The homozygous mutations or deletions of the SMN1 gene produce a shortage of SMN protein, which causes degeneration of motor neurons in the spinal cord, resulting in spinal muscular atrophy. 3,4

In individuals with spinal muscular atrophy, degeneration of motor neurons in the spinal cord results in skeletal muscular atrophy and weakness commonly involving the limbs. The bulbar and respiratory muscles are more variably affected.1,2

The lower motor neurons, located in the spinal cord, are important cells involved in motor function in the central nervous system (CNS)5

Cognitive ability does not appear to be impacted by spinal muscular atrophy. Individuals with spinal muscular atrophy are often noted at diagnosis to have a bright, alert expression that contrasts with their general weakness.2

Clinical literature shows a wide range of the incidence and prevalence of spinal muscular atrophy; in the United States, the estimated incidence of spinal muscular atrophy is 1 in 11,000 live births.6

The genetic deficit underlying spinal muscular atrophy is well characterized

The role of the survival motor neuron 1 (SMN1) gene is to produce SMN protein, which is highly expressed in the spinal cord and is known to be essential for motor neuron survival.1,7

Nearly all people, including those with spinal muscular atrophy, have a second, virtually duplicate gene to SMN1, known as the survival motor neuron 2 (SMN2) gene8,9

  • SMN2 gene is nearly identical in genomic sequence to the SMN1 gene; there are only 5 nucleotides different3
  • However, a C-to-T nucleotide change in the SMN2 gene creates an exonic splicing suppressor (ESS) that leads to a skipping of exon 7 during transcription2
  • This results in the SMN2 gene producing a truncated, non-functional, and rapidly degrading unstable protein2,10

Approximately 10% of SMN2 transcripts result in full-length SMN protein, providing patients with an insufficient amount of SMN protein to sustain survival of spinal motor neurons in the CNS.2

Generally, the number of SMN2 gene copies is inversely related to the severity of spinal muscular atrophy

SMN2 gene copy numbers are variable in individuals with spinal muscular atrophy. Higher numbers typically correlate with less severe disease2,9:

  • More than 95% of individuals with spinal muscular atrophy retain at least 1 copy of the SMN2 gene
  • About 80% of individuals with Type I spinal muscular atrophy have 1 or 2 copies of the SMN2 gene
  • About 82% of individuals with Type II spinal muscular atrophy have 3 copies of the SMN2 gene
  • About 96% of individuals with Type III spinal muscular atrophy have 3 or 4 copies of the SMN2 gene

The SMN2 gene copy number is related to, but not predictive of, disease severity, and care decisions should not be made based on copy number alone.11,12

  • In any case of spinal muscular atrophy, SMN2 gene copy number is less predictive of prognosis than age of onset and the achievement of functional abilities10,13
  • In addition to the SMN2 gene, there is some evidence of other genetic modifiers of disease severity, including levels of the protein Plastin-312

Click here for information about the clinical presentation of individuals with spinal muscular atrophy.


1. Lunn MR, Wang CH. Spinal muscular atrophy. Lancet. 2008;371(9630):2120-2133. 2. Darras BT, Royden Jones H Jr, Ryan MM, De Vivo DC, eds. Neuromuscular Disorders of Infancy, Childhood, and Adolescence: A Clinician’s Approach. 2nd ed. London, UK: Elsevier; 2015. 3. Lefebvre S, Bürglen L, Reboullet S, et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell. 1995;80(1):155-165. 4. Genetics Home Reference. SMN1. Published April 20, 2016. Accessed April 25, 2016. 5. Islander G. Anesthesia and spinal muscular atrophy. Paediatr Anaesth. 2013;23(9):804-816. 6. Sugarman EA, Nagan N, Zhu H, et al. Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: clinical laboratory analysis of >72,400 specimens. Eur J Hum Genet. 2012;20(1):27-32. 7. Kolb SJ, Kissel JT. Spinal muscular atrophy. Arch Neurol. 2011;68(8):979-984. 8. Swoboda KJ. Romancing the spliceosome to fight spinal muscular atrophy. N Engl J Med. 2014;371(18):1752-1754. 9. Fang P, Li L, Zeng J, et al. Molecular characterization and copy number of SMN1, SMN2 and NAIP in Chinese patients with spinal muscular atrophy and unrelated healthy controls. BMC Musculoskelet Disord. 2015;16(11):1-8. 10. Burnett BG, Crawford TO, Sumner CJ. Emerging treatment options for spinal muscular atrophy. Curr Treat Options Neurol. 2009;11(2):90-101. 11. TREAT-NMD. Diagnostic testing and care of new SMA patients. Accessed May 10, 2016. 12. Butchbach ME. Copy number variations in the survival motor neuron genes: implications for spinal muscular atrophy and other neurodegenerative diseases. Front Mol Biosci. 2016;3:7. 13. Prior TW, Krainer AR, Hua Y, et al. A positive modifier of spinal muscular atrophy in the SMN2 gene. Am J Hum Genet. 2009;85(3):408-413.

Clinical presentation for SMA may differ according to the age of onset and disease severity.1

Learn about the signs and symptoms