|Muscle-controlling nerve cells (motor neurons) are located mostly in the spinal cord. Long, wirelike projections connect the motor neurons to muscles in the limbs and trunk. Normally, signals from the neurons to the muscles cause muscles to contract. In SMA, motor neurons are lost, and muscles can’t function.|
SMA is characterized by the loss of nerve cells in the spinal cord called motor neurons. It is classified as a motor neuron disease.
The most common form of SMA (types 1-4) is caused by a defect (mutation) in the SMN1 gene on chromosome 5. (People have two SMN1 genes — one on each chromosome 5.)
A mutation in the SMN1 gene leads to a deficiency of a motor neuron protein called SMN, for survival of motor neuron. As its name implies, this protein seems to be necessary for normal motor neuron function.
More rarely, a mutation in an X-chromosome gene called UBE1 causes X-linked SMA. The UBE1 gene carries instructions for ubiquitin-activating enzyme 1, which normally helps attach a molecular tag to proteins to mark them for destruction by a cell.
Flaws in the cytoplasmic dynein 1 heavy chain 1 (DYNC1H1) gene on chromosome 14 have been found to lead to another rare form of SMA, called SMA-LED.
Normally, SMN1 genes produce full-length and fully functional SMN protein. But when the SMN1 gene has mutations, as in the chromosome 5-related form of SMA, insufficient levels of SMN protein are produced.
There is a neighboring gene on chromosome 5, called SMN2, which also produces SMN protein. Most of the protein made from instructions carried by SMN2 genes is not functional, but a small percentage is.
People can have multiple copies of the SMN2 gene. In the chromosome 5 form of SMA, the more SMN2 genes a person has, the more functional SMN protein is available. And the milder the disease course is likely to be.
Genetic testing can tell how many SMN2 genes a person has and roughly predict the course of SMA that is likely to result.
SMA severity also may depend on disease modifiers, which don't cause disease but can affect (modify) onset and severity by influencing various biological pathways. Levels of both the plastin 3 protein  and the ZPR1 protein  have been identified as modifiers of SMN-related SMA and could become therapeutic targets. In addition, testing for these protein levels could help predict disease severity, and insight into the activities of these proteins could shed new light on disease processes.
|Genetic information moves from its storage form as DNA to a set of instructions known as RNA, from which protein molecules are made. Most of the RNA instructions from the SMN1 gene tell the cell to make full-length SMN protein. Most of the instructions from the SMN2 gene tell the cell to make short SMN protein.|
Chromosome 5 SMA (types 1 through 4) follows an inheritance pattern known as autosomal recessive, which often takes families by surprise. (The autosomes are the numbered chromosomes — that is, all the chromosomes except the X and the Y, which determine gender.)
Diseases that are recessive require two gene flaws — usually one from each parent, but occasionally one from one parent and one that occurs as a fetus is being formed.
People who have only one gene flaw for a recessive disease are said to be carriers and usually show no symptoms. Often, a family has no idea that some members are carriers until a child is born with a recessive disorder.
If both parents are carriers of the chromosome 5 gene flaw, the risk of each pregnancy producing a child with the disease is 25 percent. This risk doesn’t change no matter how many children a couple has. The "dice are rolled" with each new conception.
Genetic testing for chromosome 5 SMA is available for those suspected of having the disease, including unborn babies, and for carriers of the disease.
Genetic testing is expanding and changing rapidly, but its implications can be complex. It’s best to talk with a genetic counselor before embarking on testing. (A genetic counseling referral can be obtained through your MDA clinic )
X-linked SMA is inherited in an X-linked manner (via the X chromosome). Females have two X chromosomes, and those with a gene flaw on one X chromosome are usually considered carriers of an X-linked disease. Males, however, have no second X to protect them from the full effects of a gene flaw on the X chromosome and show the full effects of such a flaw.
SMA caused by mutations in the DYNC1H1 gene on chromosome 14 is dominantly inherited, meaning that only one DYNC1H1 gene mutation, inherited from one parent, is sufficient to cause the disease.
To read more about the genetics of SMA and genetic testing for this disease, also see: