Causes and Risk Factors of Spinal Muscular Atrophy (SMA)

A rare disease with a well-understood genetic cause

In This Article

Spinal muscular atrophy (SMA) is an inherited progressive neurodegenerative disease. SMA is caused by alterations (mutations) in the genes that make proteins needed to support motor neuron function. The degree of genetic involvement determines what type of SMA you have as well as the severity of symptoms.

Since SMA is a genetic condition, there are no specific lifestyle factors known to cause or prevent it. However, there are ways to reduce the risk for complications if you have SMA.

Structural Causes

Normal, healthy muscles move in response to receiving signals from motor neurons in the spinal cord. In SMA, those motor neurons degenerate due to a lack of survival motor neuron (SMN) protein. Without enough SMN protein, even motor neurons that have already formed and work will eventually lose their structure and function.

When this happens, the motor signals from the brain cannot reach the nerves and the skeletal muscles won't move. Muscles that do not receive consistent nerve stimulation eventually begin to shrink and get weak or atrophy. In SMA, atrophy occurs gradually due to the lack of muscle movement.

Genetic Causes

More than 94% of SMA cases are caused by a homozygous mutation of the SMN1 gene. A homozygous mutation means that you inherit identical versions of this mutated gene from both parents.

Roles of the SMN1 and SMN2 Genes

The SMN1 and SMN2 genes both code for the production of SMN protein. The SMN1 gene typically directs most of the body’s SMN protein production, while the SMN2 gene only directs a small amount.

The proteins made from the SMN2 gene are shorter and less stable than those from the SMN1 gene. However, they can help make up some of a protein deficiency when the SMN1 gene is altered.

Inheritance Pattern of SMA

Every person typically has two copies of the SMN1 gene, one from each parent. Most people have one to two copies of the SMN2 gene, but some people have been found to have as many as eight copies.

SMA is typically inherited in an autosomal recessive manner. This means you develop the condition because you inherited an altered SMN1 gene from both parents. This mutation is most often a deletion (a portion of the genetic code is missing), which causes a shortage of SMN protein. 

Having two mutated copies of the SMN1 gene means your body is unable to make SMN protein with that gene. If you have three or more copies of the SMN2 gene, you can partially make up for the missing SMN protein. Therefore, you'll have a mild version of SMA. If you only have one or two SMN2 genes, you will have more of a SMN protein deficiency and your case of SMA will be more severe.

Sometimes people have an SMA gene even though there's no family history of the condition. When a gene mutation arises in this way, it's called a de novo mutation. Whether you have a de novo or inherited mutation, you still need to have two copies of the altered SMN gene for SMA to develop.

If you only have one altered SMN1 gene, you will also have one normal SMN1 that codes for SMN protein. Having at least one gene that can code for the proteins means you won't be affected by SMA.

The mutations in SMN1 genes determine if someone will inherit SMA, and the number of SMN2 genes influences how severe the condition will be.

Rare Genetic Causes

Rarely, two other genes associated with SMA may cause the condition: DYNC1H1 and UBA1.

An alteration of the cytoplasmic dynein 1 heavy chain 1 (DYNC1H1) gene is found on chromosome 14. The mutation is passed down through an autosomal dominant pattern. This means a person only needs to inherit one copy of the altered gene to develop SMA.

Another gene rarely linked to SMA is UBA1, which codes for ubiquitin-activating enzyme 1. This protein is involved in the survival of motor neurons.

UBA1 is found on the X-chromosome. X-linked inheritance rarely affects females because they have two X-chromosomes. Having one normal X-chromosome is protective against SMA caused by a UBA1 gene mutation.

However, if a female parent has the mutation, they can pass it on to male offspring—even if they don't have symptoms of the condition.

Risk Factors for Complications

Certain lifestyle risk factors have been linked to several types of motor neuron disease, but researchers don't know if any are specifically linked to SMA.

However, there are some lifestyle factors and habits that may make it more likely you could develop complications from the condition. 

Lifestyle factors that can predispose someone with SMA to complications or other health problems include:

  • Sedentary lifestyle. If you have motor weakness, inactivity can contribute to health problems, such as upper respiratory infections, constipation, and bedsores (pressure ulcers). An exercise program that's customized to your abilities can help you maintain or improve muscle function.
  • Exposure to infectious diseases. Chronic conditions like SMA can affect your immune system. Avoiding people who are sick with contagious infections helps you avoid potentially serious complications of infectious illnesses.
  • Unhealthy diet. A diet that's lacking in nutrition makes it harder for the body to fight infections. If the body doesn't get adequate energy from food, it may make muscle weakness from SMA feel worse.

Optimizing your overall health with lifestyle strategies cannot alter SMA, but it can help you minimize the risk of complications and improve your quality of life.

A Word From Verywell

The genetics of SMA are complex but well-understood by medical professionals and scientists. Since discovering how the genes lead to the condition, researchers have been able to focus on developing more effective screening and treatment for SMA.

If you are thinking about starting a family and wondering if you carry genes linked to SMA, talk to your doctor or a genetic counselor.

 

Was this page helpful?
Article Sources
Verywell Health uses only high-quality sources, including peer-reviewed studies, to support the facts within our articles. Read our editorial process to learn more about how we fact-check and keep our content accurate, reliable, and trustworthy.
  1. National Organization for Rare Disorders (NORD). Spinal Muscular Atrophy. NORD’s Rare Disease Database.

  2. D’Amico A, Mercuri E, Tiziano FD, Bertini E. Spinal muscular atrophyOrphanet Journal of Rare Diseases. 2011;6(1):71. doi:10.1186/1750-1172-6-71

  3. Su Y-N, Hung C-C, Lin S-Y, Chen F-Y, Chern JPS, Tsai C, et al. Carrier Screening for Spinal Muscular Atrophy (SMA) in 107,611 Pregnant Women during the Period 2005–2009: A Prospective Population-Based Cohort StudyPLoS ONE. 2011;6(2):e17067. doi:10.1371/journal.pone.0017067

  4. U.S. Department of Health & Human Services, National Institutes of Health. Spinal Muscular Atrophy. Genetics Home Reference.

  5. The Muscular Dystrophy Association (MDA). Spinal Muscular Atrophy - Research.

  6. U.S. Department of Health & Human Services, National Institutes of Health, National Library of Medicine, Lister Hill National Center for Biomedical Communications. SMN2 Gene. Genetics Home Reference.

  7. National Human Genome Research Institute. About Spinal Muscular Atrophy. Genome.gov.

  8. Cleveland Clinic. Spinal Muscular Atrophy (SMA).

  9. Prior TW, Leach ME, Finanger E. Spinal Muscular Atrophy. 2000 Feb 24 [Updated 2019 Nov 14]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019.

  10. National Organization for Rare Disorders (NORD). Werdnig-Hoffmann Disease. NORD's Rare Disease Database.

  11. Das J, Lilleker JB, Jabbal K, Ealing J. A missense mutation in DYNC1H1 gene causing spinal muscular atrophy - Lower extremity, dominant. Neurol Neurochir Pol. 2018 Mar;52(2):293-297. doi:10.1016/j.pjnns.2017.12.004

  12. Balak CD, Hunter JM, Ahearn ME, Wiley D, D'urso G, Baumbach-reardon L. Functional characterizations of rare UBA1 variants in X-linked Spinal Muscular Atrophy. F1000Res. 2017;6:1636. doi:10.12688/f1000research.11878.1

  13. The Motor Neuron Disease (MND) Association. What Causes MND?

  14. Lewelt A, Krosschell K, Stoddard G et al. Resistance strength training exercise in children with spinal muscular atrophy. Muscle Nerve. 2015;52(4):559-567. doi:10.1002/mus.24568

  15. Deguise M-O, Kothary R. New insights into SMA pathogenesis: immune dysfunction and neuroinflammationAnn Clin Transl Neurol. 2017;4(7):522-530. doi:10.1002/acn3.423

  16. Sproule D. General Nutrition Guidelines for SMA Children (PDF). The Spinal Muscular Atrophy (SMA) Clinical Research Center, Columbia University, Department of Neurology; 2018.

Additional Reading
Related Articles