Spinal muscular atrophy (SMA) is a rare but now treatable disease. Our objective is to highlight limitations of the current diagnostic approach for SMA testing, describe alternative mechanisms of SMA pathogenicity, and discuss the impact of molecular diagnosis on treatment. 

We report a case of SMA in an infant with a novel genotype.

3-month-old term male with severe hypotonia since birth was transferred for further evaluation of congenital weakness and respiratory failure requiring ventilatory support. Although clinical presentation was suggestive of SMA Type 0, the initial SMA test resulted as negative with 2 copies of SMN1. Electrodiagnostic testing was significant for sensory and motor polyneuropathy. Muscle biopsy was suggestive of SMA. Due to high clinical suspicion, risdiplam was started while further testing was pursued. Diagnosis of SMA was confirmed with Sanger sequencing, identifying a homozygous c.796T>C (p.Ser266Pro) mutation within SMN1 and one copy of SMN2. A compound heterozygous p.Ser266Pro mutation with exon 7 deletion has been previously reported in an SMA patient. This pathogenic variant is located in the SMN YG-box oligomerization domain and has been implicated in disrupting proper assembly of the SMN complex in SMA model systems. Due to a single SMN2 copy, therapies that alter splicing of SMN2 transcript, such as nusinersen and risdiplam, would be less effective than gene therapy, which introduces the wild type gene. Onasemnogene abeparvovec was infused at 5-months of age without complications. Patient has shown consistent, subtle improvements in motor skills and respiratory status. 

These findings represent the first in vivo evidence that loss of higher-order SMN oligomerization causes a severe SMA phenotype in humans. Current diagnostic screening tests for SMA, including newborn screening, have limitations in detecting non-deletion mutations. Electrodiagnostic testing can be misleading in severe cases of SMA. Accurate molecular diagnosis has implications for timely and appropriate treatment.