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Original Investigation |

Clinical-Genetic Associations in the Prospective Huntington at Risk Observational Study (PHAROS) Implications for Clinical Trials

JAMA Neurol. 2016;73(1):102-110. doi:10.1001/jamaneurol.2015.2736.
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Importance  Identifying measures that are associated with the cytosine-adenine-guanine (CAG) expansion in individuals before diagnosis of Huntington disease (HD) has implications for designing clinical trials.

Objective  To identify the earliest features associated with the motor diagnosis of HD in the Prospective Huntington at Risk Observational Study (PHAROS).

Design, Setting, and Participants  A prospective, multicenter, longitudinal cohort study was conducted at 43 US and Canadian Huntington Study Group research sites from July 9, 1999, through December 17, 2009. Participants included 983 unaffected adults at risk for HD who had chosen to remain unaware of their mutation status. Baseline comparability between CAG expansion (≥37 repeats) and nonexpansion (<37 repeats) groups was assessed. All participants and investigators were blinded to individual CAG analysis. A repeated-measures analysis adjusting for age and sex was used to assess the divergence of the linear trend between the expanded and nonexpanded groups. Data were analyzed from April 27, 2010, to September 3, 2013.

Exposure  Huntington disease mutation status in individuals with CAG expansion vs without CAG expansion.

Main Outcomes and Measures  Unified Huntington’s Disease Rating Scale motor (score range, 0-124; higher scores indicate greater impairment), cognitive (symbol digits modality is the total number of correct responses in 90 seconds; lower scores indicate greater impairment), behavioral (score range, 0-176; higher scores indicate greater behavioral symptoms), and functional (Total Functional Capacity score range, 0-13; lower scores indicate reduced functional ability) domains were assessed at baseline and every 9 months up to a maximum of 10 years.

Results  Among the 983 research participants at risk for HD in the longitudinal cohort, 345 (35.1%) carried the CAG expansion and 638 (64.9%) did not. The mean (SD) duration of follow-up was 5.8 (3.0) years. At baseline, participants with expansions had more impaired motor (3.0 [4.2] vs 1.9 [2.8]; P < .001), cognitive (P < .05 for all measures except Verbal Fluency, P = .52), and behavioral domain scores (9.4 [11.4] vs 6.5 [8.5]; P < .001) but not significantly different measures of functional capacity (12.9 [0.3] vs 13.0 [0.2]; P = .23). With findings reported as mean slope (95% CI), in the longitudinal analyses, participants with CAG expansions showed significant worsening in motor (0.84 [0.73 to 0.95] vs 0.03 [−0.05 to 0.11]), cognitive (−0.54 [−0.67 to −0.40] vs 0.22 [0.12 to 0.32]), and functional (−0.08 [−0.09 to −0.06] vs −0.01 [−0.02 to 0]) measures compared with those without expansion (P < .001 for all); behavioral domain scores did not diverge significantly between groups.

Conclusions and Relevance  Using these prospectively accrued clinical data, relatively large treatment effects would be required to mount a randomized, placebo-controlled clinical trial involving premanifest HD individuals who carry the CAG expansion.

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Figure.
Unified Huntington’s Disease Rating Scale Scores Over Time by Mutation Status

A, The difference in mean (SE) total motor scores between individuals with vs those without cytosine-adenine-guanine (CAG) expansion was significant at baseline (year 0) and at comparison of longitudinal change (both P < .001). B, The difference in mean Symbol Digit Modalities between individuals with vs those without CAG expansion was significant at baseline (year 0) (P = .03) and at comparison of longitudinal change (P < .001). C, The difference in mean behavioral score between individuals with vs those without CAG expansion was significant at baseline(P < .001) but not at comparison of longitudinal change (P = .57). D, The difference in mean Total Functional Capacity between individuals with vs those without CAG expansion was not significant at baseline (P = .23) but was significant at comparison of longitudinal change (P < .001).

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