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PLoS One. 2019 Mar 14;14(3):e0213680. doi: 10.1371/journal.pone.0213680. eCollection 2019.

Systemic nature of spinal muscular atrophy revealed by studying insurance claims.

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Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts, United States of America.
Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, United States of America.
Center for Assessment Technology & Continuous Health (CATCH), Massachusetts General Hospital, Boston, Massachusetts, United States of America.
Boston Children's Hospital, Boston, Massachusetts, United States of America.
Harvard Stem Cell Institute, Cambridge, Massachusetts, United States of America.



We investigated the presence of non-neuromuscular phenotypes in patients affected by Spinal Muscular Atrophy (SMA), a disorder caused by a mutation in the Survival of Motor Neuron (SMN) gene, and whether these phenotypes may be clinically detectable prior to clinical signs of neuromuscular degeneration and therefore independent of muscle weakness.


We utilized a de-identified database of insurance claims to explore the health of 1,038 SMA patients compared to controls. Two analyses were performed: (1) claims from the entire insurance coverage window; and (2) for SMA patients, claims prior to diagnosis of any neuromuscular disease or evidence of major neuromuscular degeneration to increase the chance that phenotypes could be attributed directly to reduced SMN levels. Logistic regression was used to determine whether phenotypes were diagnosed at significantly different rates between SMA patients and controls and to obtain covariate-adjusted odds ratios.


Results from the entire coverage window revealed a broad spectrum of phenotypes that are differentially diagnosed in SMA subjects compared to controls. Moreover, data from SMA patients prior to their first clinical signs of neuromuscular degeneration revealed numerous non-neuromuscular phenotypes including defects within the cardiovascular, gastrointestinal, metabolic, reproductive, and skeletal systems. Furthermore, our data provide evidence of a potential ordering of disease progression beginning with these non-neuromuscular phenotypes.


Our data point to a direct relationship between early, detectable non-neuromuscular symptoms and SMN deficiency. Our findings are particularly important for evaluating the efficacy of SMN-increasing therapies for SMA, comparing the effectiveness of local versus systemically delivered therapeutics, and determining the optimal therapeutic treatment window prior to irreversible neuromuscular damage.

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Conflict of interest statement

The majority of authors have no conflicts of interest. Dr. Darras reports grants from Biogen, grants from National Institutes of Health/National Institute of Neurological Disorders and Stroke, grants from Ionis, grants from Cytokinetics, grants from SMA Foundation, grants from Slaney Fund for SMA, personal fees from Biogen, personal fees from AveXis, personal fees from Cytokinetics, personal fees from Marathon Pharma, personal fees from PTC Therapeutics, personal fees from Roche, personal fees from Sarepta, personal fees from BMS, grants from Fibrogen, grants from Summit, grants from AveXis, grants from Santhera, outside the submitted work.

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