Trinucleotide repeat length and clinical progression in Huntington's disease

We examined the relationship between length of the trinucleotide (CAG) repeat at IT-15 and clinical progression of Huntington's disease in 46 mildly to moderately affected patients over a 2-year interval. Patients were divided into those with short mutations (37 to 46 repeats; n = 25) and those with long mutations (greater than or equal to 47 repeats; n = 21). Patients with long repeat lengths had earlier age at onset and were younger and less functionally impaired than those with short repeats at the initial visit, but the groups did not differ in severity of neurologic or cognitive impairment. However, the long-repeat group displayed significantly greater decline in both neurologic and cognitive functioning over the 2-year follow-up period. The length of the CAG repeat correlated highly with age at onset (r = -0.72, p < 0.001) and was a strong predictor of decline in both neurologic and cognitive function. The mechanism of gene action, and the means by which longer expansions result in a more malignant disease process, remain to be elucidated.