Missense CACNA1A mutation causing episodic ataxia type 2

Objectives: To characterize the nature of CACNA1A mutation in a previously unreported family with episodic ataxia type 2 (EA2) and to better delineate EA2 clinical features. Background: Episodic ataxia type 2 is an autosomal dominant disorder characterized by the recurrence of acetazolamide-responsive spells of cerebellar ataxia, usually starting during childhood or adolescence. The mutated gene, CACNA1A, is located on chromosome 19 and encodes the alpha 1A subunit voltage-dependent calcium channel. So far, most CACNA1A mutations detected in patients with EA2 have led to a truncated CACNA1A protein, whereas missense mutations cause familial hemiplegic migraine. Methods: All 47 exons of CACNA1A were screened by a combination of single-strand conformer polymorphism and sequencing analysis. Results: A CACNA1A missense mutation, Glu 1757 Lys, was identified. it was absent in 200 control chromosomes. it is predicted to result in an amino acid substitution at a highly phylogenetically conserved position, within a domain that plays a major role in the function of the channel. Conclusions: The Glu 1757 Lys missense mutation is likely to be pathogenic, causing episodic ataxia within a family whose phenotype is indistinguishable from EA2 except for a slightly later age of onset. These data strongly suggest that additional work is needed to fully establish genotype/phenotype correlations for CACNA1A mutations.