MOLECULAR ANALYSIS AND CLINICAL CORRELATIONS OF THE HUNTINGTONS-DISEASE MUTATION

The genetic mutation underlying Huntington's disease (HD) has been ide ntified as an expansion and instability of a specific CAG repeat seque nce in a gene (IT15) on chromosome 4. We have investigated the relatio n of the phenotype of HD to this molecular defect and assessed the fea sibility of HD mutation analysis in diagnosis and prediction. Analysis of DNA from 449 HD patients (351 familial and 98 apparently isolated cases) revealed the mutation in more than 95% of patients from both gr oups. No molecular difference was found between patients presenting wi th psychiatric symptoms and those in whom chorea or other motor defect s were the principal features; additionally, there was a wide range of age at onset for any specific repeat number, though the small group w ith juvenile onset and presenting with rigidity showed the largest exp ansions. The findings suggest that molecular analysis will be an accur ate and specific diagnostic test for HD and valuable in presymptomatic detection in individuals at risk. However, such testing will require considerable caution to avoid serious difficulties; the well-establish ed guidelines developed for the use of linked markers in relation to t he prediction of HD should continue to be followed, though they will r equire reassessment in relation to use in diagnosis.