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

2015; American Medical Association; Volume: 73; Issue: 1 Linguagem: Inglês

10.1001/jamaneurol.2015.2736

2168-6157

Kevin Biglan, Ira Shoulson, Karl Kieburtz, David Oakes, Elise Kayson, M. Aileen Shinaman, Hongwei Zhao, Megan Romer, Anne B. Young, Steven M. Hersch, Jack Penney, Karen Marder, Jane S. Paulsen, Kimberly A. Quaid, Eric Siemers, Caroline M. Tanner, William Mallonee, Greg Suter, Richard Dubinsky, Carolyn Steele Gray, Martha Nance, Scott R. Bundlie, Dawn Radtke, Sandra K. Kostyk, Corrine Baic, James B. Caress, Francis O. Walker, Victoria Hunt, Christine J. O’Neill, Sylvain Chouinard, Stewart A. Factor, J. Timothy Greenamyre, Cathy Wood‐Siverio, Jody Corey‐Bloom, David Song, Guerry M. Peavy, Carol Moskowitz, Melissa Wesson, Ali Samii, Thomas D. Bird, Hillary Lipe, Karen Blindauer, Frederick J. Marshall, Carol Zimmerman, Jody Goldstein, Diana Rosas, Péter Novák, John N. Caviness, Charles H. Adler, Amy Duffy, Vicki Wheelock, Teresa Tempkin, David P. Richman, Lauren Seeberger, Roger L. Albin, Kelvin L. Chou, Brad A. Racette, Joel S. Perlmutter, Susan Perlman, Yvette Bordelon, W. R. Wayne Martin, Marguerite Wieler, Blair R. Leavitt, Lynn A. Raymond, Joji Decolongon, Lorne A. Clarke, Joseph Jankovic, Christine Hunter, Robert A. Hauser, Juan Sanchez‐Ramos, Sarah Furtado, Oksana Suchowersky, Mary Lou Klimek, Mark Guttman, Rustom Sethna, Andrew Feigin, Marie Cox, Barbara Shannon, Alan K. Percy, Leon Dure, Madaline B. Harrison, William Johnson, Donald S. Higgins, Eric Molho, Constance Nickerson, Sharon Evans, Douglas Hobson, Carlos Singer, Néstor Gálvez-Jiménez, Kathleen M. Shannon, Cynthia Comella, Christopher A. Ross, Marie Saint‐Hilaire, Claudia Testa, Adam Rosenblatt, Penelope Hogarth, William J. Weiner, Peter G. Como, Rajeev Kumar, Candace Cotto, Julie C. Stout, Alicia Brocht, Arthur Watts, Shirley Eberly, Christine Weaver, Tatiana Foroud, James F. Gusella, Marcy E. MacDonald, Richard H. Myers, Stanley Fahn, Clifford W. Shults,

Mitochondrial Function and Pathology

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.To identify the earliest features associated with the motor diagnosis of HD in the Prospective Huntington at Risk Observational Study (PHAROS).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.Huntington disease mutation status in individuals with CAG expansion vs without CAG expansion.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.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.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.