Özge’s background is in research; she holds a MSc. in Molecular Genetics from the University of Leicester and a PhD. in Developmental Biology from the University of London. Özge worked as a bench scientist for six years in the field of neuroscience before embarking on a career in science communication. She worked as the research communication officer at MDUK, a UK-based charity that supports people living with muscle-wasting conditions, and then a research columnist and the managing editor of resource pages at BioNews Services before joining Rare Disease Advisor.
Spinal muscular atrophy (SMA) is a rare neuromuscular disease characterized by muscle weakness and atrophy. It is an autosomal recessive disorder with an estimated incidence of 1 in 6000 to 1 in 10,000 live births. The estimated carrier frequency of the disease is 1 in 40 to 1 in 60.1
Spinal muscular atrophy etiology is determined through diagnostic testing showing that most cases of SMA are caused by a homozygous deletion in the SMN1 gene, which resides in the long arm of chromosome 5. This generally shows an absence in exon 7 of the gene.2
In some instances, there may also be a deletion in one allele and a point mutation in the other. Most of these point mutations occur in exons 3 and 6 and sometimes in exon 1.2
SMN1 Mutations and SMA Symptoms
The SMN1 gene encodes for the survival motor neuron (SMN) protein, which is essential for the health of motor neurons that control the movement of skeletal muscles. When there is not enough SMN protein due to the mutations in the SMN1 gene, motor neurons die. The result is muscle weakness and atrophy.3
The SMN protein is thought to also play other roles, including pre-mRNA splicing, mRNA transportation along the axons of motor neurons, and DNA repair, which could be responsible for motor neuron degeneration. It could also be important for the function of glial cells, which play a role in neuronal communication and are involved in neuroinflammation, suggesting that SMA could also be a neuroinflammatory disease.
Range of Symptom Severity in SMA Etiology
Based on the clinical severity of the symptoms, there are 5 types of SMA. SMA type 0 is the most severe form of the disease, with symptoms appearing even before birth in the form of reduced fetal movements. On the other end of the spectrum is SMA type 4, in which symptoms usually do not appear until the third decade of life. All 5 types of SMA are caused by mutations in the SMN1 gene.
Scientific consensus concludes that the wide range of symptom severity is governed by other genetic modifiers. The copy number of the SMN2 gene is the main genetic modifier affecting symptom severity.4 SMN2 is highly homologous to the SMN1 gene and also encodes for the SMN protein. However, due to alternative splicing, only about 10% to 15% of the SMN protein synthesized from this gene is functional; the rest is shorter and quickly degraded by cells.5
Research has shown that the higher the number of copies of the SMN2 gene, the milder the disease.4 Accordingly, patients with SMA type 0 usually have one copy of the SMN2 gene. Those with SMA type 1, in which symptoms usually appear within 6 months of birth, have 2 copies of the SMN2 gene. In SMA type 2, symptoms generally appear between ages 6 months and 12 months, and these patients usually have 3 copies of the SMN 2 gene. Patients whose symptoms appear after 18 months are diagnosed with SMA type 3 and have 3 or 4 copies of the SMN2 gene. Patients with SMA type 4 have 4 or more copies of the SMN2 gene. Some can have as many as 8 copies of the gene.
Other genetic modifiers of SMA include PLS3 and ZPR1.6 PLS3 encodes for Plastin 3, a protein involved in the formation and stabilization of actin bundles. It is a sex-specific protective modifier that resides on the X chromosome. ZPR1 encodes for Zinc Finger Protein 1 and is also a protective modifier of SMA. It is thought to interact with the SMN protein and stabilize it, preventing turnover. It is not known what causes the overexpression of PLS3 or ZPR1 in some people.
How SMA Is Inherited
SMA is inherited in an autosomal recessive manner. Carriers of one abnormal allele usually do not show any symptoms. However, two carriers have a 25% chance of having a child with the SMA phenotype if the child receives 2 abnormal copies of the allele. Likewise, 2 carriers have a 50% chance of having a child that is simply a carrier like themselves and unlikely to express an SMA phenotype, and a 25% chance of having a child who is not a carrier of an abnormal allele and completely unaffected by the disease.
Genetic testing is available to identify the carrier status of people and is usually offered to couples with a family history of the disease. Prenatal genetic testing is also available and can determine, before birth, whether a fetus has inherited SMA.8
Etiology of Rarer Forms of SMA
Although most cases of SMA are caused by mutations in the SMN1 gene, there are rarer forms of the disease that are caused by mutations in other genes.9 These include the UBA1 gene, which resides on the X chromosome and causes X-linked SMA, the IGHMBP2 gene located on chromosome 11, mutations in which cause SMA with respiratory distress (SMARD), and the DYNC1H1 gene, which resides on chromosome 14 and causes SMA with lower extremity predominance (SMA-LED) when mutated.
X-linked SMA is inherited in an X-linked recessive manner and mostly affects boys, while SMA-LED is inherited in an autosomal dominant manner.7
Reviewed by Michael Sapko, MD on 7/1/2021
- D’Amico A, Mercuri E, Tiziano FD, Bertini E. Spinal muscular atrophy. Orphanet J Rare Dis. 2011;2;6:71. doi:10.1186/1750-1172-6-71
- De Holanda Mendonça R, Matsui C, Polido GJ, et al. Intragenic variants in the SMN1 gene determine the clinical phenotype in 5q spinal muscular atrophy. Neurol Genet. 2020;1;6(5):e505. doi:10.1212/NXG.0000000000000505
- Spinal muscular atrophy. Medline Plus. Accessed May 25, 2021.
- Butchbach MER. Copy number variations in the survival motor neuron genes: implications for spinal muscular atrophy and other neurodegenerative diseases. Front. Mol. Biosci. 2016;10;3:7.doi: 10.3389/fmolb.2016.00007
- SMN2 gene. Medline Plus. Accessed May 25, 2021.
- Lamar KM, McNally EM. Genetic modifiers for neuromuscular diseases. J Neuromuscul Dis. 2014;1(1):3-13. doi:10.3233/JND-140023
- Causes/inheritance. Muscular Dystrophy Association. Accessed May 25, 2021.
- Prior TW, Leach ME, Finanger E. Spinal muscular atrophy. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews. University of Washington; 2000. Updated December 3, 2020. Accessed May 25, 2021.
- Types of SMA. Muscular Dystrophy Association. Accessed May 25, 2021.