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 genetic disease and one of the most common genetic conditions affecting children. It is characterized by progressive skeletal muscle weakness and atrophy.1
Various types of SMA exist, but the most common form, known as 5q SMA, is caused by mutations in the SMN1 gene, located on chromosome 5.2 SMA is classified into 5 types, SMA types 0 through 4, depending on the clinical features of the disease. Rarer forms of SMA also exist; these are caused by mutations in other genes (non-5q SMA).
Causes of 5q SMA
Most cases of 5q SMA are caused by a homozygous deletion of the SMN1 gene.3 In some people, 1 copy of the SMN1 gene is deleted, and the other carries an intragenic point mutation. As a result, functional survival motor neuron (SMN) protein, which is essential for the health of motor neurons, is not produced. When the body cannot make enough SMN protein, motor neurons die, resulting in muscle weakness and wasting.
A second gene, SMN2, also produces some SMN protein.4 However, because of a single nucleotide change, only 10% to 15% of the SMN protein from this gene is functional; the rest is shorter than normal and quickly degraded by cells. The copy number of the SMN2 gene varies from person to person. The number of SMN2 gene copies correlates with disease severity because more copies tend to produce more SMN protein, resulting in milder disease.5
How 5q SMA Is Inherited
SMA types 0 through 4 are inherited in an autosomal recessive manner.6 The carrier frequency of SMA in the United States is estimated to be approximately 1 in 35.7
In very rare cases, 5q SMA can be the result of a mutation that occurs de novo in an egg or sperm or during early development, even without a family history of the disease.8 In some instances, one of the parents is a carrier and a mutation occurs de novo in the SMN1 gene during gametogenesis in the other parent. A child with SMA is subsequently born to this couple, and genetic counseling before the birth would have detected only the parent carrier.
Members of the family of a child with SMA should be offered genetic testing and genetic counseling to determine their carrier status and calculate their risk of having a child with the disease.
Because biallelic deletion mutations are responsible for 95% of cases of SMA, standard genetic testing looks specifically for this mutation. However, this form of genetic testing will miss about 5% to 10% of the cases that occur when 1 parent has a point mutation of the SMN1 gene.9
Testing for the same biallelic deletion is used to diagnose SMA in children and also will miss 5% to 10% of cases in which a point mutation on one allele and a deletion of the other leads to the SMA phenotype. When SMA is strongly suspected, SMN1 can be sequenced to look for a point mutation.
A prenatal diagnosis can also be offered to women with at-risk pregnancies through amniocentesis and chorionic villus sampling (CVS).
How Non-5q SMA Is Inherited
Other, rarer forms of SMA are caused by mutations in genes other than SMN1. These include SMA with respiratory distress (SMARD), distal SMA, and X-linked SMA.10
SMARD, which is caused by the IGHMBP2 gene located on chromosome 11, and most forms of distal SMA are inherited in an autosomal recessive manner, like 5q SMA.
A type of distal SMA called SMA lower extremity dominant, or SMA-LED, is caused by mutations in the DYNC1H1 gene on chromosome 14 and is inherited in an autosomal dominant manner.11,12
X-linked SMA is caused by a mutation in the UBA1 gene, which is located on the X chromosome.13 Therefore, it affects mostly males because they lack a second X chromosome carrying a healthy UBA1 gene that can compensate for the mutated gene.
Boys usually inherit the disease from a carrier mother. A carrier mother has a 50% chance of having a carrier daughter and a 50% chance of having an unaffected daughter. Because male patients do not usually live past early childhood, it is very unlikely that an affected male will reproduce and pass the mutated gene on to his children.
Like autosomal recessive forms of SMA, X-linked SMA can be the result of a de novo mutation that occurs during egg or sperm production.14
If the UBA1 pathogenic variant has been identified in a family, family members at risk should be offered carrier testing. Women who have at-risk pregnancies should also be offered prenatal testing.15
In some other very rare forms of SMA, the causative genes have not been identified. Research is ongoing to identify other genetic variants of this disease.
Reviewed by Michael Sapko, MD on 7/1/2021
- Spinal muscular atrophy. National Organization for Rare Disorders. Accessed June 8, 2021
- What is 5q spinal muscular atrophy? Spinal muscular atrophy UK. Accessed June 8, 2021.
- The genetics of 5q spinal muscular atrophy. Spinal muscular atrophy UK. Accessed June 8, 2021.
- SMN2 gene. MedlinePlus. Updated August 18, 2020. Accessed June 8, 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
- About spinal muscular atrophy. National Human Genome Research Institute. Updated February 19. 2012. Accessed June 8, 2021.
- Chong JX, Oktay AA, Dai Z, Swoboda KJ, Prior TW, Ober C. A common spinal muscular atrophy deletion mutation is present on a single founder haplotype in the US Hutterites. Eur J Hum Genet. 2011;19(10):1045-1051. doi:10.1038/ejhg.2011.85
- Spinal muscular atrophy. MedlinePlus. Updated August 18, 2020. Accessed June 8, 2021.
- The genetics of spinal muscular atrophy. Families of SMA. Published November 2009. Accessed June 8, 2021.
- Types of SMA. Muscular Dystrophy Association. Accessed June 8, 2021.
- DYNC1H1 gene. MedlinePlus. Updated August 18, 2020. Accessed June 8, 2021.
- Causes/inheritance. Muscular Dystrophy Association. Accessed June 8, 2021.
- X-linked infantile spinal muscular atrophy. MedlinePlus. Updated August 18, 2020. Accessed June 8, 2021.
- Jędrzejowska M, Jakubowska-Pietkiewicz E, Kostera-Pruszczyk A. X-linked spinal muscular atrophy (SMAX2) caused by de novo c.1731C>T substitution in the UBA1 gene. Neuromuscul Disord. 2015;25(8):661-6. doi:10.1016/j.nmd.2015.05.001
Baumbach-Reardon L, Sacharow SJ, Ahearn ME. Spinal muscular atrophy, X-linked infantile. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviewsⓇ. University of Washington, Seattle; 2008. Updated September 13, 2012. Accessed June 8, 2021.