Spinal muscular atrophy (SMA) is an autosomal recessive genetic disorder characterized by progressive muscle weakness and caused by a loss of specialized nerve cells (motor neurons) in the spinal cord and in the part of the brain that is connected to the spinal cord (the brain tem).

Motor neurons control voluntary muscle movement, including the movements of the arms and legs, trunk or face.

SMA genetics

SMA is a genetic disease, meaning that it runs in families, and it is passed from parents to their children through their genes.

In our body we have millions of cells, each of them containing a nucleus. It is in the cell nucleus that chromosomes are located. These are made of proteins and DNA molecules, which contain the biological instructions that make each species and each person unique. The molecules’ structure keeps DNA tightly packed. DNA is a very long molecule and is packaged as chromosomes.

Each of us have 46 chromosomes arranged in 23 pairs, one inherited from the mother and the other from the father. Twenty-two of the chromosomal pairs are known as autosomes because they are found in both genders. The 23rd pair is the sex chromosome and determines your gender (XX for females and XY for males).

The main function of chromosomes is to ensure that DNA is accurately copied and distributed during cell division. However, mistakes occur on rare occasions. In an autosomal disorder such as SMA, the mutation occurs in one of the 22 non-sex chromosomes (autosomes). As a result, the disease may affect both males and females.

SMA is also a recessive condition, meaning that people who carry one mutated gene and one healthy gene will not have the condition, but will be carriers who may pass the disease onto their children.

When two people carrying a mutation in their SMN1 gene have a child together, their child has a risk of carrying two faulty copies of the gene. The child will then have spinal muscular atrophy (SMA). The risk stays the same for each pregnancy. Here are some examples of inheriting SMA:

Both parents are carriers:

  • 25 percent chance of having a child without SMA
  • 25 percent chance of having a child with SMA
  • 50 percent chance of having a carrier child without SMA

One parent is a carrier: 

  • 50 percent chance of having a child without SMA
  • 50 percent chance of having a carrier child without SMA

One parent has SMA, the other doesn’t and isn’t a carrier:

  • 100 percent of having a carrier child without SMA

One parent has SMA and the other is a carrier:

  • 50 percent chance of having a child with SMA
  • 50 percent chance of having a carrier child without SMA

Both parents have SMA:

  • 100 percent chance of having a child with SMA

Mutations in which genes cause SMA

The most common types of SMA (0, 1, 2, 3 and 4) are associated with a mutation in the SMN1 gene, which is located on chromosome 5. About 95 percent of people with SMA have mutations where a section of the SMN1 gene (exon 7) is deleted in both copies of the gene. The SMN1 gene provides instructions for making the survival motor neuron (SMN) protein that is found in all parts of the body, and exists in high levels in the spinal cord. This protein is important for maintaining the function of motor neuron cells.

As a result of mutations in the SMN1 gene, little or no SMN protein is made. Research findings indicate that motor neurons are particular vulnerable to a shortage of the SMN protein and die prematurely.

In humans, there is a second gene called SMN2. Some people have three or more copies of the SMN2 gene. Like the SMN1 gene, the SMN2 genes provide instructions for making the SMN protein. Extra SMN2 genes can help provide some of the SMN protein. But fewer full-size SMN protein is produced from SMN2 genes compared to the SMN1 gene. In these people, SMA symptoms are much less severe (SMA types 2, 3 or 4).

Finkel type SMA is associated with mutations in the VAPB gene located on chromosome 20. This gene contains instructions to produce VAPB protein that is associated with the membrane that surrounds the endoplasmatic reticulum, which is where newly-made proteins acquire their three-dimentional structure and are prepared to be transported within the cell or to the cell surface.

A mutation causes the amino acid proline to be replaced with the amino acid serine at position 56. This causes amyothrophic lateral sclerosis (ALS) in some people and SMA in others (the reason is not known). The mutated protein cannot activate the unfolded protein response, resulting in protein aggregates that lead to cell death. Motor neurons are particularly vulnerable to cell death, caused by protein aggregates.

The DYNC1H1 gene – located on chromosome 14 – provides instructions to make a protein that is part of a complex group of proteins, known as dynein, which are found in the cytoplasm (fluid inside the cell). In neurons, dynein moves proteins and other cellular materials away from the junctions between neurons (synapses) to the center of the cell, facilitating the passage of chemical messages from one neuron to another. Mutations in the DYNC1H1 gene cause a form of SMA called SMA-LED (spinal muscular atrophy, lower extremity, dominant), which primarily affects the legs. As a result, movement of proteins and cellular materials is impaired, resulting in a decrease in chemical messaging between neurons that control muscle movement.

Mutations in the UBA1 gene cause the X-linked infantile SMA condition (also known as Kennedy’s disease). This gene, located on the X chromosome, is responsible for making the ubiquitin-activating enzyme called E1 involved in the degradation of proteins within cells. Protein degradation is essential to remove damaged or unnecessary proteins and to maintain the normal function of cells. At least three mutations in the UBA1 gene have been found.

Two of them (one is written as 1617 G > T, meaning a letter G on the DNA is turned to a letter T at position 1617, and another is 1639 A > G) are thought to lead to an enzyme with impaired function. The third (written as 1731 C > T) results in a decreased activity of the gene, leading to production of less enzyme, which ultimately disrupts the process of protein degradation and causes protein buildup. Motor neurons are vulnerable to damage and cell death from protein buildup.

SMA prevalence in the US

According to the SMA foundation 1 in 6,000 to 1 in 10,000 children are born with SMA. It is believed that approximately six million people in the U.S. carry a faulty SMN1 gene.

Note: 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.