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 muscle weakness caused by degeneration of nerves in the spinal cord. This condition develops due to a protein deficiency. SMA is a genetic disease that is typically inherited in an autosomal recessive manner, which means that a person will only develop the disease if they inherit the altered gene from both parents. 

There are a few types of SMA, with a range in the severity of muscle weakness. The magnitude of genetic involvement corresponds to the degree of clinical symptoms. 

There are no lifestyle factors that can cause or prevent SMA, but complications of the disease can affect aspects of day-to-day life with SMA.

Common Causes

SMA is a progressive (gradually worsening) neurological disease. Normally, healthy muscles move after they receive a signal from motor nerves. SMA occurs when motor neurons in the spinal cord degenerate. As a result of motor neuron degeneration, the motor signals from the brain cannot reach the nerves, and the muscles cannot move. 

SMA affects several structures in the body:

  • Motor neurons located in the anterior horn of the spinal cord normally receive signals from the brain and send them to the peripheral motor nerves to trigger skeletal muscle movement.
  • The anterior horn of the spinal cord is located in the central region of the spinal cord, towards the front of the body.
  • Skeletal muscles are the muscles that control voluntary (on purpose) movement of the body. 

In SMA, the motor neurons in the spine degenerate over time. This is due to a lack of survival motor neuron (SMN) protein, a protein that supports the health of motor neurons. Without enough SMN protein, motor neurons that are already formed and functioning eventually degenerate, losing their structure and function. Muscle weakness occurs because the motor nerves do not send their signals to the peripheral motor nerves—and muscle movement cannot be triggered.

SMA does not affect involuntary muscles that control the internal organs of the body.

Muscle Atrophy

Atrophy is degeneration and shrinking of the muscles. This process occurs gradually, due to the lack of muscle movement of SMA. Most of the time, when muscles do not receive consistent nerve stimulation, they begin to atrophy.

Genetics

The most common cause of SMA is a mutation (alteration) on chromosome five. The SMN1 gene and the SMN2 genes are located near each other on chromosome five—and they both code for the production of SMN protein. A mutation of the SMN1 gene causes spinal muscular atrophy, and variations in the SMN2 gene determine which type of spinal muscular atrophy a person develops. 

The mutation of SMN1 in SMA is usually a deletion, which means that a portion of the genetic code is missing. Mutations of the SMN1 gene can be inherited, or may rarely develop de novo (a change in the genetic code that is not inherited). 

Roles of the SMN1 and SMN2 Genes 

All people normally have two copies of SMN1 gene—one from their father and one from their mother. Interestingly, most people have many copies of the SMN2 gene on chromosome five—as many as eight or 10 copies of the gene. 

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

If a person inherits a mutation in both of their SMN1 genes, then they will develop spinal muscular atrophy. A person who has many copies of SMN2 genes will have a mild version of the condition because they can still produce some SMN protein, while a person who has only a few copies of SMN2 genes will have a severe condition due to a profound deficiency of SMN protein.

Inheritance Pattern of SMA

SMA is typically inherited in an autosomal recessive manner. This means that in order for a person to develop SMA, they must inherit an altered SMN1 gene from their father and from their mother. This results in an inability to produce SMN protein from the SMN1 gene. And the number of copies of SMN2 gene determines whether a person can produce any SMN protein at all.

A person can inherit SMA without having a family history of the condition because family members (including parents) who only have one altered SMN1 gene also have a normal SMN1 that codes for SMN protein—so they wouldn’t be affected by the condition.

If a person develops SMA due to a de novo mutation—they also must have two copies of the altered SMN gene. Both copies could be altered de novo or one copy may be inherited.

Variable Genes

Two other genes that have been associated with SMA may also rarely cause the condition.

An alteration of the cytoplasmic dynein 1 heavy chain 1 (DYNC1H1) gene is found on chromosome 14. It is inherited in an autosomal dominant pattern, meaning that a person who inherits only one copy of the altered gene would develop SMA.

Another gene, UBE1, found on the X-chromosome, is also rarely associated with SMA. This gene codes for ubiquitin-activating enzyme 1, a protein that is involved in the survival of motor neurons. X-linked inheritance rarely affects females because they have two X-chromosomes—and one normal X-chromosome is protective against the condition. However, males can inherit the condition from their asymptomatic (without symptoms) mother.

Lifestyle Risk Factors

There are no known lifestyle habits that can cause or increase the chances of developing SMA. But some factors can affect your predisposition to complications. 

Lifestyle factors that have an impact on your condition include:

  • Sedentary lifestyle: When you have motor weakness, inactivity can contribute to health problems, such as respiratory infections, constipation, and bedsores.
  • Exposure to infectious diseases: When you have a condition such as SMA, it is best to avoid people who you know are sick with a contagious infection.
  • Unhealthy diet: A lack of nutrients, such as proteins and vitamins and minerals can prevent you from fighting infections and having energy.

Overall, lifestyle strategies can help optimize your health and quality of life if you have SMA. These approaches cannot alter the condition itself, but they can minimize potential complications.

A Word From Verywell

SMA is an inherited motor neuron condition. The genetics and heredity are fairly complicated, but they are well understood. The discovery of the biological cause of SMA has led to the development of effective medical treatments that target the causative issues on a molecular level.

For many families, information about the family’s genetic predisposition to SMA can help with family planning.

 

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