Genetics of SMA

The inheritance pattern of chromosome 5q-related SMA is autosomal recessive. The different forms of 5q-SMA are caused by biallelic deletions or mutations in the SMN1 gene on chromosome 5q13.2, resulting in a deficiency of the SMN1 protein. The most common mutation of SMN1 is a deletion of exon 7. Approximately 94 percent of patients with clinically typical SMA carry homozygous deletions of exon 7. SMN protein appears to play a role in mRNA synthesis in motor neurons and may inhibit apoptosis.

The differences in SMN protein activity and phenotypic expression are partly related to a modifying gene called survival motor neuron 2 (SMN2). The SMN1 and SMN2 genes are more than 99 percent identical and lie within an inverted duplication on chromosome 5q13.2. SMN1 lies telomeric of SMN2. The main difference between them is a C to T transition in exon 7 of SMN2. This change leads to the production of a truncated, nonfunctional SMN protein from the majority of SMN2-derived mRNAs. However, approximately 10 to 15 percent of mRNAs from SMN2 contain exon 7 and can produce some functional, full-length SMN protein. Thus, the loss of the SMN1 protein is partially compensated by SMN2 protein synthesis, a mechanism that explains some but not all of the phenotypic variability in patients with SMA. Disease severity in SMA generally correlates inversely with SMN2 copy number, which varies from 0 to 8 in the normal population, and to a lesser degree with the level of SMN protein. The presence of four or more copies of SMN2 is associated with a milder phenotype.

While the most common forms of SMA are caused by deletions or mutations in the SMN1 on chromosome 5q (ie, 5q SMAs), there are many rare non-5q spinal muscular atrophies. The non-5q SMAs are genetically and clinically heterogeneous.