Clinical severity of Huntington's disease does not always correlate with neuropathologic stage

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by a triplet-repeat, CAG expansion mutation. Although CAG repeat length is thought to correlate with pathologic burden and disease severity, considerable variability in clinical phenotype remains. This study examined whether neuropathologic burden at autopsy corresponded with severity of clinical phenotype in HD. The brains of 24 patients with a clinical and genetic diagnosis of HD were analyzed at autopsy. Subjects were stratified on the basis of Vonsattel staging as mild/moderate (stage 1-2; n = 7) or severe (stage 3-4; n = 17). Clinical severity was assessed on the basis of the Mini-Mental State Examination (MMSE; 0-30) and two Unified Huntington's Disease Rating Scale (UHDRS) functional components: the Independence Scale (10-100) and the Total Functional Capacity (0-13). Mild/moderate subjects were significantly older, had lower CAG repeat lengths, and greater fixed brain weights than those classified as severe. Patients who were pathologically classified as severe at autopsy were, on average, younger at age of onset and death and less well educated. Despite obvious clinical and pathological differences between mild-moderate and severe HD subjects at autopsy, mean MMSE scores of the two groups before death were surprisingly similar. Correlations between Vonsattel stage and functional assessment scores before death were low and not statistically significant. Our results suggest that the extent of striatal changes in HD may not always correlate with clinical disease severity as measured by UHDRS functional scales.