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 charac
terized 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 volt
age-dependent calcium channel. So far, most CACNA1A mutations detected in p
atients 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-s
trand 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 ac
id substitution at a highly phylogenetically conserved position, within a d
omain 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 indistinguishab
le from EA2 except for a slightly later age of onset. These data strongly s
uggest that additional work is needed to fully establish genotype/phenotype
correlations for CACNA1A mutations.