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The Relationship Between CAG Repeat Length and Age of Onset Differs for Huntington's Disease Patients with Juvenile Onset or Adult Onset

2006; Wiley; Volume: 71; Issue: 3 Linguagem: Inglês

10.1111/j.1469-1809.2006.00335.x

1469-1809

J. Michael Andresen, Javier Gayán, Luc Djoussé, Simone Roberts, Denise Brocklebank, Stacey S. Cherny, Lon R. Cardon, James F. Gusella, Marcy E. MacDonald, Richard H. Myers, David E. Housman, Nancy S. Wexler, Judith Lorimer, Julie Porter, Fidela Gomez, Carol Moskowitz, Kelly Posner Gerstenhaber, Edith Shackell, Karen Marder, Graciela K. Penchaszadeh, Simone Roberts, Adam M. Brickman, Jacqueline S. Gray, Stephen R. Dlouhy, Sandra Wiktorski, M. E. Hodes, P.M. Conneally, John B. Penney, Jang seong ho, Micheal Irizarry, Diana Rosas, Steven M. Hersch, Zane Hollingsworth, Anne B. Young, Margot Mieja de Young, Ernesto Bonilla, Theresa Stillings, Américo Negrette, S. Robert Snodgrass, Maria Dolores Martinez-Jaurrieta, Maria A. Ramos-Arroyoh, Jacqueline Bickham, Juan Sanchez Ramos, Frederick J. Marshall, Ira Shoulson, Gustavo J. Rey, Andrew Feigin, Norman Arnheim, Amarilis Acevedo-Cruz, Leticia Acosta, José Alvir, Kenneth H. Fischbeck, Leslie M. Thompson, Angela M. Young, Leon Dure, Christopher O’Brien, Jane S. Paulsen, Shelley Peery Moran, Denise Krch, Penelope Hogarth, Donald S. Higgins, G. Bernhard Landwehrmeyer, Michael R. Hayden, E. Almqvist, Ryan R. Brinkman, Oksana Suchowersky, Alexandra Durr, Catherine Dodé, Ferdinando Squitieri, Patrick J. Morrison, Martha Nance, Christopher A. Ross, Russell L. Margolis, Adam Rosenblatt, Gómez Tortosai Estrella, David Mayo Cabrero, Ronald J. Trent, Elizabeth McCusker, Andrea Novelletto, Marina Frontali, Jane S. Paulsen, Randi Jones, Andrea Zanko, Tetsuo Ashizawa, Alice Lazzarini, Jian‐Liang Li, Vanessa C. Wheeler, Ana L. Russ, Gang Xu, Jayalakshmi Srinidhi Mysore, Tammy Gillis, Michael Hakky, L. Adrienne Cupples, Marie Saint‐Hilaire, Steven M. Hersch,

Neurological disorders and treatments

Summary Age of onset for Huntington's disease (HD) varies inversely with the length of the disease‐causing CAG repeat expansion in the HD gene. A simple exponential regression model yielded adjusted R‐squared values of 0.728 in a large set of Venezuelan kindreds and 0.642 in a North American, European, and Australian sample (the HD MAPS cohort). We present evidence that a two‐segment exponential regression curve provides a significantly better fit than the simple exponential regression. A plot of natural log‐transformed age of onset against CAG repeat length reveals this segmental relationship. This two‐segment exponential regression on age of onset data increases the adjusted R‐squared values by 0.012 in the Venezuelan kindreds and by 0.035 in the HD MAPS cohort. Although the amount of additional variance explained by the segmental regression approach is modest, the two slopes of the two‐segment regression are significantly different from each other in both the Venezuelan kindreds [F(2, 439) = 11.13, P = 2 × 10 −5 ] and in the HD MAPS cohort [F(2, 688) = 38.27, P = 2 × 10 −16 ]. In both populations, the influence of each CAG repeat on age of onset appears to be stronger in the adult‐onset range of CAG repeats than in the juvenile‐onset range.