Phenotypes of Spinocerebellar Ataxia Type 6 and Familial Hemiplegic Migraine Caused by a Unique CACNA1A Missense Mutation in Patients From a Large Family

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Abstract
Background Different mutations in the α1A-subunit of the brain P/Q-type calcium channel gene (CACNA1A) are responsible for familial hemiplegic migraine (FHM), episodic ataxia type 2, and spinocerebellar ataxia type 6 (SCA6). Missense and splice site mutations have been found in FHM and episodic ataxia type 2, respectively, whereas a CAG repeat in theCACNA1Agene was found expanded in patients with SCA6. Objective To identify the disease causing mutation in a large family of patients with phenotypes of hemiplegic migraine with or without cerebellar signs or permanent cerebellar ataxia without migraine inherited in a dominant manner. Patients and Methods We examined 15 patients from a large family identified through a systematic survey of hereditary ataxias being conducted in Portugal. Linkage analysis was performed withCACNA1Agene markers, and mutation analysis was performed by single strand conformational polymorphism analysis and sequencing. Results Genetic linkage analysis withCACNA1Aintragenic markers showed positive LOD scores. The maximal LOD score was obtained with the polymorphic CAG repeat (Zmax= 4.47, θ = 0). By single-strand conformational polymorphism analysis, a shift in exon 13 of theCACNA1Agene was detected in all patients. A G-to-A substitution was then identified, resulting in an arginine-to-glutamine change at codon 583 of this calcium channel α1A-subunit. Conclusions The disease-causing mutation in this family was identified, showing that a unique mutation in theCACNA1Agene causes several phenotypes, including those of SCA6 and FHM, thus suggesting that SCA6 and FHM are not only allelic diseases but are the same disorder with a large phenotypic variability.