Spinal Muscular Atrophy (SMA) was first described in 1891. More than a century later, in 1995, the disease-causing mutation in the Survival of Motor Neuron (SMN1) gene was discovered, and a second gene (SMN2) also was identified that helped to explain the phenotypic diversity: the more SMN2 copies, the milder the clinical phenotype. There was only a single strategic difference between the two genes, as pointed out by Umrao Monani and colleagues; and this difference introduced a splicing error in the SMN2 gene. As a result, the SMN2 gene produces full-length protein only about 10% of the time. SMA is divided phenotypically into 4 types according to clinical severity with type 1 being the most severe (and having the fewest SMN2 copies) and type 4 being the mildest. About 60% of the patients have type 1, 27% have type 2, 12% have type 3, and 1% have type 4.
SMA type 1 is truly life-threatening, and all forms of SMA are life-altering. SMA is the second most common autosomal recessive trait affecting humans, and the most common genetic cause of death in infancy. Approximately 2% of people carry this trait, and approximately 1 in every 8000 newborn babies are affected genotypically with SMA. Clinical symptoms of hypotonia, weakness, respiratory insufficiency and scoliosis emerge at some point post-natally in these patients depending on the severity of their phenotype.
The SMN2 splicing error now can be corrected with the ISIS SMNRx therapeutic, an antisense oligonucleotide (ASO) that displaces splicing in favor of exon splice enhancement. This ASO therapeutic has been approved for clinical trials in humans, and these trials currently are being conducted at the Columbia SMA Clinical Research Center and elsewhere in the world. The SMA Clinical Research Center is affiliated with the MNC. The MNC and the SMA Clinical Research Center have been supported continuously by the SMA Foundation since their inception.