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