Abstract
BackgroundCareful characterization of the phenotype and genotype of Huntington disease (HD) can foster better understanding of the condition.MethodsWe conducted a cohort study in the United States, Canada, and Australia of members of families affected by HD. We collected demographic and clinical data, conducted the Unified Huntington's Disease Rating Scale and Mini-Mental State Examination, and determined Huntingtin trinucleotide CAG repeat length. We report primarily on cross-sectional baseline data from this recently completed prospective, longitudinal, observational study.ResultsAs of December 31, 2009, 2,318 individuals enrolled; of these, 1,985 (85.6%) were classified into six analysis groups. Three groups had expanded CAG alleles (36 repeats or more): individuals with clinically diagnosed HD [n = 930], and clinically unaffected first-degree relatives who had previously pursued [n = 248] or not pursued [n = 112] predictive DNA testing. Three groups lacked expanded alleles: first-degree relatives who had previously pursued [n = 41] or not pursued [n = 224] genetic testing, and spouses and caregivers [n = 430]. Baseline mean performance differed across groups in all motor, behavioral, cognitive, and functional measures (p<0.001). Clinically unaffected individuals with expanded alleles weighed less (76.0 vs. 79.6 kg; p = 0.01) and had lower cognitive scores (28.5 vs. 29.1 on the Mini Mental State Examination; p = 0.008) than individuals without expanded alleles. The frequency of “high normal” repeat lengths (27 to 35) was 2.5% and repeat lengths associated with reduced penetrance (36 to 39) was 2.7%.ConclusionBaseline analysis of COHORT study participants revealed differences that emerge prior to clinical diagnosis. Longitudinal investigation of this cohort will further characterize the natural history of HD and genetic and biological modifiers.Trial RegistrationClinicaltrials.gov NCT00313495
Highlights
Huntington disease (HD) is an autosomal dominant neurodegenerative disorder resulting from an unstable expansion of a cytosine-adenine-guanine (CAG) trinucleotide repeat in the Huntingtin gene [1]
Participants Between February 14, 2006 and December 31, 2009, 2,318 participants enrolled in the Cooperative Huntington Observational Research Trial (COHORT) study
Data from 333 (14.4%) participants were excluded from this analysis for the following reasons: 288 had incomplete genotypic data, 32 had inconsistent genotypic and clinical data, seven were second-degree relatives excluded due to low enrollment, and six were missing data necessary for classification of an individual into a group [Figure 1]
Summary
Huntington disease (HD) is an autosomal dominant neurodegenerative disorder resulting from an unstable expansion of a cytosine-adenine-guanine (CAG) trinucleotide repeat in the Huntingtin gene [1]. The CAG repeat length normally varies from 6 to 35 CAG units. Repeat lengths from 36 to 39 exhibit reduced penetrance, with disease manifestations occurring at a later age or not at all [3,4,5]. Alleles with forty or more repeats are fully penetrant and inevitably associated with neuronal degeneration and the progressive motor, cognitive, and behavioral features of HD [6]. Longer CAG repeat expansions are associated with earlier disease manifestation [7,8,9], age of onset varies considerably for any given CAG repeat expansion [10]. Careful characterization of the phenotype and genotype of Huntington disease (HD) can foster better understanding of the condition
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