Spinal muscular atrophy causes and genetics

Written by Marisa Wexler, MS | Fact-checked by Inês Martins, PhD | Updated Dec. 18, 2024

Medically reviewed by Edward Smith, MD

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 SMA 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. Mutations in the SMN1 gene result in an inadequate amount of SMN protein being made.

As its name suggests, this protein plays an important role in the functioning and maintenance of motor neurons. While the reduced levels of SMN can affect other cells throughout the body, motor neurons are especially impacted. Their loss results in the progressive muscle weakness and atrophy that marks SMA.

In these five SMA types, the most common disease-causing mutation — accounting for approximately 94% 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 production.

In addition to SMN1, another gene called SMN2 also provides instructions for making the 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 only partially compensate mutations in SMN1.

Most people have two copies of the SMN2 gene, but some individuals have extra copies, which can increase the production of functional SMN. While there are exceptions, patients with more copies are generally better at compensating for the loss of the SMN1 gene, so they tend to have less severe SMA.

Inheritance

In almost all cases, the SMN1 gene mutations that cause SMA are inherited, meaning they 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 carriers. They will not develop SMA themselves, but could pass the disease-causing mutation along to their children.

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

• 1 in 4 (25%) chance that the child will inherit two healthy copies of the gene, and neither have SMA nor be a carrier
• 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 both mutated copies of the SMN1 gene and develop SMA.

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 an SMA carrier, then their children will all be carriers, as they will inherit one mutated SMN1 copy from the SMA parent and one healthy copy from the noncarrier parent.

In turn, if someone with SMA conceives a child with 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%) chance 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. Of note, because currently available SMA disease-modifying therapies are designed to increase the levels of the SMN protein, these rarer types of SMA do not respond to those treatments.

Autosomal recessive inheritance

For rare SMA forms inherited in an autosomal recessive manner, the inheritance 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 type 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 codes for an enzyme involved in the breakdown of certain fatty molecules 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. The protein encoded by 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 of misfolded proteins leads to cell death.
• SMA with lower extremity predominance (SMA-LED), a result of mutations in the DYNC1H1 or the BICD2 genes. 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. These mutations compromise essential cellular functions, such as protein synthesis and modification, as well as cellular trafficking.

X-linked inheritance

X-linked forms of SMA are caused by mutations in genes 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 carries provides the instructions for making androgen receptor protein. Androgens are hormones important for normal male sexual development, the most famous one being testosterone.
• X-linked infantile SMA (XL-SMA), which is linked to changes in the UBA1 gene. UBA1 codes for a protein that is involved in the process of breaking down old or damaged 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, so women who inherit one mutated copy most likely will not show any SMA symptoms. However, these female carriers have a 50% chance of having a son with the disease, and there’s a 50% likelihood that their daughters will also be carriers.

Men with any of these X-linked conditions will pass 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,or a sideways curvature of the spine
• contractures (when muscles around a joint become tight and hard, limiting movement)
• bone fractures 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 symptom onset and disease type. In general, a younger age at symptom onset is associated with more severe SMA — and, consequently, a higher risk of complications such as 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. Complications of SMA are most likely to develop 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 occupational therapy, specialized equipment, and physical therapy, can help to limit or manage complications of the disease.

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