Episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6) due to CAG repeat expansion in the CACNA1A gene on chromosome 19p

Point mutations of the CACNA1A gene coding for the alpha(1A) voltage-dependent calcium channel subunit are responsible for familial hemiplegic migraine (FHM) and episodic ataxia type 2 (EA2). In addition, expansions of the CAG repeat motif at the 3' end of the gene, smaller than those responsible for dynamic mutation disorders, were found in patients with a progressive spinocerebellar ataxia, named SCAG, In the present work, the analysis of two new families with small CAG expansions of the CACNA1A gene is presented, in one family, with a clinical diagnosis of EA2, a CAG(23) repeat allele segregated in patients showing different interictal symptoms, ranging from nystagmus only to severe progressive cerebellar ataxia, No additional mutations in coding and intron-exon junction sequences in disequilibrium with the CAG expansion were found, In the second family, initially classified as autosomal dominant cerebellar ataxia of unknown type, an inter-generational allele size change showed that a CAG(20) allele was associated with an EA2 phenotype and a CAG(25) allele with progressive cerebellar ataxia, These results show that EA2 and SCAG are the same disorder with a high phenotypic variability, at least partly related to the number of repeats, and suggest that the small expansions may not be as stable as previously reported, A refinement of the coding and intron-exon junction sequences of the CACNA1A gene is also provided.