Causes and Risk Factors of Spinal Muscular Atrophy (SMA)

A rare disease with a well-understood genetic cause

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Spinal muscular atrophy (SMA) is a progressive neurodegenerative disease. It is a rare genetic condition caused by alterations (mutations) in the genes that make proteins needed to support motor neuron function.

There are a few types of SMA. The degree of genetic involvement in each type corresponds to the severity of clinical symptoms, specifically muscle weakness.

SMA is inherited in an autosomal recessive manner. This means a person develops the condition because they get a copy of the altered gene from both their parents. 

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 complications and improve a person's quality of life if they have SMA.

Common Causes

Normal, healthy muscles move in response to receiving signals from motor neurons in the spinal cord. In SMA, the motor neurons degenerate. When this happens, the motor signals from the brain cannot reach the nerves and the muscles won't move.

SMA primarily affects the central nervous system. More specifically, it affects several structures in the body related to movement, including:

  • Motor neurons. Located in the anterior horn of the spinal cord, these neurons normally receive signals from the brain and send them to the peripheral motor nerves, which trigger skeletal muscle movement.
  • Anterior horn of the spinal cord. A section of grey matter located in the central region of the spinal cord, toward the front of the body. The anterior horn contains alpha motor neuron cells, which tell skeletal muscles to move.
  • Skeletal muscles. These muscles control the purposeful (voluntary) movement of the body. 

In SMA, the motor neurons in the spine degenerate over time due to a lack of survival motor neuron (SMN) protein (a protein supports the health of motor neurons).

Without enough SMN protein, even motor neurons that have already formed and work will eventually lose their structure and function.

When motor nerves do not send signals to the peripheral motor nerves, muscle movement cannot be triggered.

Muscle Atrophy

Muscles that do not receive consistent nerve stimulation eventually begin to shrink and get weak (atrophy). In SMA, atrophy occurs gradually due to the lack of muscle movement.

Genetics

The most common cause of SMA is a mutation on chromosome five. The SMN1 and SMN2 genes both code for the production of SMN protein. They are located near each other on chromosome five.

A mutation of the SMN1 gene causes spinal muscular atrophy. Variations in the SMN2 gene determine which type of spinal muscular atrophy a person develops. 

In SMA, the mutation of SMN1 is most often a deletion (a portion of the genetic code is missing). SMN1 mutations are usually inherited. Rarely, they develop without being inherited (de novo mutation).

Roles of the SMN1 and SMN2 Genes 

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

The SMN1 gene directs most of the body’s SMN protein production, while the SMN2 gene only directs some.

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

If someone has many copies of the SMN2 gene, they can still produce some SMN protein. Therefore, they'll have a mild version of SMA.

However, if they only have a few SMN2 genes, they will have a profound SMN protein deficiency. This means their case of SMA will be more severe.

Inheritance Pattern of SMA

SMA is typically inherited in an autosomal recessive manner. This means a person develops the condition because they inherited an altered SMN1 gene from both parents.

Having two mutated copies of the SMN1 gene means their body is unable to make SMN protein with that gene. They may be able to produce some SMN protein if they have several copies of the SMN2 gene.

The number of SMN2 gene copies a person has determines whether their case of SMA is mild or 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 a person has a de novo or inherited mutation, they still need to have two copies of the altered SMN gene for SMA to develop.

A person who only has one altered SMN1 gene will also have one normal SMN1 that codes for SMN protein. Having at least one gene that can code for the proteins means they won't be affected by SMA.

Sometimes, one mutated gene is de novo and the other is inherited. It's also possible for both gene mutations to be de novo.

Variable Genes

Rarely, two other genes associated with SMA may cause the condition: DYNC1H1 and UBE1.

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 UBE1, which codes for ubiquitin-activating enzyme 1. This protein is involved in the survival of motor neurons.

UBE1 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 UBE1 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.

Lifestyle Risk Factors

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 a person 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).
  • Exposure to infectious diseases. Chronic conditions like SMA can affect your immune system. Avoiding people who 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.

While there is a strong hereditary component to SMA, it's also possible for the gene mutations that cause the condition to arise de novo. SMA can also result due to a combination of inherited and de novo mutations.

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.

 

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Article Sources

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