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 8.5 to 10.3 per 100,000 live births.2-4

In Europe the annual incidence varies greatly by country and type; global annual incidence per 100,000 live births ranged from 3.5 to 7.1 for type I, 1.0 to 5.3 for type II, and 1.5 to 4.6 for type III.15

In children 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. Children with spinal muscular atrophy are often noted at diagnosis to have a bright, alert expression that contrasts with their general weakness.2

The genetic deficit underlying spinal muscular atrophy is well characterised

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 survival1,3

In spinal muscular atrophy, homozygous mutations or deletions of SMN1 produce a shortage of SMN protein, which causes degeneration of motor neurons in the spinal cord.6,8

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

  • SMN2 is nearly identical in genomic sequence to SMN1; there are only 5 nucleotides different6
  • However, a C-to-T nucleotide difference at position 6 of SMN2 creates an exonic splicing suppressor (ESS) that leads to a skipping of exon 7 during transcription2
  • This results in SMN2 producing a truncated, nonfunctional, and rapidly degrading SMN protein2

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

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

Copy number of SMN2 is variable in patients with spinal muscular atrophy, and higher copy numbers of SMN2 correlate with less-severe disease2 :

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

SMN2 copy number is related to, but not predictive of, disease severity, and care decisions should not be made based on copy number alone10,11

  • In any case of spinal muscular atrophy, SMN2 copy number is less predictive of prognosis than age of onset and functional abilities12,13
  • In addition to SMN2, there is some evidence of other genetic modifiers of disease severity, including levels of the protein Plastin-311

REFERENCES

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. Kolb SJ, Kissel JT. Spinal muscular atrophy. Arch Neurol. 2011;68(8):979-984. 4. Data on file. Biogen Inc, Cambridge, MA. 5. Islander G. Anesthesia and spinal muscular atrophy. Paediatr Anaesth. 2013;23(9):804-816. 6. Lefebvre S, Bürglen L, Reboullet S, et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell. 1995;80(1):155-165. 7. Ogino S, Wilson RB. Spinal muscular atrophy: molecular genetics and diagnostics. Expert Rev Mol Diagn. 2004;4(1):15-29. 8. Genetics Home Reference. SMN1. https://ghr.nlm.nih.gov/gene/SMN1. Published 20 April 2016. Accessed 25 April 2016. 9. Swoboda KJ. Romancing the spliceosome to fight spinal muscular atrophy. N Engl J Med. 2014;371(18):1752-1754. 10. TREAT-NMD. Diagnostic testing and care of new SMA patients. http://www.treat-nmd.eu/downloads/file/standardsofcare/sma/english/sma_soc_en.pdf. Accessed 10 May 2016. 11. 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. 12. 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. 13. Burnett BG, Crawford TO, Sumner CJ. Emerging treatment options for spinal muscular atrophy. Curr Treat Options Neurol. 2009;11(2):90-101. 14. Monani UR. Spinal muscular atrophy: a deficiency in a ubiquitous protein; a motor neuron-specific disease. Neuron. 2005;48(6):885-896. 15. Jones C. PP09.1 – 2352: Systematic review of incidence and prevalence of spinal muscular atrophy (SMA). European Journal of Paediatric Neurology. 2015, 19, Supp 1: S64–S65.

Because of its potential role in modulating disease severity, SMN2 is a target for investigational treatments.14

See the clinical trials