Characterization of a large group of individuals with huntington disease and their relatives enrolled in the COHORT study

Huntington Study Group COHORT Investigators, E Ray Dorsey, Ira Shoulson, James Gusella, Tatiana Foroud, Daniel P Van Kammen, Tatiana Foroud, E Ray Dorsey, John Warner, Joseph Giuliano, Louise Vetter, Oksana Suchowersky, Christopher Beck, David Oakes, Frederick Marshall, Karen Marder, Steven Frucht, Carol Moskowitz, Ronda Clouse, Paula Wasserman, Kathleen Shannon, Jeana Jaglin, Josepth Jankovic, Alicia Palao, Madaline Harrison, Carlos Singer, Monica Quesada, Steven Hersch, Diana Rosas, Kaloyan Tanev, Keith Malarick, Amy Colcher, Juan Sanchez-Ramos, Sandra Kostyk, Jane Paulsen, Joel Perlmutter, Samer Tabbal, Christopher Ross, E Ray Dorsey, Frederick Nucifora, Richard Dubinsky, Hilary Dubinsky, Oksana Suchowersky, Mary Lou Klimek, Randi Jones, Claudia Testa, Stewart Factor, Dana Jennings, John Morgan, Donald Higgins, Eric Molho, John Adams, Samuel Frank, Marie Saint-Hilaire, Melissa Diggin, Sarah Furtado, Francis Walker, Christines O'Neill, Vicki Hunt, Kimberly Quaid, Mark LeDoux, Lynn Raymond, Blair Leavitt, Joji Decolongon, Susan Perlman, Jody Corey-Bloom, Guerry Peavy, Jodi Goldstein, Rajeev Kumar, Elizabeth McCusker, Jane Griffith, Clement Loy, Vicki Wheelock, Terry Tempkin, Amanda Martin, Martha Nance, Un Kang, William Mallonee, Greg Suter, Fred Revilla, Maureen Gartner, Carolyn Drazinic, Mary Jane Fitzpatrick, Michel Panisset, Kevin Duff, Burton Scott, William Weiner, Bradley Robottom, Edmond Chiu, Olga Yastrubetskaya, Andrew Churchyard, Timothy John Greenamyre, Pinky Agarwal, David Oakes, Christopher Beck, Suzanne Robertson, Dustina Holt, Ken Eaton, Patricia Lindsay, Lisa Deuel, Marcy MacDonald, Irina Antonijevic, Charlyne Hickey, Lisa Muratori, Elan Louis, Nick Doucette, Ergun Uc, Robert Rodnitzky, Anne Leserman, Stacie Vik, Robert Davis, Susan Dietrich, Vicki Segro, Diane Erickson, Vicki Hunt, Nancy Lucarelli, Janice Broyles, Jeanen DeLaRosa, Elan Louis, Peter Panegyres, Amy Schmidt, Stacey Barton, Elaine Sperin, Claudia Testa, S Elizabeth Zauber, Melissa Wesson, Robert McInnis, Claire Welsh, Melissa Wesson, Allison Coleman, Huntington Study Group COHORT Investigators, E Ray Dorsey, Ira Shoulson, James Gusella, Tatiana Foroud, Daniel P Van Kammen, Tatiana Foroud, E Ray Dorsey, John Warner, Joseph Giuliano, Louise Vetter, Oksana Suchowersky, Christopher Beck, David Oakes, Frederick Marshall, Karen Marder, Steven Frucht, Carol Moskowitz, Ronda Clouse, Paula Wasserman, Kathleen Shannon, Jeana Jaglin, Josepth Jankovic, Alicia Palao, Madaline Harrison, Carlos Singer, Monica Quesada, Steven Hersch, Diana Rosas, Kaloyan Tanev, Keith Malarick, Amy Colcher, Juan Sanchez-Ramos, Sandra Kostyk, Jane Paulsen, Joel Perlmutter, Samer Tabbal, Christopher Ross, E Ray Dorsey, Frederick Nucifora, Richard Dubinsky, Hilary Dubinsky, Oksana Suchowersky, Mary Lou Klimek, Randi Jones, Claudia Testa, Stewart Factor, Dana Jennings, John Morgan, Donald Higgins, Eric Molho, John Adams, Samuel Frank, Marie Saint-Hilaire, Melissa Diggin, Sarah Furtado, Francis Walker, Christines O'Neill, Vicki Hunt, Kimberly Quaid, Mark LeDoux, Lynn Raymond, Blair Leavitt, Joji Decolongon, Susan Perlman, Jody Corey-Bloom, Guerry Peavy, Jodi Goldstein, Rajeev Kumar, Elizabeth McCusker, Jane Griffith, Clement Loy, Vicki Wheelock, Terry Tempkin, Amanda Martin, Martha Nance, Un Kang, William Mallonee, Greg Suter, Fred Revilla, Maureen Gartner, Carolyn Drazinic, Mary Jane Fitzpatrick, Michel Panisset, Kevin Duff, Burton Scott, William Weiner, Bradley Robottom, Edmond Chiu, Olga Yastrubetskaya, Andrew Churchyard, Timothy John Greenamyre, Pinky Agarwal, David Oakes, Christopher Beck, Suzanne Robertson, Dustina Holt, Ken Eaton, Patricia Lindsay, Lisa Deuel, Marcy MacDonald, Irina Antonijevic, Charlyne Hickey, Lisa Muratori, Elan Louis, Nick Doucette, Ergun Uc, Robert Rodnitzky, Anne Leserman, Stacie Vik, Robert Davis, Susan Dietrich, Vicki Segro, Diane Erickson, Vicki Hunt, Nancy Lucarelli, Janice Broyles, Jeanen DeLaRosa, Elan Louis, Peter Panegyres, Amy Schmidt, Stacey Barton, Elaine Sperin, Claudia Testa, S Elizabeth Zauber, Melissa Wesson, Robert McInnis, Claire Welsh, Melissa Wesson, Allison Coleman

Abstract

Background: Careful characterization of the phenotype and genotype of Huntington disease (HD) can foster better understanding of the condition.

Methods: We 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.

Results: As 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%.

Conclusion: Baseline 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 registration: Clinicaltrials.gov NCT00313495.

Conflict of interest statement

Competing Interests: J. Giuliano, D. van Kammen, and J. Warner are employed by CHDI Foundation Inc, the sponsor of this study. No other authors have financial disclosures related to this manuscript. This does not alter the authors' adherence to all the PLoS ONE policies on sharing data and materials.

Figures

Figure 1. Enrollment and baseline classification of…
Figure 1. Enrollment and baseline classification of COHORT research participants.
Figure 2. Distribution of the CAG repeat…
Figure 2. Distribution of the CAG repeat length of the larger Huntingtin allele for all individuals carrying an expanded allele in the COHORT study.

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