Natural History of Huntington Disease

Abstract

untington disease (HD) is an autosomal-dominant neurodegenerative disorder resulting from an unstable cytosine-adenine-guanine (CAG) repeat in the Huntingtin gene 1 that is clinically characterized by involuntary movements, cognitive decline, and behavioral changes. 2-4 Several studies have previously described the natural history of the disease. 4-22 Many, however, have been either small, narrowly focused, short in duration, or uncontrolled. Highquality longitudinal data will inform the design of clinical trials aimed at slowing progression and may inform patients and clinicians about the disease course. We, therefore, analyzed longitudinal data from the recently concluded, prospective, multicenter, observational study Cooperative Huntington's Observational Research Trial (COHORT). Methods Study The Johns Hopkins Medicine institutional review board reviewed and approved this analysis of COHORT study data. All COHORT study participants provided written informed consent or, if unable, had an authorized representative provide consent on their behalf. The COHORT project was an observational study that collected phenotypic and genotypic data from individuals with HD and their families from February 14, 2006, until June 30, 2011. The study design and initial baseline characteristics have been previously described. 23 In brief, the study, which was conducted at 44 research sites in Aus-IMPORTANCE Understanding the natural history of Huntington disease will inform patients and clinicians on the disease course and researchers on the design of clinical trials. OBJECTIVE To determine the longitudinal change in clinical features among individuals with Huntington disease compared with controls. DESIGN, SETTING, AND PARTICIPANTS Prospective, longitudinal cohort study at 44 research sites in Australia (n = 2), Canada (n = 4), and the United States (n = 38). Three hundred thirty-four individuals with clinically manifest Huntington disease who had at least 3 years of annually accrued longitudinal data and 142 controls consisting of caregivers and spouses who had no genetic risk of Huntington disease. MAIN OUTCOMES AND MEASURES Change in movement, cognition, behavior, and function as measured by the Unified Huntington's Disease Rating Scale, the Mini-Mental State Examination, and vital signs. RESULTS Total motor score worsened by 3.0 points (95% CI, 2.5-3.4) per year and chorea worsened by 0.3 point per year (95% CI, 0.1-0.5). Cognition declined by 0.7 point (95% CI, 0.6-0.8) per year on the Mini-Mental State Examination. Behavior, as measured by the product of frequency and severity score on the Unified Huntington's Disease Rating Scale, worsened by 0.6 point per year (95% CI, 0.0-1.2). Total functional capacity declined by 0.6 point per year (95% CI, 0.5-0.7). Compared with controls, baseline body mass index was lower in those with Huntington disease (25.8 vs 28.8; P < .001), and average pulse was higher (74.2 vs 69.6 beats/min; P < .001). CONCLUSIONS AND RELEVANCE Over 3 years, the cardinal features of Huntington disease all d...

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