TRINUCLEOTIDE EXPANSION WITHIN THE MJD1 GENE PRESENTS CLINICALLY AS SPINOCEREBELLAR ATAXIA AND OCCURS MOST FREQUENTLY IN GERMAN SCA PATIENTS

Autosomal dominant spinocerebellar ataxia (SCA) is a clinically and ge netically heterogeneous neurodegenerative disorder which leads to prog ressive cerebellar ataxia, A gene responsible for SCA type 3 has been mapped to human chromosome 14q, close to the Machado-Joseph disease (M JD) locus. The MJD1 gene has recently been cloned and the disease caus ing mutation has been identified as an unstable and expanded (GAG)(n) trinucleotide repeat. As some clinical features of MJD overlap with th ose of SCA we investigated the MJD mutation in 38 German families with dominantly inherited SCA. The MJD1 (GAG)(n) expansion was identified in 19 families, In contrast, the trinucleotide expansion was not obser ved in 21 ataxia patients without family history of the disease, Analy sis of the (GAG)(n) repeat length in 30 patients revealed an inverse c orrelation with the age of onset, The (GAG)(n) stretch of the affected allele varied between 67 and 78 trinucleotide units, the normal allel es carried between 12 and 28 simple repeats, These results demonstrate that the MJD mutation causes the disease phenotype of most SCA patien ts in Germany.