JAPANESE FAMILIES WITH AUTOSOMAL-DOMINANT PURE CEREBELLAR-ATAXIA MAP TO CHROMOSOME 19P13.1-P13.2 AND ARE STRONGLY ASSOCIATED WITH MILD CAG EXPANSIONS IN THE SPINOCEREBELLAR ATAXIA TYPE-6 GENE IN CHROMOSOME 19P13.1

Autosomal dominant cerebellar ataxia is a group of clinically and gene tically heterogeneous disorders, We carried out genomewide linkage ana lysis in 15 families with autosomal dominant pure cerebellar ataxia (A DPCA). Evidence for linkage to chromosome 19p markers was found in nin e families, and combined multipoint analysis refined the candidate reg ion to a 13.3-cM interval in 19p13.1-p13.2. The remaining six families were excluded for this region. Analysis of GAG-repeat expansion in th e alpha1A-voltage-dependent calcium channel (CACNL1A4) gene lying in 1 9p13.1, recently identified among 8 small American kindreds with ADPCA (spino-cerebellar ataxia type 6 [SCA6]), revealed that 8 of the 15 fa milies studied had similar, very small expansion in this gene: all aff ected individuals had larger alleles (range of CAG repeats 21-25), com pared with alleles observed in neurologically normal. Japanese (range 5-20 repeats). Inverse correlation between the GAG-repeat number and t he age at onset was found in affected individuals with expansion. The number of CAG repeats in expanded chromosomes was completely stable wi thin each family, which was consistent with the fact that anticipation was not statistically proved in the SCA6 families that we studied, We conclude that more than half of Japanese cases of ADPCA map to 19p13. 1-p13.2 and are strongly associated with the mild CAG expansion in the SCAG/CACNL1A4 gene.