Clinical-Genetic Associations in the Prospective Huntington at Risk Observational Study (PHAROS)
Authors: Kevin Michael Biglan, Ira Shoulson, Karl Kieburtz, David Oakes, Elise Kayson, M. Aileen Shinaman, Hongwei Zhao, Megan Romer, Anne Young, Steven Hersch, Jack Penney, Karen Marder, Jane Paulsen, Kimberly Quaid, Eric Siemers, Caroline Tanner, William Mallonee, Greg Suter, Richard Dubinsky, Carolyn Gray, Martha Nance, Scott Bundlie, Dawn Radtke, Sandra Kostyk, Corrine Baic, James Caress, Francis Walker, Victoria Hunt, Christine O’Neill, Sylvain Chouinard, Stewart Factor, Timothy Greenamyre, Cathy Wood-Siverio, Jody Corey-Bloom, David Song, Guerry Peavy, Carol Moskowitz, Melissa Wesson, Ali Samii, Thomas Bird, Hillary Lipe, Karen Blindauer, Frederick Marshall, Carol Zimmerman, Jody Goldstein, Diana Rosas, Peter Novak, John Caviness, Charles Adler, Amy Duffy, Vicki Wheelock, Teresa Tempkin, David Richman, Lauren Seeberger, Roger Albin, Kelvin L. Chou, Brad Racette, Joel S. Perlmutter, Susan Perlman, Yvette Bordelon, Wayne Martin, Marguerite Wieler, Blair Leavitt, Lynn Raymond, Joji Decolongon, Lorne 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 Percy, Leon Dure, Madaline Harrison, William Johnson, Donald Higgins, Eric Molho, Constance Nickerson, Sharon Evans, Douglas Hobson, Carlos Singer, Nestor Galvez-Jimenez, Kathleen Shannon, Cynthia Comella, Christopher Ross, Marie H. Saint-Hilaire, Claudia Testa, Adam Rosenblatt, Penelope Hogarth, William Weiner, Peter Como, Rajeev Kumar, Candace Cotto, Julie Stout, Alicia Brocht, Arthur Watts, Shirley Eberly, Christine Weaver, Tatiana Foroud, James Gusella, Marcy MacDonald, Richard Myers, Stanley Fahn, Clifford Shults
Journal: JAMA Neurology (2015)

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.