Trinucleotide expansion within the <i>MJD1</i> gene presents clinically as spinocerebellar ataxia and occurs most frequently in German SCA patients

Autosomal dominant spinocerebellar ataxia (SCA) is a clinically and genetically heterogeneous neurodegenerative disorder which leads to progressive cerebellar ataxia. A gene responsible for SCA type 3 has been mapped to human chromosome 14q, close to the Machado-Joseph disease (MJD) locus. The MJD1 gene has recently been cloned and the disease causing mutation has been identified as an unstable and expanded (CAG)n trinucleotide repeat. As some clinical features of MJD overlap with those of SCA we investigated the MJD mutation in 38 German families with dominantly inherited SCA. The MJD1 (CAG)n expansion was identified in 19 families. In contrast, the trinucleotide expansion was not observed in 21 ataxia patients without family history of the disease. Analysis of the (CAG)n repeat length in 30 patients revealed an inverse correlation with the age of onset. The (CAG)n stretch of the affected allele varied between 67 and 78 trinucleotide units, the normal alleles carried between 12 and 28 simple repeats. These results demonstrate that the MJD mutation causes the disease phenotype of most SCA patients in Germany.