DNA ANALYSIS IN HEREDITARY DENTATORUBRAL-PALLIDOLUYSIAN ATROPHY - CORRELATION BETWEEN CAG REPEAT LENGTH AND PHENOTYPIC VARIATION AND THE MOLECULAR-BASIS OF ANTICIPATION

Hereditary dentatorubral-pallidoluysian atrophy (DRPLA) is an autosoma l dominant neurodegenerative disease with variable clinical phenotypes . Progressive ataxia, choreoathetosis, and dementia are the main clini cal features of adult-onset cases, whereas the main feature in juvenil e-onset DRPLA is progressive myoclonus epilepsy. Earlier onset is appa rent in successive generations (anticipation). The molecular abnormali ty underlying DRPLA is an expanded, unstable CAG trinucleotide repeat on chromosome 12p. We analyzed 71 DNA samples obtained from 12 Japanes e DRPLA pedigrees that included 38 affected individuals. Normal allele s had 7 to 23 repeats, DRPLA alleles 53 to 88 repeats. DRPLA alleles a lso were detected in five asymptomatic family members. Patients with j uvenile onset had significantly larger repeats than did those with adu lt onset, and there was a significant negative correlation between CAG repeat length and age at onset. In 80% of the paternal transmissions, there was an increase of more than five repeats, whereas all the mate rnal transmissions showed either a decrease or an increase of fewer th an five repeats. There was a significant correlation between father-ch ild differences in repeat length and differences in age at onset. The analysis of CAG repeat length is a reliable diagnostic test for DRPLA and is of value for the presymptomatic detection of individuals at ris k. The expansion of CAG repeats is important in phenotypic variation a nd anticipation. In addition, the sex of the transmitting parent has a significant effect on the molecular mechanism of anticipation.