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-d ependent calcium channel subunit are responsible for familial hemipleg ic migraine (FHM) and episodic ataxia type 2 (EA2). In addition, expan sions of the CAG repeat motif at the 3' end of the gene, smaller than those responsible for dynamic mutation disorders, were found in patien ts with a progressive spinocerebellar ataxia, named SCAG, In the prese nt work, the analysis of two new families with small CAG expansions of the CACNA1A gene is presented, in one family, with a clinical diagnos is of EA2, a CAG(23) repeat allele segregated in patients showing diff erent interictal symptoms, ranging from nystagmus only to severe progr essive 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 domina nt cerebellar ataxia of unknown type, an inter-generational allele siz e change showed that a CAG(20) allele was associated with an EA2 pheno type and a CAG(25) allele with progressive cerebellar ataxia, These re sults show that EA2 and SCAG are the same disorder with a high phenoty pic 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 sequence s of the CACNA1A gene is also provided.