Genetics of Spinal Muscular Atrophy

Spinal muscular atrophy (SMA) results from mutations in the SMN1 (survival motor neuron) gene on chromosome 5q13. SMA is a common recessive disorder with an incidence of about 1:6,000 births. [Jones: 2015] In 95-98% of cases, patients have identical mutations, a homozygous deletion of exon 7 of the SMN1 gene. Carrier frequency for this common mutation is 1:40 individuals, second only to cystic fibrosis among recessive disorders. [Cusin: 2003]
Genetic testing for the exon 7 deletion mutation is standard-of-care and is the first diagnostic test in most infants and children with suspected SMA. A high clinical suspicion of SMA in patients with 1 copy of the exon 7 deletion should lead to additional testing by sequencing of the SMN1 gene since these patients may be compound heterozygous for the common mutation on 1 allele and a novel mutation elsewhere in the SMN1 gene on the second allele.
Severity of SMA is dependent in part on a second gene, also on 5q13. SMN2 is the result of an ancestral duplication and is identical to SMN1 except for the presence of a splicing mutation on exon 7, which results in an inactive transcript. While the mutation in SMN2 usually results in an inactive transcript, there is production of normal transcript at a very low rate. Severity of SMA is controlled in large part by the number of copies of SMN2 since more copies of SMN2 results in more normal transcripts. While not perfectly correlated, most SMA type I patients have 1 or 2 SNM2 copies, and most SMA type III patients have 3 or more copies. Targeting up-regulation of expression of normal transcript from SMN2 so that more normal protein is produced is being explored as a potential treatment for SMA in a number of different clinical trials. [Swoboda: 2007]
Gene conversion events between SMN1 and SMN2 complicate the inheritance of these genes. [Russman: 2007] Ten to fifteen percent of normal people have no SMN2 copies and approximately 4% of normals have 3 copies of the SMN1 gene. Although statistically unlikely, a carrier might test negative because he or she may have 2 copies of the SMN1 gene on the same chromosome and none on the other. Potential carriers should be aware of this possibility. [Prior: 2007]
The benefit of early identification of children with SMA is thought to be more important than the risk of early identification of carriers. While treatments are not yet available for SMA, many promising treatments are now undergoing clinical trials. Early diagnosis is likely to become a more significant issue in the very near future because these treatments will likely require early diagnosis before significant loss of motor neurons becomes permanent. Such early diagnosis is will likely require newborn screening. [Phan: 2015]


Information & Support

For Professionals

Spinal Muscular Atrophy (GeneReviews)
An expert-authored, peer-reviewed, current disease description that applies genetic testing to diagnosis and management information; U.S. National Library of Medicine.

Genetics in Primary Care Institute (AAP)
The goal of this site is to increase collaboration in the care of children with known or suspected genetic disorders. Includes health supervision guidelines and other useful resources; a collaboration among the Health Resources & Services Administration, the Maternal and Child Health Bureau, and the American Academy of Pediatrics.

Helpful Articles

PubMed search for spinal muscular atrophy in children, last 2 years.

Finkel RS, McDermott MP, Kaufmann P, Darras BT, Chung WK, Sproule DM, Kang PB, Foley AR, Yang ML, Martens WB, Oskoui M, Glanzman AM, Flickinger J, Montes J, Dunaway S, O'Hagen J, Quigley J, Riley S, Benton M, Ryan PA, Montgomery M, Marra J, Gooch C, De Vivo DC.
Observational study of spinal muscular atrophy type I and implications for clinical trials.
Neurology. 2014;83(9):810-7. PubMed abstract / Full Text


Author: Lynne M Kerr, MD, PhD - 1/2009
Reviewing Authors: Meghan Candee, MD - 8/2016
Russell Butterfield, MD, PhD - 8/2016
Kathy Swoboda, MD - 1/2009
Content Last Updated: 8/2016

Page Bibliography

Cusin V, Clermont O, Gérard B, Chantereau D, Elion J.
Prevalence of SMN1 deletion and duplication in carrier and normal populations: implication for genetic counselling.
J Med Genet. 2003;40(4):e39. PubMed abstract / Full Text

Jones C, Oskoui M, Zielinski D, Vinikoor L, Farwell W.
Systematic review of incidence and prevalence of spinal muscular atrophy (SMA).
European Journal of Paediatric Neurology. 2015; 19(1):oral presentation. Elservier Ltd.;
Provides a summary of Spinal Muscular Atrophy incidence and prevalence worldwide.

Phan HC, Taylor JL, Hannon H, Howell R.
Newborn screening for spinal muscular atrophy: Anticipating an imminent need.
Semin Perinatol. 2015;39(3):217-29. PubMed abstract

Prior TW.
Spinal muscular atrophy diagnostics.
J Child Neurol. 2007;22(8):952-6. PubMed abstract

Russman BS.
Spinal muscular atrophy: clinical classification and disease heterogeneity.
J Child Neurol. 2007;22(8):946-51. PubMed abstract

Swoboda KJ, Kissel JT, Crawford TO, Bromberg MB, Acsadi G, D'Anjou G, Krosschell KJ, Reyna SP, Schroth MK, Scott CB, Simard LR.
Perspectives on clinical trials in spinal muscular atrophy.
J Child Neurol. 2007;22(8):957-66. PubMed abstract