Hemiplegic migraine (HM) is a rare and severe subtype of autosomal dominant migraine, characterized by a complex aura including some degree of motor weakness. Mutations in four genes (CACNA1A, ATP1A2, SCN1A and PRRT2) have been detected in familial and in sporadic cases. This genetically and clinically heterogeneous disorder is often accompanied by permanent ataxia, epileptic seizures, mental retardation, and chronic progressive cerebellar atrophy. Here we report a mutation screening in the CACNA1A and ATP1A2 genes in 18 patients with HM. Furthermore, intragenic copy number variant (CNV) analysis was performed in CACNA1A using quantitative approaches. We identified four previously described missense CACNA1A mutations (p.Ser218Leu, p.Thr501Met, p.Arg583Gln, and p.Thr666Met) and two missense changes in the ATP1A2 gene, the previously described p.Ala606Thr and the novel variant p.Glu825Lys. No structural variants were found. This genetic screening allowed the identification of more than 30% of the disease alleles, all present in a heterozygous state. Functional consequences of the CACNA1A-p.Thr501Met mutation, previously described only in association with episodic ataxia, and ATP1A2-p.Glu825Lys, were investigated by means of electrophysiological studies, cell viability assays or Western blot analysis. Our data suggest that both these variants are disease-causing.

The work was funded by the Spanish Ministry of Science and Innovation, the Spanish Ministry of Economy and Competitiveness,Fondos Europeos de Desarrollo Regional (FEDER) and Plan E (Grants SAF2012 -31089, SAF2012-3814 0, BES-2010-033895, SAF2009-13182-C03-01,/nSAF2009-13182-C03-02, and SAF2009-13182-C03-03), Fondo de Investigación Sanitaria (Cardiovascular Disease Network RD12/0042/0014) and Generalitat de Catalunya (grants 2009SGR0971, 2009SGR0078 and 2009SGR1369). M. A. V. and N. F.-C. are the recipients of an ICREA Academia Award (Generalitat de Catalunya) and a grant from “CIBER-ER,” respectively. C. T. was supported by the European Union (Marie Curie, PIEF-GA-2009-254930).