Date Published: March 14, 2019
Publisher: Public Library of Science
Author(s): Scott L. Lipnick, Denis M. Agniel, Rahul Aggarwal, Nina R. Makhortova, Samuel G. Finlayson, Alexandra Brocato, Nathan Palmer, Basil T. Darras, Isaac Kohane, Lee L. Rubin, Matti Douglas Allen.
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.
Spinal Muscular Atrophy (SMA) is a rare autosomal recessive disorder caused by a pair of missing or defective Survival of Motor Neuron 1 (SMN1) genes . A modifier gene, SMN2, also produces SMN protein, but, due to a point mutation, the yield is only a fraction of what is produced by SMN1 . As the name of the SMN protein implies, the SMA pathology is widely thought to be attributed to the highly selective degeneration of motor neurons. As such, disease severity is typically described by age of detectable changes in motor symptoms and best motor performance achieved . This simplistic representation of SMA is not unlike that of other neurological disorders in which each disease is defined and studied primarily in the context of the near-exclusive involvement of a specific subtype of central nervous system (CNS) neurons.
The Harvard Medical School Institutional Review Board approved this research.
Growing evidence indicates that SMA is not solely a motor neuron disease. This includes observations made using a severe SMA mouse model, post-SMA diagnosis clinical studies and reports based on small numbers of patients. This is consistent with gene expression data showing that SMN is transcribed in all tissues and cellular data demonstrating that SMN plays a broad and important role in mRNA splicing in all cells. However, evidence is lacking that SMN deficiency directly translates into detectable non-neuromuscular phenotypes in humans, and, if so, at which times during disease progression. One reason for this is that historical SMA studies focused on patients after SMA diagnosis [33–38], when phenotypes can be masked by neuromuscular degeneration or characterized as downstream complications. Given the current and pending approvals of SMN increasing therapies, understanding the complete pathophysiology of SMA is of critical importance in order to provide more comprehensive measures of treatment efficacy, support comparative effectiveness studies of local versus systemic interventions, and to determine whether early clinically detectable signs exist that could be used to support pre-symptomatic intervention in milder patients.