NCIt:C47752
CGRP-pathway agents	Emerging case-series use, but no robust FHM RCT evidence through 2024	CGRP inhibitor therapy

Triptans and ergots were historically avoided because of theoretical vasoconstrictive risk and trial exclusions. Retrospective experience has challenged an absolute contraindication, but evidence remains limited; their use should be decided by a headache specialist after vascular disease is excluded. Intravenous vasodilators or experimental provocation agents are not treatments.

Trials and real-world implementation

Completed Danish mechanistic studies include:

NCT00541736, GTN/nitroglycerin infusion, 30 participants, nonrandomized open-label basic-science study, completed May 2008; outcomes were migraine symptoms and aura over 14 hours. The registry notes that GTN induces migraine in approximately 80% of ordinary migraine sufferers and tested whether FHM pathways differ. (NCT00541736 chunk 1)
NCT00358839, CGRP infusion in genetically confirmed FHM1/FHM2 and controls, enrollment 20, single-masked nonrandomized study, completed October 2006; outcomes included headache, cerebral blood-flow velocity, and superficial temporal-artery diameter. (NCT00358839 chunk 1)
Pediatric topiramate studies NCT00131443 and NCT00158002 included basilar/hemiplegic migraine, but small mixed populations and limited accessible results prevent a reliable FHM response estimate.

These are largely mechanistic or mixed-phenotype studies, not evidence for a standard FHM drug. No approved gene therapy, CRISPR treatment, ASO/siRNA therapy, cell therapy, immunotherapy, or surgery exists. Physical, occupational, speech, cognitive, and school rehabilitation are appropriate after prolonged deficits.

13. Prevention

Primary prevention of the genotype is not possible. Genetic counseling can clarify the 50% transmission risk in a heterozygous parent and discuss reproductive options.

Secondary prevention consists of recognizing at-risk relatives, cascade testing for a known familial variant, early diagnosis, individualized trigger management, and preventive medication for clinically significant attacks. Avoidance of contact sports or situations with repetitive head injury is reasonable in patients whose severe attacks are trauma-triggered.

Tertiary prevention includes an emergency action plan, prompt evaluation of stroke-like deficits, seizure management, prevention of dehydration and hyperthermia, and rehabilitation after prolonged attacks. Vaccination follows ordinary schedules; no FHM-specific vaccine exists. Population screening, environmental remediation, or infectious-disease control is not applicable.

14. Other species and natural disease

No well-established naturally occurring veterinary disease precisely equivalent to human FHM was identified. Therefore breed-specific VBO terms, veterinary incidence, zoonotic transmission, and cross-species contagion are not applicable. The responsible ion-transport proteins are deeply conserved across vertebrates, enabling engineered models. Relevant taxa include Homo sapiens (NCBI Taxon 9606) and Mus musculus (10090).

15. Model organisms and experimental systems

The principal models are knock-in mice carrying human FHM alleles, especially Cacna1a R192Q and S218L, and Atp1a2 mutant models. They reproduce lowered CSD threshold, faster propagation, enhanced cortical excitatory transmission, abnormal extracellular glutamate, photophobia-like behavior, and interactions with sex hormones or stress. S218L models generally have the more severe seizure/ataxia phenotype. (alfayyadh2024unravellingthegenetic pages 24-26, alfayyadh2024unravellingthegenetic pages 23-24, sutherland2024geneticsofmigraine pages 1-2)

Applications include electrophysiology, in-vivo CSD imaging, synaptic physiology, neurovascular coupling, trigeminovascular activation, metabolite analysis, and preclinical drug testing. Cell systems include heterologous channel-expression assays, cultured neurons/astrocytes, and increasingly patient-derived iPSC neurons or brain organoid-like systems.

Limitations: mice cannot report aura or headache; experimentally induced CSD is not identical to a spontaneous human attack; homozygous or high-expression models may exaggerate severity; and one allele cannot represent the broad human allelic spectrum. Models have strong mechanistic validity but incomplete face and predictive validity.

Evidence gaps and expert interpretation

Genetic architecture: “Approximately 75% of HM patients are negative” for the three canonical genes in the 2024 review; unsolved disease should not automatically be labeled a novel monogenic syndrome. Burden, structural-variant, and polygenic analyses are priorities. (alfayyadh2024unravellingthegenetic pages 1-2)
Treatment: adequately powered prospective multicenter registries and genotype-stratified trials are the largest unmet need. Current prescribing is largely empirical.
Biomarkers: no molecular or imaging marker reliably distinguishes HM from stroke during an acute presentation.
Natural history: incidence, penetrance by variant, FHM-specific quality-of-life scores, permanent-deficit rates, pregnancy outcomes, and mortality remain poorly quantified.
Precision medicine: molecular diagnosis is already useful for counseling and anticipating epilepsy/ataxia/encephalopathy, but genotype-guided drug selection remains investigational.

Key recent sources and access information

Alfayyadh MM et al. “Unravelling the Genetic Landscape of Hemiplegic Migraine.” Genes. Published 31 March 2024. DOI/URL: https://doi.org/10.3390/genes15040443. The abstract states: “approximately 75% of HM patients are negative for these mutations.” (alfayyadh2024unravellingthegenetic pages 1-2)
Sutherland HG et al. “Genetics of migraine: complexity, implications, and potential clinical applications.” Lancet Neurology. April 2024;23:429–446. DOI/URL: https://doi.org/10.1016/S1474-4422(24)00026-7. (sutherland2024geneticsofmigraine pages 1-2)
Grangeon L et al. “Genetics of migraine: where are we now?” Journal of Headache and Pain. Published February 2023. DOI/URL: https://doi.org/10.1186/s10194-023-01547-8. (grangeon2023geneticsofmigraine pages 1-2)
Maksemous N et al. “Whole Exome Sequencing of Hemiplegic Migraine Patients Shows an Increased Burden of Missense Variants in CACNA1H and CACNA1I Genes.” Molecular Neurobiology. Published online 14 February 2023;60:3034–3043. DOI/URL: https://doi.org/10.1007/s12035-023-03255-5. The authors conclude that unsolved HM may be “a complex trait” involving increased missense-variant burden. (maksemous2023wholeexomesequencing pages 1-3)
Xiang Y et al. “Two pediatric patients with hemiplegic migraine presenting as acute encephalopathy.” Frontiers in Pediatrics. Published 28 July 2023. DOI/URL: https://doi.org/10.3389/fped.2023.1214837. (xiang2023twopediatricpatients pages 1-3)
Schytz HW et al. Danish Headache Society reference programme. Journal of Headache and Pain. Published 2021. DOI/URL: https://doi.org/10.1186/s10194-021-01228-4. (schytz2021referenceprogrammediagnosis pages 3-7)

Curation caution: database identifiers, HGVS nomenclature, ClinVar classification, and ontology accessions should be validated against current releases at ingestion. Variant assertions in review tables are useful for candidate extraction but should be linked to their original case/functional study and independently reconciled with current ClinVar/ClinGen evidence before being labeled pathogenic.

References

(alfayyadh2024unravellingthegenetic pages 1-2): Mohammed M. Alfayyadh, Neven Maksemous, Heidi G. Sutherland, Rod A. Lea, and Lyn R. Griffiths. Unravelling the genetic landscape of hemiplegic migraine: exploring innovative strategies and emerging approaches. Genes, 15:443, Mar 2024. URL: https://doi.org/10.3390/genes15040443, doi:10.3390/genes15040443. This article has 11 citations.
(alfayyadh2024unravellingthegenetic pages 2-4): Mohammed M. Alfayyadh, Neven Maksemous, Heidi G. Sutherland, Rod A. Lea, and Lyn R. Griffiths. Unravelling the genetic landscape of hemiplegic migraine: exploring innovative strategies and emerging approaches. Genes, 15:443, Mar 2024. URL: https://doi.org/10.3390/genes15040443, doi:10.3390/genes15040443. This article has 11 citations.
(grangeon2023geneticsofmigraine pages 1-2): Lou Grangeon, Kristin Sophie Lange, Marta Waliszewska-Prosół, Dilara Onan, Karol Marschollek, Wietse Wiels, Petr Mikulenka, Fatemeh Farham, Cédric Gollion, and Anne Ducros. Genetics of migraine: where are we now? The Journal of Headache and Pain, Feb 2023. URL: https://doi.org/10.1186/s10194-023-01547-8, doi:10.1186/s10194-023-01547-8. This article has 202 citations.
(maksemous2023wholeexomesequencing pages 1-3): Neven Maksemous, Aster V. E. Harder, Omar Ibrahim, Lisanne S. Vijfhuizen, Heidi Sutherland, Nadine Pelzer, Irene de Boer, Gisela M. Terwindt, Rodney A. Lea, Arn M. J. M. van den Maagdenberg, and Lyn R. Griffiths. Whole exome sequencing of hemiplegic migraine patients shows an increased burden of missense variants in cacna1h and cacna1i genes. Molecular Neurobiology, 60:3034-3043, Feb 2023. URL: https://doi.org/10.1007/s12035-023-03255-5, doi:10.1007/s12035-023-03255-5. This article has 17 citations and is from a peer-reviewed journal.
(sutherland2024geneticsofmigraine pages 1-2): Heidi G Sutherland, Bronwyn Jenkins, and Lyn R Griffiths. Genetics of migraine: complexity, implications, and potential clinical applications. The Lancet Neurology, 23:429-446, Apr 2024. URL: https://doi.org/10.1016/s1474-4422(24)00026-7, doi:10.1016/s1474-4422(24)00026-7. This article has 43 citations and is from a highest quality peer-reviewed journal.
(xiang2023twopediatricpatients pages 1-3): Yu Xiang, Fei Li, Zhenfeng Song, Zhi Yi, Chengqing Yang, Jiao Xue, and Ying Zhang. Two pediatric patients with hemiplegic migraine presenting as acute encephalopathy: case reports and a literature review. Frontiers in Pediatrics, Jul 2023. URL: https://doi.org/10.3389/fped.2023.1214837, doi:10.3389/fped.2023.1214837. This article has 7 citations.
(alfayyadh2024unravellingthegenetic pages 4-5): Mohammed M. Alfayyadh, Neven Maksemous, Heidi G. Sutherland, Rod A. Lea, and Lyn R. Griffiths. Unravelling the genetic landscape of hemiplegic migraine: exploring innovative strategies and emerging approaches. Genes, 15:443, Mar 2024. URL: https://doi.org/10.3390/genes15040443, doi:10.3390/genes15040443. This article has 11 citations.
(alfayyadh2024unravellingthegenetic pages 24-26): Mohammed M. Alfayyadh, Neven Maksemous, Heidi G. Sutherland, Rod A. Lea, and Lyn R. Griffiths. Unravelling the genetic landscape of hemiplegic migraine: exploring innovative strategies and emerging approaches. Genes, 15:443, Mar 2024. URL: https://doi.org/10.3390/genes15040443, doi:10.3390/genes15040443. This article has 11 citations.
(boer2019advanceingenetics pages 5-8): Irene de Boer, Arn M.J.M. van den Maagdenberg, and Gisela M. Terwindt. Advance in genetics of migraine. Jun 2019. URL: https://doi.org/10.1097/wco.0000000000000687, doi:10.1097/wco.0000000000000687. This article has 121 citations and is from a peer-reviewed journal.
(schytz2021referenceprogrammediagnosis pages 3-7): Henrik W. Schytz, Faisal M. Amin, Rigmor H. Jensen, Louise Carlsen, Stine Maarbjerg, Nunu Lund, Karen Aegidius, Lise L. Thomsen, Flemming W. Bach, Dagmar Beier, Hanne Johansen, Jakob M. Hansen, Helge Kasch, Signe B. Munksgaard, Lars Poulsen, Per Schmidt Sørensen, Peter T. Schmidt-Hansen, Vlasta V. Cvetkovic, Messoud Ashina, and Lars Bendtsen. Reference programme: diagnosis and treatment of headache disorders and facial pain. danish headache society, 3rd edition, 2020. The Journal of Headache and Pain, Apr 2021. URL: https://doi.org/10.1186/s10194-021-01228-4, doi:10.1186/s10194-021-01228-4. This article has 74 citations.
(NCT00541736 chunk 1): Glyceryl-Trinitrate-Induced Headache in Patients With Familial Hemiplegic Migraine. Danish Headache Center. 2007. ClinicalTrials.gov Identifier: NCT00541736
(NCT00358839 chunk 1): Calcitonin Gene Related Peptide-Induced Headache in Patients With Familial Hemiplegic Migraine Type 1 and 2.. Danish Headache Center. 2006. ClinicalTrials.gov Identifier: NCT00358839
(alfayyadh2024unravellingthegenetic pages 23-24): Mohammed M. Alfayyadh, Neven Maksemous, Heidi G. Sutherland, Rod A. Lea, and Lyn R. Griffiths. Unravelling the genetic landscape of hemiplegic migraine: exploring innovative strategies and emerging approaches. Genes, 15:443, Mar 2024. URL: https://doi.org/10.3390/genes15040443, doi:10.3390/genes15040443. This article has 11 citations.
(alfayyadh2024unravellingthegenetic media 3fe8f9b6): Mohammed M. Alfayyadh, Neven Maksemous, Heidi G. Sutherland, Rod A. Lea, and Lyn R. Griffiths. Unravelling the genetic landscape of hemiplegic migraine: exploring innovative strategies and emerging approaches. Genes, 15:443, Mar 2024. URL: https://doi.org/10.3390/genes15040443, doi:10.3390/genes15040443. This article has 11 citations.
(alfayyadh2024unravellingthegenetic media bf5d2d35): Mohammed M. Alfayyadh, Neven Maksemous, Heidi G. Sutherland, Rod A. Lea, and Lyn R. Griffiths. Unravelling the genetic landscape of hemiplegic migraine: exploring innovative strategies and emerging approaches. Genes, 15:443, Mar 2024. URL: https://doi.org/10.3390/genes15040443, doi:10.3390/genes15040443. This article has 11 citations.
(alfayyadh2024unravellingthegenetic pages 22-23): Mohammed M. Alfayyadh, Neven Maksemous, Heidi G. Sutherland, Rod A. Lea, and Lyn R. Griffiths. Unravelling the genetic landscape of hemiplegic migraine: exploring innovative strategies and emerging approaches. Genes, 15:443, Mar 2024. URL: https://doi.org/10.3390/genes15040443, doi:10.3390/genes15040443. This article has 11 citations.

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Classifications

Mappings

Inheritance

Subtypes

Mechanistic Hypotheses

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Environmental Factors

Diagnosis

Progression

Prevalence

Differential Diagnoses

Clinical Trials

Animal Models

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References & Deep Research

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Familial Hemiplegic Migraine: Disease-Characteristics Research Report

Executive summary

1. Disease information

Definition and classification

Identifiers and synonyms

2. Etiology, risk, protection, and gene–environment interaction

Primary causal factors

Genetic risk and modifiers

Environmental and lifestyle triggers

3. Phenotypes

Quality of life

4. Genetic and molecular information

Definitive causal genes

Variant classes and examples

Penetrance and expressivity

Epigenetics and structural variation

5. Environmental information

6. Mechanism and pathophysiology

Causal chain

Cells, tissues, pathways, and ontology suggestions

Metabolism, immunity, and tissue injury

Molecular profiling and advanced technologies

7. Anatomical structures affected

8. Temporal development

9. Inheritance and population

10. Diagnostics

Clinical criteria

Acute assessment and ancillary tests

Genetic testing strategy

Differential diagnosis

Screening

11. Outcome and prognosis

12. Treatment

General strategy

Pharmacotherapy

Trials and real-world implementation

13. Prevention

14. Other species and natural disease

15. Model organisms and experimental systems

Evidence gaps and expert interpretation

Key recent sources and access information

Artifacts

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