Spinal muscular atrophy causes and genetics

Last updated Feb. 2, 2023, by Marisa Wexler, MS
Fact-checked by Ines Martins, PhD

Spinal muscular atrophy (SMA) is a rare genetic condition mostly caused by inherited mutations in the SMN1 gene, although rarer forms of the disease can arise due to mutations in a number of other genes.

These genetic mutations lead to the progressive loss of motor neurons — the specialized nerve cells that control voluntary movement — ultimately resulting in symptoms like muscle weakness and wasting.

Genetic cause of SMA

The most common types of SMA (types 0, 1, 2, 3, and 4) are caused by mutations in the SMN1 gene, which provides instructions for making the SMN or survival motor neuron protein. As a result of mutations in the SMN1 gene, little or no SMN protein is made.

The lack of SMN protein affects cells throughout the body, but motor neurons are especially sensitive to the lack of SMN — without sufficient amounts of this protein, motor neurons grow sickly and die off. Their loss results in the progressive muscle weakness and atrophy that marks SMA.

In these main SMA types, the most common disease-causing mutation — accounting for more than 95% of cases — is the complete loss of exon 7 in both copies of the SMN1 gene. Exons are the sections of a gene that contain instructions for protein production. This mutation essentially causes a large chunk of the genetic code to be missing, which interferes with SMN protein production.

In addition to SMN1, another gene called SMN2 also provides instructions for making SMN protein. However, due to a slight difference in the genetic sequence, the SMN2 gene produces only about 10% as much functional SMN protein as the SMN1 gene. As such, SMN2 can compensate partially, but not completely, for mutations in SMN1.

Most people have two copies of the SMN2 gene, but some individuals have extra copies. More copies of SMN2 facilitate increased SMN protein production, so patients with more copies tend to have less severe SMA.

Inheritance

In almost all cases, the SMN1 gene mutations that cause SMA are inherited, meaning the mutations are passed from parents to their biological children. Everyone inherits two copies of the SMN1 gene — one from each biological parent.

The main forms of SMA caused by SMN1 mutations are inherited in an autosomal recessive manner, which means that SMA will only develop if disease-causing mutations are present in both copies of the SMN1 gene.

Children who inherit only one mutated copy of SMN1 (along with one healthy gene copy) are said to be a carrier, because they will not develop SMA themselves, but could pass the disease-causing mutation along to their children.

If two people who are both carriers conceive a child, there is a:

• 1 in 4 (25%) chance that the child will inherit both mutated genes and develop SMA
• 1 in 2 (50%) chance that any offspring will inherit just one mutated copy, meaning they will be a carrier like their parents but will not have SMA
• 1 in 4 (25%) chance that the child will inherit two healthy copies of the gene, and neither have SMA nor be a carrier.

If a person with SMA chooses to have biological children, he or she is guaranteed to pass on one mutated copy of the SMN1 gene. As such, if someone with SMA has biological children with someone who is not a carrier, then their children will all be carriers, as they will inherit one mutated SMN1 copy from the SMA patient and one healthy copy from the noncarrier patient.

In turn, if someone with SMA conceives a child with someone who is a carrier of the disease, there is a:

• 1 in 2 (50%) chance that the child will inherit only one mutated copy of SMN1 and be a carrier
• 1 in 2 (50%) likelihood that the child will inherit two mutated copies of the gene and develop SMA.

If two people with SMA conceive a child together, their offspring are guaranteed to inherit two mutated copies of the SMN1 gene, and will also have SMA.

In about 2% of SMA cases, mutations in the SMN1 gene occur de novo, meaning they arise spontaneously rather than being inherited from a parent.

What causes rarer types of SMA?

The less common types of SMA are caused by mutations in genes other than SMN1. These rarer types also may be inherited in an autosomal recessive manner, or through different mechanisms.

Autosomal recessive inheritance

For rare SMA forms inherited in an autosomal recessive manner, the mechanisms are similar to the disease types caused by SMN1 mutations. Specifically, the disease will only develop if both copies of the relevant gene are mutated. Among these other autosomal recessive forms are:

• SMA with respiratory distress 1 (SMARD1), which is caused by changes in the IGHMBP2 gene. That gene provides instructions for making a protein involved in DNA replication, the process by which a new DNA copy is made during cell division.
• SMA with progressive myoclonic epilepsy (SMA-PME), also known as SMA plus. This type is linked to mutations in the ASAH1 gene, which contains the instructions for making an enzyme involved in fatty molecule breakdown inside cells.

Autosomal dominant inheritance

Other forms of SMA are inherited in an autosomal dominant manner, meaning that a person only needs to inherit one mutated copy of the relevant gene for the disease to develop. People with these diseases have a 50% risk of passing the mutated gene to their children, who will develop the condition if they do inherit the gene. Autosomal dominant types of SMA include:

• Finkel type SMA, which is caused by mutations in the VAPB gene. VAPB is thought to be involved in the detection of unfolded or misfolded proteins, and to activate cellular events to prevent their toxic accumulation in cells. Mutations prevent this process, and the resulting accumulation leads to cell death.
• SMA with lower extremity predominance (SMA-LED), a result of changes in the DYNC1H1 or the BICD2 gene. These genes provide instructions for making proteins that are part of a complex involved in moving materials within cells.
• Distal spinal muscular atrophy (DSMA), which can be caused by mutations in several genes, including BSCL2, GARS1, and REEP1. It is thought these genes play roles in the complex molecular machinery that cells use to make and modify new proteins.

X-linked inheritance

X-linked forms of SMA are caused by mutations located on the X chromosome, one of the two chromosomes that determine biological sex — the other being the Y chromosome. These SMA types include:

• Kennedy’s disease, also called spinal and bulbar muscular atrophy (SBMA). This type is caused by mutations in the AR gene, which provides the instructions for making a protein receptor of androgens. Androgens are hormones important for normal male sexual development, the most famous one being testosterone.
• X-linked infantile SMA, which is linked to changes in the UBA1 gene. UBA1 is involved in the process of breaking down proteins that are no longer needed inside cells.

Because men only have one X chromosome, inherited from the mother, those who inherit the mutated gene will develop X-linked diseases. In women — who have two X chromosomes, one from each parent — a healthy gene copy can compensate for the mutated copy. That means these women most likely will not show any SMA symptoms. However, these female carriers have a 50% chance of having a son with the disease, and a 50% risk of having a daughter who also will be a carrier.

Men with any of these conditions will transmit the disease-causing mutation to all their daughters who will be carriers, but not to a son, because boys receive a Y sex chromosome from their fathers instead of an X chromosome.

Risk factors for SMA-related complications

Due to the muscle weakness that characterizes the genetic disorder, people with SMA are at increased risk of a number of disease-associated complications. These include:

• scoliosis (a sideways curvature of the spine)
• contractures (when muscles around a joint grow tight and hard, limiting movement)
• fractures (broken bones) and dislocations, especially of the hips
• difficulty feeding, due to weakness of muscles around the mouth and jaw
• trouble breathing, due to weakness of muscles needed to push air in and out of the lungs
• infections, particularly respiratory infections associated with weak chest muscles

The main factors that affect the risk of developing these complications are age at onset and disease type. In general, a younger age at which symptoms first appear is associated with more severe SMA — and, consequently, a higher risk of complications like trouble breathing or eating.

Among the five main types of SMA, the most severe is type 0, where symptoms begin prior to birth; the least severe is type 4, in which symptoms do not become apparent until adulthood. More complications are likely in the more severe disease types.

Other factors that can contribute to complications include:

• a sedentary lifestyle that fails to counteract the early muscle weakness and the bone and joint issues associated with SMA
• poor dietary choices that worsen the gastrointestinal symptoms of SMA and do not provide the nutrients needed for a healthy body and immune system.

SMA treatment with disease-modifying therapies that slow disease progression also may reduce the risk of developing complications by helping to maintain muscle health. Other kinds of supportive care, such as assistive devices and physical therapy, can help to limit or manage complications of the disease.

SMA News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.