OBJECTIVE:
Huntington disease (HD) is an
autosomal dominant neurodegenerative disorder caused by a CAG repeat expansion in the HD gene (HTT). We aimed to assess whether interaction between CAG repeat sizes in the
mutant and normal
allele could affect disease severity and progression. METHODS: Using
linear regression and mixed-effects models, the influence of
mutant and normal CAG repeat sizes interaction was assessed on 1) age at onset in 921 patients with HD, 2) clinical severity and progression in 512 of these patients with follow-up data available, and 3)
basal ganglia volume on
magnetic resonance images in 16 premanifest HD
mutation carriers. RESULTS: Normal and
mutant CAG repeat sizes interacted to influence 1) age at onset (p = 0.001), 2) severity or progression of motor, cognitive, and functional, but not behavioral,
symptoms in patients with HD (all p < 0.05), and 3) in premanifest subjects,
basal ganglia volumes (p < 0.05). In subjects with
mutant CAG expansions in the low range, increasing size of the normal repeat
correlated with more severe
symptoms and
pathology, whereas for those subjects with expansions in the high range, increasing size of the normal repeat
correlated with less severe
symptoms and
pathology. CONCLUSIONS: Increasing CAG repeat size in normal HTT diminishes the association between
mutant CAG repeat size and disease severity and progression in
Huntington disease. The underlying mechanism may involve interaction of the polyglutamine domains of normal and
mutant huntingtin (fragments) and needs further elucidation. These findings may have predictive value and are essential for the design and interpretation of future therapeutic trials.
