Connect with others who understand.

sign up log in
Resources
About mySMAteam
Powered By

Causes of Spinal Muscular Atrophy

Updated on April 19, 2021
View reactions
Medically reviewed by
Amit M. Shelat, D.O.
Article written by
Alison Channon

Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder characterized by muscle weakness that worsens over time. Depending on type and age of onset, other symptoms of SMA can include respiratory difficulties, inability to stand or walk, and problems chewing and swallowing. Severe breathing problems are common in infant or child-onset SMA and can contribute to a reduced life expectancy. Adult-onset SMA generally does not influence life span.

What Causes Spinal Muscular Atrophy?

SMA is an inherited genetic disorder. Spinal muscular atrophy types 0-4, which account for nearly all cases of SMA, are caused by a mutation in the survival motor neuron (SMN) genes on both copies of chromosome 5. (Note that most people have two copies of 23 chromosomes.) SMN genes tell the body to make SMN protein, which is crucial for the function of motor neurons. Motor neurons are nerve cells that transmit signals from the brain and spinal cord to the muscles. Without sufficient SMN protein, motor neurons die, and the brain cannot signal the muscles to function. The result is progressive muscle weakness that impacts functions ranging from walking to breathing.

There are two SMN genes on chromosome 5 — SMN1 and SMN2. In a person without spinal muscular atrophy, the SMN1 gene produces the majority of the SMN protein required for the muscles to function, while the SMN2 gene only produces a minor amount of SMN protein. People without SMA will possess two normal SMN1 copies and one or two SMN2 copies, though some people have several copies of the SMN2 gene and some have none.

A mutation on both copies of a person’s SMN1 gene determines whether a person will have SMA. The type of SMA a person develops, the severity of symptoms, and life expectancy, is often, but not always, related to the number of SMN2 copies they possess. Babies with type 0, the most severe form of SMA, may only have one SMN2 copy, those with type 1 (Werdnig-Hoffmann disease) usually have one or two copies, and people with type 2 often have three copies. In comparison, those with type 3 (Kugelberg-Welander Disease) might have three or four SMN2 copies, and those with type 4 may have four or more SMN2 copies.

Two types of gene therapy are currently available to treat types 0-4.

Read more about treatments for spinal muscular atrophy.

Other Types of SMA

Other spinal muscular atrophy types are caused by mutations on different genes. They include the following.

SMA With Respiratory Distress

SMA with respiratory distress (SMARD) is caused by a mutation on the immunoglobulin mu DNA binding protein 2 (IGHMBP2) gene. The SMARD mutation leads to the creation of compromised proteins that contribute to motor neuron damage and death.

Distal SMA

Distal SMA can be caused by a mutation on the Berardinelli-Seip congenital lipodystrophy 2 (BSCL2) or glycyl-tRNA synthetase (GARS1) genes. Mutations on the BSCL2 gene lead to malformed proteins within cells that may damage or kill motor neurons. The GARS1 gene helps the body create certain enzymes required for producing proteins. The precise reason why a GARS1 mutation leads to distal SMA is unknown, however scientists hypothesize that a lack of certain enzymes may damage the ability of nerves to communicate with muscles.

Kennedy’s Disease

Kennedy's disease (X-linked spinal and bulbar muscular atrophy) primarily affects men and is caused by a mutation in the androgen receptor (AR) gene on the X chromosome. The AR gene tells the body to make androgen receptors. Androgen receptors are important for the development of male sex characteristics and are also important for female hormonal function. The precise reason this mutation leads to muscle weakness requires more research.

SMA With Progressive Myoclonic Epilepsy

SMA with progressive myoclonic epilepsy (SMA-PME) is the result of a mutation on the N-acylsphingosine amidohydrolase 1 (ASAH1) gene. This gene is involved in the production of ceramides, fats that contribute to the creation of myelin. Myelin protects nerve cells. The mutated ASAH1 gene functions at less than a third of the capacity as a normal ASAH1 gene, which is believed to be the reason for the nerve cell damage that causes SMA-PME.

SMA With Lower Extremity Predominance

SMA with lower extremity predominance (SMA-LED) can be caused by mutations on the dynein cytoplasmic 1 heavy chain 1 (DYNC1H1) or BICD cargo adaptor 2 (BICD2) genes. Both of these genes are involved in the production and function of dynein proteins, which are necessary for the proper growth and function of neurons.

X-Linked Infantile SMA

X-linked infantile SMA (XL-SMA) primarily affects baby boys and results from a mutation in the ubiquitin-like modifier activating enzyme 1 (UBA1) gene on the X chromosome. The UBA1 gene provides instructions for creating an enzyme that helps maintain the body’s balance of protein creation and breakdown. If old proteins aren’t broken down, they can impair the function of other cells, such as motor neurons.

How Does a Child Inherit SMA?

Nearly all cases of SMA are recessive — meaning a child must inherit a mutated gene from both parents to develop spinal muscular atrophy. For types 0-4, a child must inherit two mutated copies of the SMN1 gene. If both parents are carriers of the mutated gene that causes SMA, a child has a 25 percent chance of developing SMA and a 50 percent chance of being a carrier of SMA. If a person is a carrier, they can pass the gene on to their children, but will not develop SMA. In the United States, about 1 in 54 people is a carrier for SMA, though this rate varies by ethnic background. However, SMA is rare — it occurs in only 1 in 11,000 births in the U.S.

A few types of SMA, including distal SMA and SMA-LED, are inherited from one parent instead of both. X-linked forms of SMA, including Kennedy's disease and X-linked infantile SMA, occur almost exclusively in boys when there is a specific genetic mutation on the X chromosome inherited from the mother.

Genetic Testing for SMA

Genetic testing is used to diagnose spinal muscular atrophy in babies, children, and adults who exhibit symptoms of SMA. Genetic testing is also available during pregnancy to determine if a fetus has inherited mutated SMN1 genes. Prenatal testing for SMA is usually only recommended in cases where both parents are carriers.

Carrier screening is available before conception to determine if potential parents are carriers of the SMA genetic mutation. Preconception screening for SMA is particularly recommended for people with a known family history of the genetic condition. Preconception carrier screening is available for many genetic disorders.

Condition Guide

References
  1. D'Amico, A., Mercuri, E., Tiziano, F. D., & Bertini, E. (2011). Spinal muscular atrophy. Orphanet Journal of Rare Diseases, 6(71).
  2. Spinal muscular atrophy. (2018, October). Retrieved December 20, 2019, from https://ghr.nlm.nih.gov/condition/spinal-muscular-atrophy
  3. Spinal Muscular Atrophy. (n.d.). Retrieved December 20, 2019, from https://rarediseases.org/rare-diseases/spinal-muscular-atrophy/
  4. How many chromosomes do people have? (n.d.). Retrieved January 28, 2020, from https://ghr.nlm.nih.gov/primer/basics/howmanychromosomes
  5. Arnold, W. D., Kassar, D., & Kissel, J. T. (2014). Spinal muscular atrophy: Diagnosis and management in a new therapeutic era. Muscle & Nerve, 51(2), 157–167. doi: 10.1002/mus.24497
  6. SMARD1. (2019, March). Retrieved December 20, 2019, from https://ghr.nlm.nih.gov/condition/spinal-muscular-atrophy-with-respiratory-distress-type-1#genes
  7. Distal Spinal Muscular Atrophy type V (DSMA-V) - Spinal Muscular Atrophy UK. (2019, March). Retrieved December 20, 2019, from https://smauk.org.uk/DSMA-V
  8. Distal hereditary motor neuropathy, type V. (2009, August). Retrieved January 28, 2020, from https://ghr.nlm.nih.gov/condition/distal-hereditary-motor-neuropathy-type-v#genes
  9. Spinal-Bulbar Muscular Atrophy (SBMA). (2018, January 31). Retrieved January 28, 2020, from https://www.mda.org/disease/spinal-bulbar-muscular-atrophy
  10. Spinal and bulbar muscular atrophy. (2012, December). Retrieved January 28, 2020, from https://ghr.nlm.nih.gov/condition/spinal-and-bulbar-muscular-atrophy#genes
  11. Spinal muscular atrophy with progressive myoclonic epilepsy. (n.d.). Retrieved January 28, 2020, from https://ghr.nlm.nih.gov/condition/spinal-muscular-atrophy-with-progressive-myoclonic-epilepsy#genes
  12. Spinal muscular atrophy with lower extremity predominance. (2019, February). Retrieved December 20, 2019, from https://ghr.nlm.nih.gov/condition/spinal-muscular-atrophy-with-lower-extremity-predominance
  13. Types of SMA. (2019, September 20). Retrieved January 28, 2020, from https://www.mda.org/disease/spinal-muscular-atrophy/types
  14. X-linked infantile spinal muscular atrophy. (2018, February). Retrieved December 20, 2019, from https://ghr.nlm.nih.gov/condition/x-linked-infantile-spinal-muscular-atrophy
  15. Sugarman, E. A., Nagan, N., Zhu, H., Akmaev, V. R., Zhou, Z., Rohlfs, E. M., … Allitto, B. A. (2011). Pan-ethnic carrier screening and prenatal diagnosis for spinal muscular atrophy: clinical laboratory analysis of >72 400 specimens. European Journal of Human Genetics, 20(1), 27–32. doi: 10.1038/ejhg.2011.134
  16. Types of SMA. (2019, July 30). Retrieved December 20, 2019, from https://www.curesma.org/type-of-sma/
  17. Kennedy's Disease Information Page. (2019, March 27). Retrieved December 20, 2019, from https://www.ninds.nih.gov/Disorders/All-Disorders/Kennedys-Disease-Information-Page
  18. FAQ: Carrier Testing for Spinal Muscular Atrophy. (2019, October 31). Retrieved from https://www.ucsfhealth.org/education/faq-carrier-testing-for-spinal-muscular-atrophy
  19. Carrier Screening FAQ. (2018, December). Retrieved January 6, 2020, from https://www.acog.org/Patients/FAQs/Carrier-Screening?IsMobileSet=false
Updated on April 19, 2021
View reactions
All updates must be accompanied by text or a picture.
Amit M. Shelat, D.O. is a fellow of the American Academy of Neurology and the American College of Physicians. Review provided by VeriMed Healthcare Network. Learn more about him here.
Alison Channon has nearly a decade of experience writing about chronic health conditions, mental health, and women's health. Learn more about her here.

Related articles

Are you an expecting parent who has a family history of spinal muscular atrophy (SMA) or a family...

What To Know About SMA Prenatal Testing and Diagnosis

Are you an expecting parent who has a family history of spinal muscular atrophy (SMA) or a family...
Spinal muscular atrophy (SMA) and Tay-Sachs disease are neurodegenerative, autosomal recessive co...

Tay-Sachs vs. Spinal Muscular Atrophy: Comparing Late-Onset Forms

Spinal muscular atrophy (SMA) and Tay-Sachs disease are neurodegenerative, autosomal recessive co...
Neuromuscular disorders such as spinal muscular atrophy (SMA) and myotubular myopathy (MTM) can b...

The Difference Between SMA and Myotubular Myopathy

Neuromuscular disorders such as spinal muscular atrophy (SMA) and myotubular myopathy (MTM) can b...
Living with spinal muscular atrophy (SMA) as an adult can lead to a lot of questions about the u...

Watch on Demand: ‘A Lifetime of SMA: Pregnancy, Dating, and Career’

Living with spinal muscular atrophy (SMA) as an adult can lead to a lot of questions about the u...
Congenital myasthenic syndrome (CMS) refers to a group of disorders that cause muscle weakness, o...

What's the Difference Between SMA and Congenital Myasthenic Syndrome?

Congenital myasthenic syndrome (CMS) refers to a group of disorders that cause muscle weakness, o...
Spinal muscular atrophy (SMA) is a genetic disease and neuromuscular disorder that destroys motor...

Understanding Depression and Spinal Muscular Atrophy

Spinal muscular atrophy (SMA) is a genetic disease and neuromuscular disorder that destroys motor...

Recent articles

About one-third of people with spinal muscular atrophy (SMA) are adults.Adults with SMA may have...

Treatment Options for Adults with SMA

About one-third of people with spinal muscular atrophy (SMA) are adults.Adults with SMA may have...
Clinical trials may test new drugs or new dosages or combinations of drugs for spinal muscular at...

5 Reasons To Consider Participating in SMA Clinical Trials

Clinical trials may test new drugs or new dosages or combinations of drugs for spinal muscular at...
Clinical trials for spinal muscular atrophy (SMA) test new treatments, new dosages of existing tr...

How Do Clinical Trials Work for SMA?

Clinical trials for spinal muscular atrophy (SMA) test new treatments, new dosages of existing tr...
Clinical trials are designed with safety as a primary concern.Before a new drug, new dosage, or n...

Are Clinical Trials Safe for People With SMA?

Clinical trials are designed with safety as a primary concern.Before a new drug, new dosage, or n...
Costs for spinal muscular atrophy (SMA) medications are high, but financial assistance programs ...

Tips for Staying on Spinal Muscular Atrophy (SMA) Therapies

Costs for spinal muscular atrophy (SMA) medications are high, but financial assistance programs ...
The SMA community officially recognizes August as Spinal Muscular Atrophy Awareness Month. In Au...

UCSF Health and mySMAteam Partnership: SMA Awareness Month 2022

The SMA community officially recognizes August as Spinal Muscular Atrophy Awareness Month. In Au...
mySMAteam My spinal muscular atrophy Team

Thank you for subscribing!

Become a member to get even more:

sign up for free

close