Alexander J Cammack1, Nazem Atassi1, Theodore Hyman1, Leonard H van den Berg1, Matthew Harms1, Robert H Baloh1, Robert H Brown1, Michael A van Es1, Jan H Veldink1, Balint S de Vries1, Jeffrey D Rothstein1, Caroline Drain1, Jennifer Jockel-Balsarotti1, Amber Malcolm1, Sonia Boodram1, Amber Salter1, Nicholas Wightman1, Hong Yu1, Alexander V Sherman1, Thomas J Esparza1, Diane McKenna-Yasek1, Margaret A Owegi1, Catherine Douthwright1, Alexander McCampbell1, Toby Ferguson1, Carlos Cruchaga1, Merit Cudkowicz1, Timothy M Miller2. 1. From the Department of Neurology (A.J.C., T.H., C.D., J.J.-B., A.M., S.B., A.S., T.J.E., C.C., T.M.M.), Washington University School of Medicine, St. Louis, MO; Department of Neurology (N.A., H.Y., A.V.S., M.C.), Neurological Clinical Research Institute, Massachusetts General Hospital, Boston; Department of Neurology (L.H.v.d.B., M.A.v.E., J.H.V., B.S.d.V.), Brain Center Rudolf Magnus, University Medical Center Utrecht, University Utrecht, the Netherlands; Department of Neurology (M.H.), Columbia University, New York, NY; Department of Neurology (R.H. Baloh), Cedars-Sinai Medical Center, Los Angeles, CA; Department of Neurology (R.H. Brown, N.W., D.M.-Y., M.A.O., C.D.), University of Massachusetts, Worcester; Department of Neurology (J.D.R.), Johns Hopkins University, Baltimore, MD; and Biogen Inc. (A.M., T.F.), Boston, MA. 2. From the Department of Neurology (A.J.C., T.H., C.D., J.J.-B., A.M., S.B., A.S., T.J.E., C.C., T.M.M.), Washington University School of Medicine, St. Louis, MO; Department of Neurology (N.A., H.Y., A.V.S., M.C.), Neurological Clinical Research Institute, Massachusetts General Hospital, Boston; Department of Neurology (L.H.v.d.B., M.A.v.E., J.H.V., B.S.d.V.), Brain Center Rudolf Magnus, University Medical Center Utrecht, University Utrecht, the Netherlands; Department of Neurology (M.H.), Columbia University, New York, NY; Department of Neurology (R.H. Baloh), Cedars-Sinai Medical Center, Los Angeles, CA; Department of Neurology (R.H. Brown, N.W., D.M.-Y., M.A.O., C.D.), University of Massachusetts, Worcester; Department of Neurology (J.D.R.), Johns Hopkins University, Baltimore, MD; and Biogen Inc. (A.M., T.F.), Boston, MA. miller.t@wustl.edu.
Abstract
OBJECTIVE: To define the natural history of the C9orf72 amyotrophic lateral sclerosis (C9ALS) patient population, develop disease biomarkers, and characterize patient pathologies. METHODS: We prospectively collected clinical and demographic data from 116 symptomatic C9ALS and 12 non-amyotrophic lateral sclerosis (ALS) full expansion carriers across 7 institutions in the United States and the Netherlands. In addition, we collected blood samples for DNA repeat size assessment, CSF samples for biomarker identification, and autopsy samples for dipeptide repeat protein (DPR) size determination. Finally, we collected retrospective clinical data via chart review from 208 individuals with C9ALS and 450 individuals with singleton ALS. RESULTS: The mean age at onset in the symptomatic prospective cohort was 57.9 ± 8.3 years, and median duration of survival after onset was 36.9 months. The monthly change was -1.8 ± 1.7 for ALS Functional Rating Scale-Revised and -1.4% ± 3.24% of predicted for slow vital capacity. In blood DNA, we found that G4C2 repeat size correlates positively with age. In CSF, we observed that concentrations of poly(GP) negatively correlate with DNA expansion size but do not correlate with measures of disease progression. Finally, we found that size of poly(GP) dipeptides in the brain can reach large sizes similar to that of their DNA repeat derivatives. CONCLUSIONS: We present a thorough investigation of C9ALS natural history, providing the basis for C9ALS clinical trial design. We found that clinical features of this genetic subset are less variant than in singleton ALS. In addition, we identified important correlations of C9ALS patient pathologies with clinical and demographic data.
OBJECTIVE: To define the natural history of the C9orf72 amyotrophic lateral sclerosis (C9ALS) patient population, develop disease biomarkers, and characterize patient pathologies. METHODS: We prospectively collected clinical and demographic data from 116 symptomatic C9ALS and 12 non-amyotrophic lateral sclerosis (ALS) full expansion carriers across 7 institutions in the United States and the Netherlands. In addition, we collected blood samples for DNA repeat size assessment, CSF samples for biomarker identification, and autopsy samples for dipeptide repeat protein (DPR) size determination. Finally, we collected retrospective clinical data via chart review from 208 individuals with C9ALS and 450 individuals with singleton ALS. RESULTS: The mean age at onset in the symptomatic prospective cohort was 57.9 ± 8.3 years, and median duration of survival after onset was 36.9 months. The monthly change was -1.8 ± 1.7 for ALS Functional Rating Scale-Revised and -1.4% ± 3.24% of predicted for slow vital capacity. In blood DNA, we found that G4C2 repeat size correlates positively with age. In CSF, we observed that concentrations of poly(GP) negatively correlate with DNA expansion size but do not correlate with measures of disease progression. Finally, we found that size of poly(GP) dipeptides in the brain can reach large sizes similar to that of their DNA repeat derivatives. CONCLUSIONS: We present a thorough investigation of C9ALS natural history, providing the basis for C9ALS clinical trial design. We found that clinical features of this genetic subset are less variant than in singleton ALS. In addition, we identified important correlations of C9ALS patient pathologies with clinical and demographic data.
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