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.

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

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

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

1. Upstream germline lesion: altered CACNA1A, ATP1A2, or SCN1A protein function.
2. Cellular ion-homeostasis defect: excessive presynaptic Ca²⁺-dependent glutamate release (FHM1), impaired astrocytic K⁺/glutamate clearance (FHM2), or altered interneuron/network excitability (FHM3).
3. Network consequence: increased extracellular glutamate/K⁺ and impaired cortical excitation–inhibition balance.
4. Threshold event: easier initiation and propagation of CSD—a slowly advancing wave of neuronal/glial depolarization followed by suppression of activity.
5. Clinical aura: propagation through visual, somatosensory, language, and motor cortex produces corresponding positive and negative neurological symptoms, including hemiparesis.
6. 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

1. Begin with a multigene episodic-neurology/HM panel including CACNA1A, ATP1A2, and SCN1A, with deletion/duplication analysis.
2. 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.
3. Use trio WES or WGS when panel-negative, syndromic, very early onset, or severe; WGS is preferable for noncoding and structural variants.
4. 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:

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

Pharmacotherapy

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

1. 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)
2. Treatment: adequately powered prospective multicenter registries and genotype-stratified trials are the largest unmet need. Current prescribing is largely empirical.
3. Biomarkers: no molecular or imaging marker reliably distinguishes HM from stroke during an acute presentation.
4. Natural history: incidence, penetrance by variant, FHM-specific quality-of-life scores, permanent-deficit rates, pregnancy outcomes, and mortality remain poorly quantified.
5. 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

1. (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.

2. (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.

3. (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.

4. (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.

5. (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.

6. (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.

7. (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.

8. (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.

9. (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.

10. (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.

11. (NCT00541736 chunk 1): Glyceryl-Trinitrate-Induced Headache in Patients With Familial Hemiplegic Migraine. Danish Headache Center. 2007. ClinicalTrials.gov Identifier: NCT00541736

12. (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

13. (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.

14. (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.

15. (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.

16. (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

• Edison artifact artifact-00

Reference Validation

Checked with linkml-reference-validator 0.2.1.

8 of 10 references resolved; the rest could not be looked up either way.