A Novel Frameshift CACNA1A Mutation Causing Episodic Ataxia Type 2

The alpha-1A subunit of neuronal voltage-dependent P/Q-type Ca2+ channels is encoded by the CACNA1A gene, and mutations in CACNA1A result in channelopathies originally thought to cause distinct, well-known allelic disorders: Spinocerebellar ataxia type 6 (SCA6), familiar hemiplegic migraine (FHM), and episodic ataxia type 2 (EA2) [4]. Certain CACNA1A mutation types are more frequently associated with distinct phenotypes: missense mutations with FHM, mutations resulting in a premature stop with EA2, and an exonic CAG trinucleotide repeat expansion with SCA6 (http://www.hgmd.cf.ac.uk/ac/gene.php?gene=CACNA1A). Recent reports, however, revealed an extensive clinical overlap between these three phenotypes [1, 9] and a high intrafamilial phenotypic variability [5, 7]. In addition, new phenotypes including seizures and mental retardation have been reported [1].

Here, we describe the identification and functional characterization of a novel CACNA1A mutation in a patient with EA2. We highlight that mutations in genes being associated with paroxysmal disorders may be overlooked as the symptomatology may be misclassified as psychogenic especially when the family history is negative.

The genetic study was approved by the ethics committee of the University of Luebeck.