CORRELATION BETWEEN CAG REPEAT LENGTH AND CLINICAL-FEATURES IN MACHADO-JOSEPH DISEASE

Machado-Joseph disease (MJD) is associated with the expansion of a CAG trinucleotide repeat in a novel gene on 14q32.1. We confirmed the pre sence of this expansion in 156 MJD patients from 33 families of differ ent geographic origins: 15 Portuguese Azorean, 2 Brazilian, and 16 Nor th American of Portuguese Azorean descent. Normal chromosomes contain between 12 and 37 CAG repeats in the MJD gene, whereas MJD gene carrie rs have alleles within the expanded range of 62-84 CAG units. The dist ribution of expanded alleles and the gap between normal and expanded a llele sizes is either inconsistent with a premutation hypothesis or mo st (if not all) of the alleles we studied descend from a common ancest or. There is a strong correlation between the expanded repeat size and the age at onset of the disease as well as the clinical presentation. There is mild instability of the CAG tract length with transmission o f the expanded alleles; both increase and decrease in size between par ents and progeny occur, with Larger variations in male than in female transmissions. Together, these effects can partly explain the variabil ity of age at onset and of phenotypic features in MJD; however, other modifying factors must exist.