| 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. (pqac-00000010, pqac-00000015) | 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. (pqac-00000010, pqac-00000015) |
| 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. (pqac-00000011, pqac-00000015, pqac-00000016) | 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. (pqac-00000011, pqac-00000015, pqac-00000016) |
| 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. (pqac-00000009, pqac-00000011) | 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. (pqac-00000009, pqac-00000011) |
| 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. (pqac-00000014, pqac-00000016, pqac-00000000) | 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. (pqac-00000014, pqac-00000016, pqac-00000000) |
| 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. (pqac-00000011, pqac-00000006, pqac-00000015) | 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. (pqac-00000011, pqac-00000006, pqac-00000015) |
| 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. (pqac-00000010, pqac-00000011, pqac-00000013) | 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. (pqac-00000011, pqac-00000013) |
| 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. (pqac-00000014, pqac-00000015, pqac-00000009) | 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. (pqac-00000014, pqac-00000015, pqac-00000009) |
| 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. (pqac-00000017, pqac-00000010, pqac-00000016) | 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. (pqac-00000017, pqac-00000010) |
| 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. (pqac-00000008, pqac-00000012, pqac-00000016) | 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. (pqac-00000008, pqac-00000012, pqac-00000016) |
| 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. (pqac-00000010, pqac-00000011, pqac-00000016) | 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. (pqac-00000010, pqac-00000016) |
| 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. (pqac-00000014, pqac-00000001, pqac-00000000) | 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. (pqac-00000014, pqac-00000001, pqac-00000000) |


*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.*