Prolonged hemiplegic episodes in children due to mutations in ATP1A2

Background

Familial hemiplegic migraine (FHM) is an unusual migraine syndrome characterised by recurrent transient attacks of unilateral weakness or paralysis as part of the migraine aura. Genetically and clinically heterogeneous, FHM1 is caused by mutations in CACNA1A and FHM2 by mutations in ATP1A2.

Aim

Three children with prolonged hemiplegia were tested for mutations in CACNA1A or ATP1A2.

Methods

Mutations in CACNA1A and ATP1A2 were screened for by denaturing high performance liquid chromatography and confirmed by sequencing. Expression studies were performed to characterise the functional consequences of these mutations.

Results

No mutation was found in the FHM1 gene while three mutations were identified in the FHM2 gene. All three mutations were missense: two were novel and one was de novo; none was found in controls. Functional studies in HeLa cells showed complete loss of mutant pump function without interfering with the wild‐type pump, consistent with haploinsufficiency.

Conclusion

We identified novel disease causing mutations in the FHM2 gene. Genetic screening for FHM should be considered in a child with prolonged hemiplegia even if there is no prior history or family history of migraine or hemiplegic episodes.Familial hemiplegic migraine (FHM) is a rare form of migraine with aura, typically inherited in an autosomal dominant fashion although sporadic cases have also been observed. A typical attack of FHM begins with unilateral paresthesia and weakness lasting from 30 to 60?min, followed by a severe pulsatile headache (often contralateral) lasting several hours. Other neurological symptoms may accompany the hemiparesis, including hemianoptic field defects, aphasia, confusion and even coma. Some patients with FHM have brainstem and cerebellar symptoms, and there appears to be an overlap between the clinical features of FHM and basilar migraine.¹Genetic heterogeneity has clearly been documented for FHM.² Mutations in three genes have been identified in families with FHM: CACNA1A (FHM1 OMIM 141500), encoding a neuronal calcium channel subunit³; ATP1A2 (FHM2; MIM 602481), encoding a catalytic subunit of a sodium potassium ATPase⁴; and SCN1A (FHM3; MIM 609634), encoding a neuronal sodium channel subunit,⁵ previously shown to be involved in rare epilepsy syndromes.^6,7 These genes code for transmembrane ion channels and ion pumps heavily expressed in the brain. Mutations in CACNA1A also cause episodic ataxia type 2 (EA2; MIM 108500)³ and most families with hemiplegic migraine caused by mutation in CACNA1A also have ataxia and interictal nystagmus.⁸ Families with mutations in ATP1A2 and SCN1A often have seizures in addition to hemiplegic migraine.^4,5In this report, we describe three children with mutations in ATP1A2 who presented with prolonged hemiplegic episodes lasting more than a week. In two of the children, this was their first episode of hemiplegia. The third child had prior, more typical episodes of hemiplegic migraine (lasting about 30?min), but had no family history of FHM. In this case, we were able to document that the mutation was de novo as neither parent harboured the mutation.