Objective: To characterize the natural history of spinal muscular atrophy type 2 and type 3 (SMA 2/3) beyond 1 year and to report data on clinical and biological outcomes for use in trial planning. Methods: We conducted a prospective observational cohort study of 79 children and young adults with SMA 2/3 who participated in evaluations for up to 48 months. Clinically, we evaluated motor and pulmonary function, quality of life, and muscle strength. We also measured SMN2 copy number, hematologic and biochemical profiles, muscle mass by dual x-ray absorptiometry (DXA), and the compound motor action potential (CMAP) in a hand muscle. Data were analyzed for associations between clinical and biological/laboratory characteristics cross-sectionally, and for change over time in outcomes using all available data. Results: In cross-sectional analyses, certain biological measures (specifically, CMAP, DXA fatfree mass index, and SMN2 copy number) and muscle strength measures were associated with motor function. Motor and pulmonary function declined over time, particularly at time points beyond 12 months of follow-up. Conclusion: The intermediate and mild phenotypes of SMA show slow functional declines when observation periods exceed 1 year. Whole body muscle mass, hand muscle compound motor action potentials, and muscle strength are associated with clinical measures of motor function. The data from this study will be useful for clinical trial planning and suggest that CMAP and DXA warrant further evaluation as potential biomarkers.
Bibliographical noteFunding Information:
P. Kaufmann reports no disclosures. M.P. McDermott serves as a scientific advisory board member for ISIS Pharmaceuticals, Biogen Idec, Inc, The ALS Association/FDA, and the Muscular Dystrophy Association; and is a consultant for the New York State Department of Health, Teva Pharmaceutical Industries, Ltd, Synosia, Inc, Smith and Nephew, Inc, and Impax Pharmaceuticals. He receives research support from the Michael J. Fox Foundation, Spinal Muscular Atrophy Foundation, Muscular Dystrophy Association, American Dental Association, and the NIH. Basil T. Darras is a consultant for ISIS Pharmaceuticals and Quest Diagnostics, received funding for travel from Athena Diagnostics, Honorarium for Virtual Grand Rounds, received research support from PTC Therapeutics, the Spinal Muscular Atrophy Foundation, Muscular Dystrophy Association, the Slaney Family Fund for SMA, and the NIH/NIAMS. R.S. Finkel serves on advisory boards for DuchenneConnect, Families of SMA, TREAT-NMD, PTC Therapeutics, Inc., and ISIS Pharmaceuticals, Inc; receives research support from PTC Therapeutics, Inc., Santhera Pharmaceuticals, the NIH, the SMA Foundation, the Muscular Dystrophy Association, Genzyme Corporation, and the Charcot-Marie-Tooth Association; and his spouse holds and has received license fees for numerous patents related to T cell activation and HIV, and receives research support from the Gates Foundation, Merck Serono, and the NIH in the field of T cell activation, HIV, and genomics of juvenile arthritis. D.M. Sproule receives research funding from PTC Therapeutics, the SMA Foundation, and NINDS sponsored Neurological Sciences Academic Development Award (K12 NS01698). P.B. Kang received travel funding from Improving the Use of Electromyography in Paediatrics, non-profit conference organization and Amy & Friends Cockayne syndrome network, non-profit entity and is a consultant for LEK consulting, commercial consulting firm, Gerson Lehrman Group, commercial consulting firm, Fundacio la Marato de TV3, non-profit entity, and Gross, Minsky & Mogul, legal firm and performs EMGs (15% effort). Dr. Kang receives honoraria from Massachusetts Medical Society, American Academy of Neurology, American Academy of Pediatrics, US Department of Health and Human Services, and US Food and Drug Administration. Dr. Kang receives research support from the NINDS, Muscular Dystrophy Association Research Grant 186796, Muscular Dystrophy Association Research Grant 114353, and his spouse receives research support from the NIH. Dr. Kang's Spouse receives royalties from a gene therapy patent Compositions and methods for treating glycogen storage diseases, 08730667.6–1212 PCT/US2008054911, filed February 25, 2008. M. Oskoui received research support from the Public Health Agency of Canada, Project RT736230, for 2 years. A. Constantinescu reports no disclosures. C.L. Gooch is a consultant for NeuralStem, a medical advisory board member of the GBS/CIDP Foundation International, and an employee of the FDA. He receives travel funding from the NIH as chair of the Data Safety Monitoring Board (IVIg in Autonomic Neuropathy). R. Foley receives research support from the Muscular Dystrophy Campaign (UK). M. Yang reports no disclosures. R. Tawil receives research support from the NIH. W. Chung and W.B. Martens report no disclosures. J. Montes is a consultant for ISIS Pharmaceuticals Inc and is funded in part by Department of Defense. V. Battista and J. O'Hagen report no disclosures. S. Dunaway is funded in part by the Department of Defense. J. Flickinger and J. Quigley report no disclosures. S. Riley received honoraria from the SMA Foundation for speaking at an SMA/Scoliosis conference at the Children's Hospital of Philadelphia. A.M. Glanzman received funding for travel and training from GlaxoSmithKline and receives research support from the NIH CTSA. M. Benton, P. Ryan, M. Punyanitya, M.J. Montgomery, J. Marra, and B. Koo report no disclosures. D.C. De Vivo serves on the scientific advisory boards for Colleen Giblin Foundation, SMA Foundation, Canavan Foundation, Pediatric Neurotransmitter Disease Association, Milestones for Children, Will Foundation, Glut1 Disease Foundation, and ISIS Pharmaceuticals. He has received compensation as a consultant for ISIS Pharmaceuticals. Dr. De Vivo receives research support from the NIH/NICHD and NINDS, SMA Foundation, Colleen Giblin Foundation, Milestones for Children, and the Will Foundation. Go to Neurology.org for full disclosures .
This study was funded by the SMA Foundation. Additional clinical research support was provided to Columbia University through CTSA grant No. UL1 RR024156 from NCATS-NCRR/NIH and the NSADA K12 program (NINDS Training Grant); to The Children's Hospital of Philadelphia through CTSA Award 1 NIH UL1-RR-024134 (NCRR/NIH); and to Harvard University through the UL1 RR025755–01 Harvard Catalyst Clinical & Translational Science Center (NCRR/NIH). The content of this report is solely the responsibility of the authors and should not be considered as the opinion or position of the NIH or its affiliates.