With an estimated incidence of approximately 1 in 10,00-11,00 live births, Spinal Muscular Atrophy (SMA) is the second most common autosomal recessive cause of death in children in the United States; incidence in European countries may be higher.1-3 The estimated prevalence of SMA in the United States, Europe, and Australia is less than 9,000 patients.2 SMA presents in five different forms, SMA types 0-4. The most prevalent form reported in published studies is SMA type 1 (~55%), followed by SMA types 2 (~30%) and 3 (~15%); SMA types 0 and 4 are extremely rare and represent collectively less than 1% of cases worldwide.2,4,5
SMA is a progressive neuromuscular disorder with an autosomal recessive inheritance. SMA is associated with homozygous variants in the Survival Motor Neuron 1 (SMN1) gene located on chromosome 5q13.4 The SMN gene sequence consists of nine exons and codes SMN protein, a 38-kDa protein comprised of 294 amino acids.4 SMN protein is critical to the survival of anterior horn cell motor neurons and appears to establish the intracellular complex needed for proper RNA splicing, but the scope of SMN’s functions and how SMN prevents neuron death are areas of ongoing investigation.6,7
Almost all patients (>95%) with the most common forms of SMA have deletions of SMN1 exon 7; the loss of exon 7 abolishes production of SMN1 protein.7,8 Most other cases of SMA are associated with a SMN1 gene variants causing loss of exon 7 in combination with a variant in the other copy of SMN1 that markedly reduces or eliminates production of SMN1 protein.3-5 In rare cases, SMA can be caused by pathogenic variants in other genes, so-called “non-5q SMA” and more than 16 genes have been implicated as potential causes of non-5q SMA.3,9
Despite a relatively consistent genetic finding of exon 7 deletion as a cause, SMA weakness can present anytime from in utero to adulthood, and this broad phenotypic range of SMA is believed to result from the presence or absence of a centromeric homologue of SMN1, the disease modifying gene SMN2.3,4,10,11 In humans, the sequence of SMN2 differs from SMN1 by five nucleotides, with only a single nucleotide difference lying within an exon coding sequence at the transition between exon 6 and 7.3 When comparing patients with the same SMN1 deletions, the number of copies of SMN2 a patient has will correlate with reduced weakness severity and longer survival between affected patients.4,8,12 Thus, SMN2 protein is believed to be able to serve as a partial compensation for a loss of effective SMN1 production.4 Unfortunately, the single nucleotide difference between exons 6 and 7 in SMN2 renders the SMN2 gene product unstable.4 Therefore, SMN2 compensation is incomplete because SMN2 cannot produce sufficient gene product to fully “rescue” cells from a total loss of SMN1, and thus SMN2 copy number is not entirely predictive of a patient’s disease severity.4,8 Non-5q genes also may modify disease severity.,9
Heterozygous carriers with a single copy of pathogenic SMN1 are asymptomatic. The carrier frequency for pathogenic variants in a SMA screening database established in New York State with a primarily Caucasian population was 1.5%.13 The observed carrier rate for SMA variants is higher in Asian populations but lower in Black or Hispanic populations.1,3 There can be instances when healthy individuals have two copies of SMN1 duplicated on the same 5q, one disease causing and one not.4
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2. Belter L, Cook SF, Crawford TO, et al. An overview of the Cure SMA membership database: Highlights of key demographic and clinical characteristics of SMA members. J Neuromuscul Dis. 2018;5(2):167-176.
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7. Maretina MA, Zheleznyakova GY, Lanko KM, Egorova AA, Baranov VS, Kiselev AV. Molecular Factors Involved in Spinal Muscular Atrophy Pathways as Possible Disease-modifying Candidates. Current genomics. 2018;19(5):339-355.
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9. Peeters K, Chamova T, Jordanova A. Clinical and genetic diversity of SMN1-negative proximal spinal muscular atrophies. Brain. 2014;137(Pt 11):2879-2896.
10. Butchbach ME. Copy Number Variations in the Survival Motor Neuron Genes: Implications for Spinal Muscular Atrophy and Other Neurodegenerative Diseases. Frontiers in molecular biosciences. 2016;3:7.
11. Mercuri E, Bertini E, Iannaccone ST. Childhood spinal muscular atrophy: controversies and challenges. The Lancet Neurology. 2012;11(5):443-452.
12. Feldkotter M, Schwarzer V, Wirth R, Wienker TF, Wirth B. Quantitative analyses of SMN1 and SMN2 based on real-time lightCycler PCR: fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy. American journal of human genetics. 2002;70(2):358-368.
13. Kraszewski JN, Kay DM, Stevens CF, et al. Pilot study of population-based newborn screening for spinal muscular atrophy in New York state. Genet Med. 2018;20(6):608-613.