Abstract
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.