The term “spinal muscular atrophy (SMA)” refers to a group of genetic disorders all characterized by degeneration of anterior horn cells and resultant muscle atrophy and weakness. The most common SMA, accounting for more than 95% of cases, is an autosomal-recessive disorder that results from a homozygous deletion or mutation in the 5q13 survival of motor neuron (SMN1) gene. The severity of SMA is highly variable and the clinical features can be classified into 4 main phenotypes on the basis of age of onset and maximum motor function achieved. There is no cure for SMA; however, an understanding of the molecular genetics of SMA has led to the development of preclinical models and numerous potential therapeutic approaches.
In humans, 2 forms of the SMN gene exist on each allele: a telomeric form (SMN1) and a centromeric form (SMN2). The SMN2 gene is identical to the SMN1 gene with the exception of a C to T substitution in an exonic splicing enhancer that results in the exclusion of exon 7 during transcription. Critically, the exclusion of exon 7 from SMN2 mRNAs is not complete, and so a small fraction of the total mRNA transcripts (approximately 10%–15%) arising from the SMN2 gene do contain exon 7, which encodes the normal SMN protein. Histone deacetylase inhibitors such as valproic acid, sodium butyrate, phenylbutyrate, and trichstatin A activate the SMN2 promoter resulting in increased full-length SMN protein.

References

1.Stephen J. Kolb, et al. Neurol Clin 33 (2015) 831–846.