Natural History of Infantile‐Onset Spinal Muscular Atrophy
2017
Objective: Infantile-onset
spinal muscular atrophy(
SMA) is the most common genetic cause of infant mortality, typically resulting in death prior to age 2. Clinical trials in this population require an understanding of disease progression and identification of meaningful biomarkers to hasten therapeutic development and predict outcomes. Methods: A longitudinal, multi-center, prospective
natural history studyenrolled 26
SMAinfants, and 27 control infants less than six months of age. Recruitment occurred at 14 centers over 21 months within the NINDS-sponsored NeuroNEXT Network. Infant motor function scales (TIMPSI, CHOP-INTEND and AIMS) and putative physiologic and molecular biomarkers were assessed prior to 6 months of age and at 6, 9, 12, 18 and 24-months with progression, correlations between motor function and biomarkers and hazard ratios were analyzed. Results: Motor function scores (MFS) and CMAP decreased rapidly in
SMAinfants, whereas MFS in all healthy infants rapidly increased. Correlations were identified between TIMPSI and CMAP in
SMAinfants. TIMPSI at first study visit was associated with risk of combined endpoint of death or permanent invasive ventilation in
SMAinfants.
Post hoc analysisof survival to combined endpoint in
SMAinfants with 2 copies of SMN2 indicated a median age of 8 months at death (95%CI: 6,17). Interpretation: These data of
SMAand control outcome measures delineates meaningful change in clinical trials in infantile-onset
SMA. The power and utility of NeuroNEXT to provide “real world”, prospective natural history data sets to accelerate public and private drug development programs for rare disease is demonstrated. This article is protected by copyright. All rights reserved.
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