Familial Hemiplegic Migraine
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. The unifying mechanistic claim is that these ion transport defects lower the threshold for cortical spreading depression, the propagating wave of neuronal and glial depolarization that produces the hemiparetic aura. FHM has served as a Mendelian model for migraine aura biology more generally.
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Classifications
Harrison's Part
Channelopathy
Mappings
ICD-10-CM
ICD10CM:G43.4
Hemiplegic migraine
semapv:ManualMappingCuration
ICD-11 Foundation
icd11f:1827007904
Familial hemiplegic migraine
semapv:ManualMappingCuration
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.
Show evidence (6 references)
"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.
"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.
"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
Subtypes
3
Familial Hemiplegic Migraine Type 1 (CACNA1A)
MONDO:0020756
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)
"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.
"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
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)
"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
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)
"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.
"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.
Discussions and Knowledge Gaps
2Does the reduced cortical spreading depression threshold measured in FHM knock-in mice actually explain the hemiparetic aura of a human FHM attack?
Attached to
The central mechanistic claim of this entry - that FHM variants lower the CSD threshold - rests on transgenic mouse data. The CSD-threshold node is supported entirely by MODEL_ORGANISM evidence, and the step from that threshold to the reversible motor weakness seen in patients is inferred rather than measured: CSD has not been recorded directly during a spontaneous human FHM attack, and the human evidence is indirect (aura semiology, imaging correlates, and the clinical genetics). The mismatch is mechanistically meaningful because mouse CSD threshold is assayed with an experimental stimulus applied to anaesthetised cortex, which measures susceptibility to provoked CSD rather than whatever initiates a spontaneous attack, and because the motor cortex representation that would have to be traversed to produce hemiparesis differs substantially between the lissencephalic mouse and the human brain. It is recorded as a HUMAN_MODEL_MISMATCH rather than a KNOWLEDGE_GAP because the model evidence is strong and reproducible; what is open is its translational validity, not its existence.
The structural counterpart of this discussion is in animal_models: the R192Q, S218L and W887R knock-in links all carry the anaesthetised-cortex and species caveats in their limitations, and the FHM2 W887R model records a FAILS_TO_RECAPITULATE link against Reversible Hemiparetic Aura - the heterozygous mutant has the cortical CSD phenotype and no apparent clinical phenotype. That negative result is the sharpest form of the mismatch: the one model in which the threshold change and the clinical attack could have been observed together shows only the former.
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.
Pathophysiology
10Cav2.1 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.
Heterozygous missense variants in conserved functional domains of the alpha1A subunit; the archetypal pure-FHM allele is R192Q and the severe allele is S218L.
Downstream
Increased presynaptic Ca2+ influx raises the probability of glutamate release at pyramidal cell synapses.
Show evidence (1 reference)
"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.
Heterozygous ATP1A2 variants acting through haploinsufficiency of the astrocytic alpha2 Na+/K+ pump.
Animal models
Atp1a2 W887R knock-in mouse (FHM2)
The molecular lesion itself: mutant alpha2 protein is strongly reduced in the brain of heterozygous mutants, consistent with ER retention and proteasomal degradation.
Downstream
A reduced astrocytic Na+ gradient limits the Na+-coupled reuptake of glutamate and potassium from the extracellular space.
Show evidence (3 references)
"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.
"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.
"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.
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.
Animal models
Cacna1a R192Q knock-in mouse (FHM1, pure hemiplegic migraine allele)
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
An in vitro CSD model established a causative link between enhanced glutamate release and CSD facilitation.
Show evidence (2 references)
"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.
"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
The FHM2-specific step. The astrocytic alpha2 Na+/K+ pump sustains the Na+ electrochemical gradient that drives Na+-coupled glutamate transporters and contributes to extracellular K+ buffering. Reduced pump activity is proposed to make glutamate clearance from the synaptic cleft inefficient, raising cortical excitatory neurotransmission. This is explicitly a hypothesis in the source knock-in study rather than a directly measured clearance deficit, and is curated at that strength.
Downstream
Inefficient glutamate reuptake is proposed to raise cortical excitatory neurotransmission.
The FHM2 knock-in mouse shows a decreased CSD induction threshold and increased propagation velocity in vivo.
Show evidence (1 reference)
"Since several lines of evidence involve a specific role of the glial α2 Na,K pump in active reuptake of glutamate from the synaptic cleft, we hypothesize that CSD facilitation in the FHM2 mouse model is sustained by inefficient glutamate clearance by astrocytes and consequent increased cortical..."
Supports the clearance-deficit mechanism, but the authors frame it as a hypothesis inferred from the pump's known role rather than a measured clearance deficit in the mutant mouse, hence PARTIAL.
GABAergic Interneuron Hyperactivity and Extracellular Potassium Accumulation
The FHM3-specific step, and a deliberate departure from the shared glutamatergic route. Because Nav1.1 is the main sodium channel of interneurons, FHM3 gain of function makes GABAergic neurons hyperexcitable. Pharmacological Nav1.1 enhancement or optogenetic activation of GABAergic interneurons is sufficient to ignite cortical spreading depression through spiking-generated extracellular K+ build-up, and neither GABAergic nor glutamatergic synaptic transmission is required for that initiation. The effect is neocortex-specific.
Downstream
Interneuron-driven extracellular K+ build-up is by itself sufficient to ignite neocortical spreading depression.
Show evidence (3 references)
"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. Neither GABAergic nor glutamatergic..."
Establishes the K+-mediated, transmission-independent route from interneuron hyperactivity to CSD, which is what makes FHM3 mechanistically distinct from FHM1 and FHM2. Graded IN_VITRO because the experiments behind this claim - Hm1a application, optogenetic stimulation, and the receptor- and Ca2+-channel-blockade series that establishes the transmission independence - were performed in brain slices. The study's in vivo arm is recorded as its own item below.
"These data confirm the results obtained in brain slices, showing that overactivation of GABAergic neurons or NaV1.1 can lead to/facilitate CSD induction also in vivo."
The in vivo arm of the same study, separated out because it is a different kind of evidence from the slice work above: it shows the effect survives in an intact animal with blood flow, long-range connections and neuromodulation present.
"Our results provide the mechanism linking NaV1.1 gain of function to CSD generation in FHM3."
Attributes the mechanism specifically to the FHM3 subtype. Graded OTHER rather than IN_VITRO or MODEL_ORGANISM because it is the authors' synthesis across all three arms of a mixed-design study - in vivo, brain slices and cell lines - so no single study type supports it. The component claims are graded individually above.
Reduced Cortical Spreading Depression Threshold
The unifying node of the entry. Cortical spreading depression (CSD) is a slowly propagating wave of neuronal and glial depolarization that is the neurophysiological correlate of migraine aura. FHM1 and FHM2 knock-in mice both show a reduced CSD induction threshold and an increased propagation velocity in vivo, and NaV1.1 gain of function ignites CSD directly - so all three classical subtypes converge on a cortex that enters and propagates CSD too readily.
Animal models
Cacna1a R192Q knock-in mouse (FHM1, pure hemiplegic migraine allele)
The in vivo CSD threshold and velocity measurement that grounds the unifying node of this entry.
Cacna1a S218L knock-in mouse (FHM1, severe allele)
An exaggerated version of the R192Q threshold phenotype, with multiple CSD events following a single trigger.
Atp1a2 W887R knock-in mouse (FHM2)
The FHM2 in vivo threshold and velocity measurement, matching the FHM1 result and supporting the convergence drawn at this node.
Downstream
A propagating cortical depolarization wave produces the transient focal neurological deficit that defines the aura, including its motor component.
In severe alleles the same process is associated with prolonged deficits, blood-brain barrier opening and cortical edema.
Show evidence (4 references)
"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.
"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.
"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.
+ 1 more reference
Reversible Hemiparetic Aura
The defining clinical expression of the mechanism. Cortical spreading depression through motor cortex and adjacent areas produces fully reversible motor weakness, obligatorily accompanied by at least one of visual, sensory or language aura. Deficits typically last under 72 hours but may persist for hours to days and outlast the headache. Onset is usually in the first or second decade and attack frequency decreases with age.
Animal models
Atp1a2 W887R knock-in mouse (FHM2)
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.
Downstream
The aura is typically followed by, or accompanied by, migrainous headache.
Show evidence (3 references)
"FHM must include motor involvement, such as hemiparesis (weakness of an extremity). Hemiparesis occurs with at least one other symptom during FHM aura."
States the obligatory motor component and its obligatory pairing with another aura symptom.
"Neurologic deficits with FHM attacks can be prolonged for hours to days and may outlast the associated migrainous headache."
Establishes that the aura deficit is reversible but may be much longer than typical migraine aura.
"Hemiplegic migraine is a severe subset of migraine with aura with symptoms including reversible hemiparesis in addition to other aura symptoms such as visual, sensory, or speech."
Contemporary review restating the defining clinical picture.
Migraine Headache Phase
The headache that follows or accompanies the hemiparetic aura. In hemiplegic migraine the headache and aura biology are regarded as continuous with typical migraine with aura, differing in threshold and severity rather than in kind; the trigeminovascular mechanisms of the headache phase are curated on the Migraine and Migraine with aura entries rather than duplicated here.
Show evidence (1 reference)
"The pathophysiology of HM is close to the process of typical migraine with aura, but appearing with a lower threshold and more severity."
Supports treating the headache phase as shared migraine biology and the FHM-specific claim as one about threshold and severity.
Prolonged Attacks with Cerebral Edema and Impaired Consciousness
A severe attack phenotype, most strongly associated with the CACNA1A S218L allele, in which hemiplegia is accompanied by altered consciousness, fever and, in some cases, delayed cerebral edema and coma - characteristically provoked by minor head trauma. Blood-brain barrier opening preceding cortical edema has been documented during a severe FHM2 attack.
Animal models
Cacna1a S218L knock-in mouse (FHM1, severe allele)
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.
Show evidence (2 references)
"This CACNA1A mutation has been associated with HM, delayed cerebral oedema and coma following minor head trauma."
Documents the severe S218L attack phenotype including trauma-provoked cerebral edema and coma.
"The proband, in addition to typical hemiplegic migraine attacks, experienced severe episodes during which hemiplegia was associated with acutely altered consciousness and fever lasting several days."
An independent family showing the severe prolonged attack phenotype with impaired consciousness and fever.
Pathograph
Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Phenotypes
17Ear 2
Vertigo During Aura
HP:0002321
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Vertigo (HP:0002321), qualified as temporality transient. HP:0002321 is a phenotype from the Human Phenotype Ontology.
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)
"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
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Tinnitus (HP:0000360), qualified as temporality transient. HP:0000360 is a phenotype from the Human Phenotype Ontology.
Hyperacusis appears in the same list but is not curated separately, because it is named only in this enumeration with no further characterization.
Show evidence (1 reference)
"hyperacusia, dysarthria, disturbed consciousness, tinnitus, and, in severe cases, coma"
Names tinnitus as a brainstem aura feature of hemiplegic migraine.
Eye 1
Nystagmus
HP:0000639
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Nystagmus (HP:0000639). HP:0000639 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"have cerebellar signs ranging from nystagmus to progressive, usually late-onset mild ataxia"
Names nystagmus as part of the CACNA1A-FHM cerebellar spectrum.
Metabolism 2
Cerebral Edema
HP:0002181
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Cerebral edema (HP:0002181), qualified as temporality transient. HP:0002181 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"delayed cerebral oedema and coma following minor head trauma"
Documents cerebral edema in the severe attack phenotype.
Fever During Severe Attacks
HP:0001945
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Fever (HP:0001945), qualified as temporality transient. HP:0001945 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"hemiplegia was associated with acutely altered consciousness and fever lasting several days"
Reports fever as a feature of severe prolonged FHM attacks.
Nervous System 10
Reversible Hemiparesis During Aura
HP:0001269
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Hemiparesis (HP:0001269), qualified as temporality transient. HP:0001269 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"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
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Migraine with aura (HP:0002077). HP:0002077 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"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
HP:0002315
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Headache (HP:0002315). HP:0002315 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"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.
Sensory Aura
Paresthesia
HP:0003401
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Paresthesia (HP:0003401), qualified as temporality transient. HP:0003401 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"sensory loss (e.g., numbness or paresthesias of the face or an extremity)"
Names the sensory aura modality in FHM.
Language Aura
Aphasia
HP:0002381
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Aphasia (HP:0002381), qualified as temporality transient. HP:0002381 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"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
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Dysarthria (HP:0001260), qualified as temporality transient. HP:0001260 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
"brainstem aura with vertigo, ataxia, hyperacusia, dysarthria, disturbed consciousness"
Names dysarthria as a brainstem aura feature of hemiplegic migraine.
"Patients frequently experience severe headache accompanied by photophobia, numbness, tingling, paresthesias, dysarthria, and temporary motor impairment that can persist from minutes to several days"
An independent source listing dysarthria among the attack features, and the reason dysarthria is also part of the stroke-mimic differential.
Cerebellar Ataxia
FREQUENT
HP:0001251
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Ataxia (HP:0001251), qualified as course progressive. HP:0001251 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"Approximately 40%-50% of families with CACNA1A-FHM have cerebellar signs ranging from nystagmus to progressive, usually late-onset mild ataxia."
Quantifies the cerebellar phenotype in CACNA1A-FHM at 40-50% of families, which maps to the FREQUENT band.
Seizures
HP:0001250
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
"Anti-seizure treatment may be necessary for seizures, which are prevalent in ATP1A2-FHM."
GeneReviews identifies seizures as a prevalent manifestation, especially in the ATP1A2 subtype.
"there were 28 families and 195 individuals, 78 of whom had epilepsy; 30 patients had focal epilepsy and 30 patients had generalized epilepsy."
Quantifies epilepsy co-occurrence across published FHM families. Note this is a literature review of reported families, so it is subject to reporting bias and is not a population frequency - which is why no frequency band is asserted here.
"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.
Impaired Consciousness and Coma
HP:0001259
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Coma (HP:0001259), qualified as temporality transient. HP:0001259 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
"This CACNA1A mutation has been associated with HM, delayed cerebral oedema and coma following minor head trauma."
Documents coma as part of the severe S218L attack phenotype.
"Acute encephalopathy is the main manifestation of severe attacks of HM in children, which adds to the difficulty of diagnosis."
Extends the severe-attack phenotype beyond the S218L allele: in children it is the leading presentation of a severe attack, across CACNA1A and ATP1A2 alike.
Intellectual Disability
HP:0001249
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
"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.
Other 2
Visual Aura
Abnormality of vision
HP:0000504
Human Phenotype Ontology (HP)
Relation: this clinical feature is this phenotype
This clinical feature is Abnormality of vision (HP:0000504), qualified as temporality transient. HP:0000504 is a phenotype from the Human Phenotype Ontology.
Bound to the broad HP:0000504 rather than a specific visual-aura term because the source states only "visual disturbance"; the specific aura phenomenology (scintillating scotoma and similar) is curated on the Migraine with aura entry.
Show evidence (1 reference)
"the neurologic symptoms of aura are unequivocally localizable to the cerebral cortex or brain stem and include visual disturbance (most common)"
Identifies visual disturbance as the most common aura symptom in migraine with aura including FHM.
Brainstem (Basilar-Type) Aura Symptoms
FREQUENT
Deliberately left without a phenotype_term. HPO has no brainstem-aura or basilar-migraine class - a search of HP for "basilar" returns only skeletal and vascular terms, and the migraine branch stops at HP:0002077 Migraine with aura - so binding this group would mean choosing one constituent symptom to stand for all of them. The constituents that do have HP terms are curated as their own entries immediately below; ataxia and impaired consciousness already have entries elsewhere in this section.
Show evidence (3 references)
"In addition, 69% had basilar migraine (BM) symptoms during FHM attacks."
Quantifies brainstem aura at 69% in 147 FHM patients ascertained nationwide, which maps to the FREQUENT band (30-79%).
"The order of the aura symptoms was usually visual, followed by sensory, aphasic, motor and, lastly, basilar-type migraine symptoms."
Places the brainstem symptoms last in the aura sequence, which is the timing claim in the description.
"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"
Enumerates the individual brainstem aura symptoms that the 69% figure covers, and is the source for the three specific phenotypes below.
Genetic Associations
6
CACNA1A
Show evidence (1 reference)
"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
Show evidence (1 reference)
"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
Show evidence (1 reference)
"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
Show evidence (2 references)
"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 cohort study establishing PRRT2 as a bona fide hemiplegic-migraine gene.
"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
Show evidence (4 references)
"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.
"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.
"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
Show evidence (1 reference)
"albeit that CACNA1I did not remain significant after multiple testing correction"
The authors' own qualification of the CACNA1I replication, which is why this evidence item is PARTIAL.
Medical Actions
8
Acetazolamide
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.
Show evidence (1 reference)
"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
Acute treatment of the headache phase is analgesic rather than migraine-specific, because the migraine-specific acute drugs (triptans, ergots) are the ones contraindicated here. This is the practical counterpart of the avoidance entry below: what is left once the vasoconstrictors are removed.
Show evidence (1 reference)
"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
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)
"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.
"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 is why this item is PARTIAL.
"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
Anti-seizure treatment where seizures occur, which is particularly relevant in ATP1A2-FHM. Drug-resistant epilepsy is rare across all FHM genotypes.
Show evidence (2 references)
"Anti-seizure treatment may be necessary for seizures, which are prevalent in ATP1A2-FHM."
GeneReviews management guidance for the epilepsy comorbidity.
"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
Corticosteroids in children with cerebral edema, to reduce life-threatening manifestations of a severe attack.
Show evidence (1 reference)
"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
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)
"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.
"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
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)
"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
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)
"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
3Minor 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)
"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.
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)
"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.
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)
"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.
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
NCI Thesaurus (NCIT)
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)
"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.
"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.
"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
NCI Thesaurus (NCIT)
Show evidence (5 references)
"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.
"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.
"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
NCI Thesaurus (NCIT)
Show evidence (3 references)
"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.
"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.
"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
2Childhood onset and first 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)
"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."
Quantifies attack duration and its genotype dependence. Nine patients across three centres, so the difference is a description of this cohort rather than an established genotype-phenotype rule.
Long-term follow-up
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)
"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.
"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.
"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
3Denmark (nationwide case-finding, hemiplegic migraine overall)
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)
"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
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)
"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)
Female predominance of 3:1 in the same nationwide survey.
Show evidence (1 reference)
"The HM sex ratio (M:F) was 1:3."
Establishes the female predominance of hemiplegic migraine.
Differential Diagnoses
4Conditions with similar clinical presentations that must be differentiated from Familial Hemiplegic Migraine:
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)
"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.
"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.
"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.
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)
"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.
"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)
"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)
"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.
Show evidence (1 reference)
"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.
Show evidence (1 reference)
"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
Publication
Pathograph links
Reduced Cortical Spreading Depression Threshold
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.
Direction: DECREASED
Interpretation: A lower induction threshold is the direct measurement behind the threshold node.
Show evidence (1 reference)
"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)
"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)
"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
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
Direction: INCREASED
Interpretation: The presynaptic measurement that connects Cav2.1 gain of function to cortical hyperexcitability.
Show evidence (1 reference)
"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)
"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)
"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.
Species
Mouse
Genotype
Cacna1a S218L knock-in (human severe FHM1 allele)
Genes
Publication
Pathograph links
Reduced Cortical Spreading Depression Threshold
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 triggering threshold and event count
Threshold, propagation velocity, and number of CSD events elicited by a single stimulus.
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 (2 references)
"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)
"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.
Prolonged Attacks with Cerebral Edema and Impaired Consciousness
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.
Limitations: 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.
Show evidence (1 reference)
"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' own claim is explicitly a proposal - may provide - which is why this link is PARTIALLY_RECAPITULATES and the evidence item is PARTIAL.
Show evidence (1 reference)
"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.
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.
Species
Mouse
Genotype
Atp1a2 W887R knock-in, heterozygous (homozygotes die after birth)
Genes
Publication
Pathograph links
Reduced Cortical Spreading Depression Threshold
The FHM2 in vivo threshold and velocity measurement, matching the FHM1 result and supporting the convergence drawn at this node.
Limitations: Same anaesthetised-cortex and species caveats as the FHM1 models. The astrocytic glutamate-clearance step that would connect the pump defect to the threshold is offered as a hypothesis in this work, not measured.
Readouts
Cortical spreading depression induction threshold and velocity
Direction: DECREASED
Interpretation: The FHM2 counterpart of the FHM1 threshold readout, measured in vivo in the heterozygous mutant.
Show evidence (1 reference)
"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)
"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
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)
"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)
"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.
Reversible Hemiparetic Aura
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.
Limitations: 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.
Show evidence (1 reference)
"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.
Show evidence (1 reference)
"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.
Source YAML
click to showname: 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. The unifying mechanistic claim is that these ion
transport defects lower the threshold for cortical spreading depression, the
propagating wave of neuronal and glial depolarization that produces the
hemiparetic aura. 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; only the FHM-specific lowering of the cortical spreading depression
threshold and the motor aura are curated here. 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 how the loss of function produces the
phenotype is not understood.
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_9_PER_100000
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
prevalence_class: BAND_1_9_PER_100000
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 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.
explanation: >-
Quantifies attack duration and its genotype dependence. Nine patients
across three centres, so the difference is a description of this cohort
rather than an established genotype-phenotype rule.
- 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
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 Ca2+ influx raises the probability of glutamate
release at pyramidal cell synapses.
- name: Astrocytic Na+/K+-ATPase Alpha2 Loss of Function
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: >-
A reduced astrocytic Na+ gradient limits the Na+-coupled reuptake of
glutamate and potassium from the extracellular space.
- name: Nav1.1 Sodium Channel Gain of Function
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.
downstream:
- target: GABAergic Interneuron Hyperactivity and Extracellular Potassium Accumulation
description: >-
Nav1.1 is the principal sodium channel of interneurons, so gain of
function makes GABAergic neurons hyperexcitable.
- 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: Reduced Cortical Spreading Depression Threshold
description: >-
An in vitro CSD model established a causative link between enhanced
glutamate release and CSD facilitation.
- name: Impaired Astrocytic Glutamate and Potassium Clearance
biological_scale: CELLULAR
description: >-
The FHM2-specific step. The astrocytic alpha2 Na+/K+ pump sustains the Na+
electrochemical gradient that drives Na+-coupled glutamate transporters and
contributes to extracellular K+ buffering. Reduced pump activity is proposed
to make glutamate clearance from the synaptic cleft inefficient, raising
cortical excitatory neurotransmission. This is explicitly a hypothesis in
the source knock-in study rather than a directly measured clearance deficit,
and is curated at that strength.
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: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: >-
Since several lines of evidence involve a specific role of the glial α2
Na,K pump in active reuptake of glutamate from the synaptic cleft, we
hypothesize that CSD facilitation in the FHM2 mouse model is sustained by
inefficient glutamate clearance by astrocytes and consequent increased
cortical excitatory neurotransmission.
explanation: >-
Supports the clearance-deficit mechanism, but the authors frame it as a
hypothesis inferred from the pump's known role rather than a measured
clearance deficit in the mutant mouse, hence PARTIAL.
downstream:
- target: Increased Cortical Glutamatergic Excitability
description: >-
Inefficient glutamate reuptake is proposed to raise cortical excitatory
neurotransmission.
- target: Reduced Cortical Spreading Depression Threshold
description: >-
The FHM2 knock-in mouse shows a decreased CSD induction threshold and
increased propagation velocity in vivo.
notes: >-
The two downstream edges are of different evidential strength. The edge to
the CSD threshold node is a directly measured in vivo result in the FHM2
mouse; the edge through glutamatergic excitability is the authors' proposed
intervening mechanism.
- name: GABAergic Interneuron Hyperactivity and Extracellular Potassium Accumulation
biological_scale: CELLULAR
description: >-
The FHM3-specific step, and a deliberate departure from the shared
glutamatergic route. Because Nav1.1 is the main sodium channel of
interneurons, FHM3 gain of function makes GABAergic neurons hyperexcitable.
Pharmacological Nav1.1 enhancement or optogenetic activation of GABAergic
interneurons is sufficient to ignite cortical spreading depression through
spiking-generated extracellular K+ build-up, and neither GABAergic nor
glutamatergic synaptic transmission is required for that initiation. The
effect is neocortex-specific.
biological_processes:
- preferred_term: GABAergic synaptic transmission
term:
id: GO:0051932
label: "synaptic transmission, GABAergic"
modifier: INCREASED
- preferred_term: potassium ion transmembrane transport
term:
id: GO:0071805
label: potassium ion transmembrane transport
modifier: INCREASED
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: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. Neither GABAergic nor
glutamatergic synaptic transmission were required for CSD initiation.
explanation: >-
Establishes the K+-mediated, transmission-independent route from
interneuron hyperactivity to CSD, which is what makes FHM3 mechanistically
distinct from FHM1 and FHM2. Graded IN_VITRO because the experiments
behind this claim - Hm1a application, optogenetic stimulation, and the
receptor- and Ca2+-channel-blockade series that establishes the
transmission independence - were performed in brain slices. The study's
in vivo arm is recorded as its own item below.
- 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
snippet: >-
These data confirm the results obtained in brain slices, showing that
overactivation of GABAergic neurons or NaV1.1 can lead to/facilitate CSD
induction also in vivo.
explanation: >-
The in vivo arm of the same study, separated out because it is a different
kind of evidence from the slice work above: it shows the effect survives
in an intact animal with blood flow, long-range connections and
neuromodulation present.
- 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: >-
Our results provide the mechanism linking NaV1.1 gain of function to CSD
generation in FHM3.
explanation: >-
Attributes the mechanism specifically to the FHM3 subtype. Graded OTHER
rather than IN_VITRO or MODEL_ORGANISM because it is the authors'
synthesis across all three arms of a mixed-design study - in vivo, brain
slices and cell lines - so no single study type supports it. The
component claims are graded individually above.
downstream:
- target: Reduced Cortical Spreading Depression Threshold
description: >-
Interneuron-driven extracellular K+ build-up is by itself sufficient to
ignite neocortical spreading depression.
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: Reduced Cortical Spreading Depression Threshold
biological_scale: TISSUE
description: >-
The unifying node of the entry. Cortical spreading depression (CSD) is a
slowly propagating wave of neuronal and glial depolarization that is the
neurophysiological correlate of migraine aura. FHM1 and FHM2 knock-in mice
both show a reduced CSD induction threshold and an increased propagation
velocity in vivo, and NaV1.1 gain of function ignites CSD directly - so all
three classical subtypes converge on a cortex that enters and propagates CSD
too readily.
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: DOI:10.1186/s10194-023-01547-8
reference_title: "Genetics of migraine: where are we now?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In monogenic migraines, including familial hemiplegic migraine and
migraine with aura associated with hereditary small-vessel disorders, the
identified genes code for proteins expressed in neurons, glial cells, or
vessels, all of which increase susceptibility to cortical spreading
depression.
explanation: >-
An independent review stating the same convergence claim this node makes,
and locating it across neuronal, glial and vascular cell types - which is
why the node carries both neuron and astrocyte cell types.
downstream:
- target: Reversible Hemiparetic Aura
description: >-
A propagating cortical depolarization wave produces the transient focal
neurological deficit that defines the aura, including its motor component.
- target: Prolonged Attacks with Cerebral Edema and Impaired Consciousness
description: >-
In severe alleles the same process is associated with prolonged deficits,
blood-brain barrier opening and cortical edema.
notes: >-
The threshold reduction has been measured directly only in FHM1 and FHM2
mouse models; the FHM3 contribution rests on pharmacological and optogenetic
ignition of CSD by NaV1.1 gain of function rather than an in vivo threshold
measurement in an FHM3 knock-in.
- name: Reversible Hemiparetic Aura
biological_scale: ORGANISM
description: >-
The defining clinical expression of the mechanism. Cortical spreading
depression through motor cortex and adjacent areas produces fully reversible
motor weakness, obligatorily accompanied by at least one of visual, sensory
or language aura. Deficits typically last under 72 hours but may persist for
hours to days and outlast the headache. Onset is usually in the first or
second decade and attack frequency decreases with age.
locations:
- preferred_term: brain
term:
id: UBERON:0000955
label: brain
evidence:
- reference: PMID:20301562
reference_title: Familial Hemiplegic Migraine.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
FHM must include motor involvement, such as hemiparesis (weakness of an
extremity). Hemiparesis occurs with at least one other symptom during FHM
aura.
explanation: >-
States the obligatory motor component and its obligatory pairing with
another aura symptom.
- reference: PMID:20301562
reference_title: Familial Hemiplegic Migraine.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Neurologic deficits with FHM attacks can be prolonged for hours to days
and may outlast the associated migrainous headache.
explanation: >-
Establishes that the aura deficit is reversible but may be much longer
than typical migraine aura.
- reference: PMID:37247170
reference_title: Hemiplegic Migraine.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Hemiplegic migraine is a severe subset of migraine with aura with symptoms
including reversible hemiparesis in addition to other aura symptoms such
as visual, sensory, or speech.
explanation: Contemporary review restating the defining clinical picture.
downstream:
- target: Migraine Headache Phase
description: >-
The aura is typically followed by, or accompanied by, migrainous headache.
- name: Migraine Headache Phase
biological_scale: ORGANISM
description: >-
The headache that follows or accompanies the hemiparetic aura. In hemiplegic
migraine the headache and aura biology are regarded as continuous with
typical migraine with aura, differing in threshold and severity rather than
in kind; the trigeminovascular mechanisms of the headache phase are curated
on the Migraine and Migraine with aura entries rather than duplicated here.
evidence:
- reference: PMID:32430436
reference_title: Diagnostic and therapeutic aspects of hemiplegic migraine.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The pathophysiology of HM is close to the process of typical migraine with
aura, but appearing with a lower threshold and more severity.
explanation: >-
Supports treating the headache phase as shared migraine biology and the
FHM-specific claim as one about threshold and severity.
- name: Prolonged Attacks with Cerebral Edema and Impaired Consciousness
biological_scale: ORGANISM
description: >-
A severe attack phenotype, most strongly associated with the CACNA1A S218L
allele, in which hemiplegia is accompanied by altered consciousness, fever
and, in some cases, delayed cerebral edema and coma - characteristically
provoked by minor head trauma. Blood-brain barrier opening preceding
cortical edema has been documented during a severe FHM2 attack.
locations:
- preferred_term: brain
term:
id: UBERON:0000955
label: brain
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: >-
Documents the severe S218L attack phenotype including trauma-provoked
cerebral edema and coma.
- 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, in addition to typical hemiplegic migraine attacks,
experienced severe episodes during which hemiplegia was associated with
acutely altered consciousness and fever lasting several days.
explanation: >-
An independent family showing the severe prolonged attack phenotype with
impaired consciousness and fever.
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.
- category: Neurological
name: Visual Aura
description: >-
Visual disturbance is the most common aura modality in migraine with aura,
including FHM.
phenotype_term:
preferred_term: Abnormality of vision
term:
id: HP:0000504
label: Abnormality of vision
temporality: TRANSIENT
evidence:
- reference: PMID:20301562
reference_title: Familial Hemiplegic Migraine.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
the neurologic symptoms of aura are unequivocally localizable to the
cerebral cortex or brain stem and include visual disturbance (most common)
explanation: >-
Identifies visual disturbance as the most common aura symptom in migraine
with aura including FHM.
notes: >-
Bound to the broad HP:0000504 rather than a specific visual-aura term
because the source states only "visual disturbance"; the specific aura
phenomenology (scintillating scotoma and similar) is curated on the
Migraine with aura entry.
- category: Neurological
name: Sensory Aura
description: >-
Numbness or paresthesias of the face or an extremity as an aura symptom.
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: Language 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: Brainstem (Basilar-Type) Aura Symptoms
description: >-
Aura symptoms localizing to the brainstem rather than the cerebral cortex,
the group historically called basilar migraine symptoms - vertigo, tinnitus,
hyperacusis, dysarthria, ataxia and impaired consciousness. In the Danish
population-based FHM series they occurred in 69% of patients during attacks,
which is why they are recorded here as a group as well as individually
below. They typically come last in the aura sequence, after the visual,
sensory, aphasic and motor symptoms.
frequency: FREQUENT
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: >-
Quantifies brainstem aura at 69% in 147 FHM patients ascertained
nationwide, which maps to the FREQUENT band (30-79%).
- 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: >-
Places the brainstem symptoms last in the aura sequence, which is the
timing claim in the description.
- 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: >-
Enumerates the individual brainstem aura symptoms that the 69% figure
covers, and is the source for the three specific phenotypes below.
notes: >-
Deliberately left without a phenotype_term. HPO has no brainstem-aura or
basilar-migraine class - a search of HP for "basilar" returns only skeletal
and vascular terms, and the migraine branch stops at HP:0002077 Migraine
with aura - so binding this group would mean choosing one constituent
symptom to stand for all of them. The constituents that do have HP terms
are curated as their own entries immediately below; ataxia and impaired
consciousness already have entries elsewhere in this section.
- 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.
notes: >-
Hyperacusis appears in the same list but is not curated separately, because
it is named only in this enumeration with no further characterization.
- 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.
- reference: PMID:41552155
reference_title: "Hemiplegic Migraine: An Imitator of Cerebrovascular Disease."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Patients frequently experience severe headache accompanied by photophobia,
numbness, tingling, paresthesias, dysarthria, and temporary motor
impairment that can persist from minutes to several days
explanation: >-
An independent source listing dysarthria among the attack features, and
the reason dysarthria is also part of the stroke-mimic differential.
- category: Neurological
name: Cerebellar Ataxia
description: >-
A permanent, usually late-onset and mild progressive cerebellar ataxia,
largely confined to the CACNA1A subtype.
subtype: FHM1
frequency: FREQUENT
phenotype_term:
preferred_term: Ataxia
term:
id: HP:0001251
label: Ataxia
clinical_course: PROGRESSIVE
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: >-
Quantifies the cerebellar phenotype in CACNA1A-FHM at 40-50% of families,
which maps to the FREQUENT band.
- 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: >-
Epilepsy co-occurs with FHM across all the FHM genes and is prevalent in
ATP1A2-FHM. In a systematic review of published FHM families, 78 of 195
individuals with accessible information had epilepsy, and drug-resistant
forms were rare.
phenotype_term:
preferred_term: Seizure
term:
id: HP:0001250
label: Seizure
evidence:
- reference: PMID:20301562
reference_title: Familial Hemiplegic Migraine.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Anti-seizure treatment may be necessary for seizures, which are prevalent
in ATP1A2-FHM.
explanation: >-
GeneReviews identifies seizures as a prevalent manifestation, especially
in the ATP1A2 subtype.
- 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: >-
Quantifies epilepsy co-occurrence across published FHM families. Note this
is a literature review of reported families, so it is subject to reporting
bias and is not a population frequency - which is why no frequency band is
asserted here.
- 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: Impaired Consciousness and Coma
description: >-
Severe attacks may involve acutely altered consciousness lasting days, and
the CACNA1A S218L allele in particular is associated with coma after minor
head trauma.
phenotype_term:
preferred_term: Coma
term:
id: HP:0001259
label: Coma
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: >-
This CACNA1A mutation has been associated with HM, delayed cerebral oedema
and coma following minor head trauma.
explanation: Documents coma as part of the severe S218L attack phenotype.
- 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: >-
Acute encephalopathy is the main manifestation of severe attacks of HM in
children, which adds to the difficulty of diagnosis.
explanation: >-
Extends the severe-attack phenotype beyond the S218L allele: in children
it is the leading presentation of a severe attack, across CACNA1A and
ATP1A2 alike.
- 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.
- 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 is reported among the persistent manifestations of
hemiplegic migraine, alongside cerebellar ataxia.
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.
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.
CACNA1A is the one FHM gene with a directly measured penetrance figure. In
a series of 117 genotyped carriers from families ascertained on hemiplegic
migraine with or without cerebellar signs, 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 pathogenic variants in a cohort of 697 consecutively screened
hemiplegic-migraine probands
case_fractions:
- population: French hemiplegic migraine cohort, 697 consecutive probands screened on four genes
case_fraction_percent: 26.0
cohort_size: 697
notes: >-
Share of the 105 individuals with a pathogenic variant, not of all
probands screened.
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 pathogenic variants in a cohort of 697 consecutively screened
hemiplegic-migraine probands
case_fractions:
- population: French hemiplegic migraine cohort, 697 consecutive probands screened on four genes
case_fraction_percent: 42.0
cohort_size: 697
notes: >-
Share of the 105 individuals with a pathogenic variant, not of all
probands screened.
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 pathogenic variants in a cohort of 697 consecutively screened
hemiplegic-migraine probands
case_fractions:
- population: French hemiplegic migraine cohort, 697 consecutive probands screened on four genes
case_fraction_percent: 15.0
cohort_size: 697
notes: >-
Share of the 105 individuals with a pathogenic variant, not of all
probands screened.
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 pathogenic variants in a cohort of 697 consecutively screened
hemiplegic-migraine probands
case_fractions:
- population: French hemiplegic migraine cohort, 697 consecutive probands screened on four genes
case_fraction_percent: 17.0
cohort_size: 697
notes: >-
Share of the 105 individuals with a pathogenic variant, not of all
probands screened.
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: HUMAN_CLINICAL
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 cohort study establishing PRRT2 as a bona fide hemiplegic-migraine
gene.
- reference: PMID:34649875
reference_title: >-
Hemiplegic Migraine Associated With PRRT2 Variations, A Clinical and
Genetic Study.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
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: HUMAN_CLINICAL
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' own qualification of the CACNA1I replication, which is why
this evidence item is PARTIAL.
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: Reduced Cortical Spreading Depression Threshold
environmental_effect: TRIGGERS
causal_link_type: DIRECT
description: >-
A weak mechanical stimulus is sufficient to ignite spreading depression in
a cortex whose threshold is already lowered, which is the step at which
trauma enters the causal chain.
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: Prolonged Attacks with Cerebral Edema and Impaired Consciousness
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: MODEL_ORGANISM
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: Reduced Cortical Spreading Depression Threshold
environmental_effect: TRIGGERS
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Named among the common precipitants of a hemiplegic migraine attack. The
route from stress to the threshold node is not characterized, hence
INDIRECT_UNKNOWN_INTERMEDIATES.
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: Reduced Cortical Spreading Depression Threshold
environmental_effect: TRIGGERS
causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
description: >-
Named among the common precipitants of an attack. No mechanism connecting
infection to the threshold node has been established, hence
INDIRECT_UNKNOWN_INTERMEDIATES.
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 Hemiparetic 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, hence PARTIAL.
evidence:
- reference: PMID:20301562
reference_title: Familial Hemiplegic Migraine.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
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: >-
Acute treatment of the headache phase is analgesic rather than
migraine-specific, because the migraine-specific acute drugs (triptans,
ergots) are the ones contraindicated here. This is the practical
counterpart of the avoidance entry below: what is left once the
vasoconstrictors are removed.
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: HUMAN_CLINICAL
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: HUMAN_CLINICAL
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: HUMAN_CLINICAL
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 is why this item is PARTIAL.
- reference: PMID:20301562
reference_title: Familial Hemiplegic Migraine.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
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: HUMAN_CLINICAL
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: HUMAN_CLINICAL
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: HUMAN_CLINICAL
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: HUMAN_CLINICAL
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: HUMAN_CLINICAL
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: HUMAN_CLINICAL
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: HUMAN_CLINICAL
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: HUMAN_CLINICAL
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: Reduced Cortical Spreading Depression Threshold
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: Reduced Cortical Spreading Depression Threshold
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: Reduced Cortical Spreading Depression Threshold
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.
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.
modeled_mechanisms:
- target: Reduced Cortical Spreading Depression Threshold
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 triggering threshold and event count
target: Reduced Cortical Spreading Depression Threshold
description: >-
Threshold, propagation velocity, and number of CSD events elicited by
a single stimulus.
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.
- 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.
- target: Prolonged Attacks with Cerebral Edema and Impaired Consciousness
relationship: PARTIALLY_RECAPITULATES
fidelity: MODERATE
description: >-
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.
limitations: >-
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: >-
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' own claim is explicitly a proposal - may provide - which
is why this link is PARTIALLY_RECAPITULATES and the evidence item is
PARTIAL.
- 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.
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.
modeled_mechanisms:
- target: Reduced Cortical Spreading Depression Threshold
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: >-
Same anaesthetised-cortex and species caveats as the FHM1 models. The
astrocytic glutamate-clearance step that would connect the pump defect
to the threshold is offered as a hypothesis in this work, not measured.
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 and velocity
target: Reduced Cortical Spreading Depression Threshold
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.
- 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.
- target: Reversible Hemiparetic Aura
relationship: FAILS_TO_RECAPITULATE
fidelity: LOW
description: >-
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.
limitations: >-
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: 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.
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.
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#Reduced Cortical Spreading Depression Threshold
- pathophysiology#Increased Cortical Glutamatergic Excitability
- pathophysiology#GABAergic Interneuron Hyperactivity and Extracellular Potassium Accumulation
rationale: >-
The convenient summary of FHM is that all three ion-transport defects raise
cortical glutamatergic excitability and so lower the CSD threshold. FHM1 and
FHM2 do fit that account - increased presynaptic Ca2+ influx and glutamate
release in one case, impaired astrocytic glutamate and K+ clearance in the
other. FHM3 does not. Nav1.1 is the principal sodium channel of GABAergic
interneurons, and the experiment that established the FHM3 mechanism found
that CSD could be ignited by interneuron hyperactivity through
spiking-generated extracellular K+ build-up with neither GABAergic nor
glutamatergic synaptic transmission required. Extracellular K+ accumulation
is therefore a candidate common currency that would unify all three arms,
but that unification has not been demonstrated: no study has measured the
same threshold-setting variable across FHM1, FHM2 and FHM3 models under
comparable conditions. This entry curates FHM3 as a parallel arm rather than
folding it into the glutamatergic node, because asserting a single
glutamate-mediated convergence would overstate what the evidence shows.
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.
- 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#Reduced Cortical Spreading Depression Threshold
- pathophysiology#Reversible Hemiparetic Aura
rationale: >-
The central mechanistic claim of this entry - that FHM variants lower the
CSD threshold - rests on transgenic mouse data. The CSD-threshold node is
supported entirely by MODEL_ORGANISM evidence, and the step from that
threshold to the reversible motor weakness seen in patients is inferred
rather than measured: CSD has not been recorded directly during a
spontaneous human FHM attack, and the human evidence is indirect
(aura semiology, imaging correlates, and the clinical genetics). The
mismatch is mechanistically meaningful because mouse CSD threshold is
assayed with an experimental stimulus applied to anaesthetised cortex,
which measures susceptibility to provoked CSD rather than whatever
initiates a spontaneous attack, and because the motor cortex representation
that would have to be traversed to produce hemiparesis differs
substantially between the lissencephalic mouse and the human brain. It is
recorded as a HUMAN_MODEL_MISMATCH rather than a KNOWLEDGE_GAP because the
model evidence is strong and reproducible; what is open is its
translational validity, not its existence.
The structural counterpart of this discussion is in animal_models: the
R192Q, S218L and W887R knock-in links all carry the anaesthetised-cortex
and species caveats in their limitations, and the FHM2 W887R model records
a FAILS_TO_RECAPITULATE link against Reversible Hemiparetic Aura - the
heterozygous mutant has the cortical CSD phenotype and no apparent clinical
phenotype. That negative result is the sharpest form of the mismatch: the
one model in which the threshold change and the clinical attack could have
been observed together shows only the former.
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.
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.
References & Deep Research
References
2Familial Hemiplegic Migraine.
No top-level findings curated for this source.
Genetics of migraine: complexity, implications, and potential clinical applications
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.
Deep Research
1
Falcon
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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
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(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.
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(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.
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(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.
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(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.
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(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.
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(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.
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(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.
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(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.
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(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.
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(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.
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(NCT00541736 chunk 1): Glyceryl-Trinitrate-Induced Headache in Patients With Familial Hemiplegic Migraine. Danish Headache Center. 2007. ClinicalTrials.gov Identifier: NCT00541736
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(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
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(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.
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(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.
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(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.
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(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.
Artifacts
Reference Validation
Checked with linkml-reference-validator 0.2.1.
| Outcome | Count |
|---|---|
| References checked | 10 |
| Resolved | 8 |
| Unresolved (possible confabulation) | 0 |
| Unverifiable | 2 |
| References weighed for topical relevance | 8 |
| On topic | 5 |
| Off topic | 0 |
8 of 10 references resolved; the rest could not be looked up either way.