Genetics of Spinal Muscular Atrophy

Spinal muscular atrophy (SMA) results from mutations in the survival motor neuron (SMN1) gene on chromosome 5q13. SMA is a common recessive disorder with an incidence of about 1:10,000 births. [Verhaart: 2017] 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 common 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
The severity of SMA is dependent on a second gene, SMN2, also on 5q13. SMN2 is the result of an ancestral duplication and is identical to SMN1 except for the presence of a missense mutation on exon 7 that disrupts a splicing enhancer but does not change the predicted protein sequence. This mutation results in deletion of exon 7 and an inactive transcript; however, at a low rate, normal splicing occurs, providing a small amount of normal transcript and normal SMN protein. Severity of clinical symptoms is correlated with the number of copies of SMN2 since patients with more copies of SMN2 produce more normal SMN protein. While not perfectly correlated, most SMA type I patients have 1 or 2 SNM2 copies, and most patients with SMA type III have 3 or more copies. Treatments targeting up-regulation of expression of normal transcript from SMN2 has proven successful clinically, resulting in approval of nusinersen in 2016. Other SMN2 modulating drugs are now going through clinical trials as well. [Parente: 2018]
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]
With the addition of SMA to the recommended uniform screening panel, newborn screening programs for SMA are rapidly coming online in many states. Early initiation of treatment leads to far better outcomes, especially if treatment is started before the onset of symptoms and before significant loss of motor neurons becomes permanent. In most cases, newborn screening will identify homozygous deletion of SMN1 and will not identify carrier status or SMN2 copy number. Confirmatory testing, including SMN2 copy number after a positive newborn screen, is essential. [Baker: 2019] [Ke: 2019]


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)
Contains health supervision guidelines and other useful resources for the care of children with genetic disorders; 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

Authors & Reviewers

Initial publication: September 2008; last update/revision: September 2019
Current Authors and Reviewers:
Author: Lynne M. Kerr, MD, PhD
Reviewer: Russell Butterfield, MD, Ph.D.
Authoring history
2016: update: Meghan Candee, MDR; Russell Butterfield, MD, Ph.D.R
2009: first version: Lynne M. Kerr, MD, PhDA; Kathy Swoboda, MDR
AAuthor; CAContributing Author; SASenior Author; RReviewer

Page Bibliography

Baker M, Griggs R, Byrne B, Connolly AM, Finkel R, Grajkowska L, Haidet-Phillips A, Hagerty L, Ostrander R, Orlando L, Swoboda K, Watson M, Howell RR.
Maximizing the Benefit of Life-Saving Treatments for Pompe Disease, Spinal Muscular Atrophy, and Duchenne Muscular Dystrophy Through Newborn Screening: Essential Steps.
JAMA Neurol. 2019. PubMed abstract

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

Ke Q, Zhao ZY, Mendell JR, Baker M, Wiley V, Kwon JM, Alfano LN, Connolly AM, Jay C, Polari H, Ciafaloni E, Qi M, Griggs RC, Gatheridge MA.
Progress in treatment and newborn screening for Duchenne muscular dystrophy and spinal muscular atrophy.
World J Pediatr. 2019;15(3):219-225. PubMed abstract

Parente V, Corti S.
Advances in spinal muscular atrophy therapeutics.
Ther Adv Neurol Disord. 2018;11:1756285618754501. PubMed abstract / Full Text

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

Verhaart IEC, Robertson A, Wilson IJ, Aartsma-Rus A, Cameron S, Jones CC, Cook SF, Lochmüller H.
Prevalence, incidence and carrier frequency of 5q-linked spinal muscular atrophy - a literature review.
Orphanet J Rare Dis. 2017;12(1):124. PubMed abstract / Full Text