Hemiplegic Migraine Associated With Variations: A Clinical and Genetic Study

Background And Objective: variants have been reported in a few cases of patients with hemiplegic migraine. To clarify the role of in familial hemiplegic migraine, we studied this gene in a large cohort of affected probands.

Methods: was analyzed in 860 probands with hemiplegic migraine, and variations were identified in 30 probands. Genotyping of relatives identified a total of 49 persons with variations whose clinical manifestations were detailed.

Results: variations were found in 12 of 163 probands who previously tested negative for , , and variations and in 18 of 697 consecutive probands screened simultaneously on the 4 genes. In this second group, pathogenic variants were found in 105 individuals, mostly in (42%), followed by (26%), 17%), and (15%). The variations included 7 distinct variants, 5 of which have already been described in persons with paroxysmal kinesigenic dyskinesia and 2 new variants. Eight probands had a deletion of the whole gene. Among the 49 patients with variations in , 26 had pure hemiplegic migraine and 16 had hemiplegic migraine associated with another manifestation: epilepsy (8), learning disabilities (5), hypersomnia (4), or abnormal movement (3). Three patients had epilepsy without migraine: 2 had paroxysmal kinesigenic dyskinesia without migraine, and 1 was asymptomatic.

Discussion: should be regarded as the fourth autosomal dominant gene for hemiplegic migraine and screened in any affected patient, together with the 3 other main genes. Further studies are needed to understand how the same loss-of-function variations can lead to a wide range of neurologic phenotypes, including paroxysmal movement disorder, epilepsy, learning disabilities, sleep disorder, and hemiplegic migraine.