Objectives: Prospective cohort study to characterize the clinical features and course of spinal muscular atrophy type I (SMA-I).Methods: Patients were enrolled at 3 study sites and followed for up to 36 months with serial clinical, motor function, laboratory, and electrophysiologic outcome assessments. Intervention was determined by published standard of care guidelines. Palliative care options were offered.

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:

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The Six-Minute Walk Test (6MWT) can be safely performed in ambulatory patients with spinal muscular atrophy (SMA), correlates with established outcome measures, and is sensitive to fatigue-related changes. The 6MWT is a promising candidate outcome measure for clinical trials in ambulatory subjects with SMA.

Body composition is sparsely described in spinal muscular atrophy (SMA). Body (BMI, mass/height in m 2 ), fat-free (FFMI, lean mass/height in m 2 ) and fat (FMI, fat mass/height in m 2 ) mass indexes were estimated in 25 children (ages 5-18) with SMA (2 type I, 13 type II, 10 type III) using dualenergy radiograph absorptiometry and anthropometric data referenced to gender and age-matched healthy children (NHANES III, New York Pediatric Rosetta Body Project). BMI was ≥ 50 th percentile in 11 (44%) and ≥ 85 th in 5 (20%). FFMI was reduced (p<0.005) and FMI was increased (P<0.005) in the overall study cohort. FMI was ≥ 50 th , ≥ 85th and 95th percentiles in 19 (76%), 10 (40%) and 5 (20%) subjects, respectively. Using a receiver operator characteristic curve, BMI above 75 th , 50 th and 3 rd percentiles maximized sensitivity and specificity for FMI ≥ 95 th , ≥ 85 th and ≥ 50 th percentiles, respectively. Children with SMA have reduced lean and increased fat mass compared to healthy children. Obesity is a potentially important modifiable source of morbidity in SMA.