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From the Departments of Neurology (N.A.A., C.K.J., R.A.C.R.), Human Genetics (W.M.C.v.R.-M., G.J.B.v.O.), and Medical Statistics (T.S.), Leiden University Medical Center, Leiden, the Netherlands; and Department of Neurology (G.B.L.), Ulm University, Ulm, Germany.
Address correspondence and reprint requests to N. Ahmad Aziz, Leiden University Medical Center, Department of Neurology, K-05-Q 110, PO Box 9600, Albinusdreef 2, 2300 RC Leiden, the Netherlands N.A.Aziz{at}lumc.nl.
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.
Abbreviations: EHDN = European Huntington Disease Network; HD = Huntington disease; TFC = total functional capacity; UHDRS = Unified Huntington Disease Rating Scale.
Supplemental data at www.neurology.org.
Editorial, page 1254.
e-Pub ahead of print on September 23, 2009, at www.neurology.org.
*A complete list of all European Huntington Disease Network (EHDN) Registry Study Group investigators can be found on http://www.euro-hd.net/html/registry.
The EHDN's Registry study is sponsored by the High Q Foundation. N.A. Aziz is supported by The Netherlands Organization for Scientific Research (grant 017.003.098).
Disclosure: Author disclosures are provided at the end of the article.
Received March 23, 2009. Accepted in final form July 30, 2009.
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Neurology 2009 73: 1254-1255.
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