Familial haemiplegic migraine

FHM is a rare and severe phenotype of migraine with aura. The neurological symptoms of aura are unequivocally localisable to the cerebral cortex or brain stem and include fully reversible visual disturbance (most common), sensory loss (numbness or paraesthesias of the face or an extremity), and dysphasia; motor involvement, typically hemiparesis, is mandatory for the diagnosis. Impaired consciousness ranging from drowsiness to coma is well described, and neurological deficits may persist for hours to days, outlasting the migrainous headache. Severity ranges from rare brief hemiparetic episodes to prolonged attacks complicated by coma, seizures or cerebral oedema. Onset is typically from childhood to early adulthood. Attack frequency ranges from one per day to fewer than five in a lifetime (mean 2-3 per year); long attack-free intervals (2-37 years) are common, and frequency tends to decrease with age. Seizures are a recognised feature, reflecting clinical and mechanistic overlap between epilepsy and migraine.

The estimated prevalence is 1/10,000. The female-to-male ratio is 3:1, with equal proportions of familial and simplex cases.

FHM is caused by heterozygous germline pathogenic variants in genes encoding neuronal ion channels and transporters that regulate cortical synaptic transmission. Four genes are implicated: CACNA1A (~12.5% of FHM), ATP1A2 (~10%), PRRT2 (~2.5%) and SCN1A (<1%). FHM-causing variants increase susceptibility to cortical spreading depolarisation: CACNA1A gain-of-function increases presynaptic glutamate release, ATP1A2 haploinsufficiency impairs synaptic glutamate clearance, SCN1A gain-of-function leads to hyperexcitation of GABAergic interneurons, and PRRT2 loss-of-function disrupts synaptic neurotransmission and voltage-gated channel regulation.

FHM is inherited in an autosomal dominant manner. Each child of an affected individual has a 50% chance of inheriting the familial pathogenic variant. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

The clinical diagnosis of FHM is established using the criteria. Neuroimaging is used to exclude alternative causes such as stroke, MELAS or CADASIL; no pathognomonic findings exist for FHM, although transient diffusion-weighted MRI changes consistent with cytotoxic oedema may appear during severe prolonged attacks.

Main differential diagnoses include:

• : migraine with aura, ischaemic stroke, cognitive decline, white-matter lesions; NOTCH3
• Mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS): migraine, stroke-like episodes, encephalopathy, hearing loss; mtDNA (MT-TL1)
• Alternating hemiplegia of childhood: transient hemiplegia onset before age 18 months, cognitive decline; ATP1A2, ATP1A3

• Establishing the diagnosis allows for accurate genetic counselling and informs medical management decisions.
• Identifying the underlying pathogenic variant supports specific and individualised surveillance for changes in attack frequency, seizures, movement disorders or learning difficulties, providing the prerequisite for targeted medical care decided by the treating physicians in consultation with the affected individual.
• Once the familial pathogenic variant has been identified, predictive testing can be offered to at-risk family members.

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