Spinal muscular atrophy (SMA) is a rare genetic condition characterized by the progressive loss of motor neurons, the specialized nerve cells that control voluntary movement, leading to muscle weakness and wasting.
Nearly all (95%) cases of the most common forms of SMA (types 0, 1, 2, 3, and 4) are caused by the complete loss of exon 7 in both copies of the SMN1 gene. This gene provides the instructions to produce survival motor neuron (SMN), a protein generated by virtually every cell in the body and involved in several cellular processes regulating protein balance. Exons are the sections of a gene that contain instructions for protein production.
As a result of mutations in the SMN1 gene, little or no SMN protein is made. Notably, while increasing evidence suggests that SMA is a whole-body disease, motor neurons appear to be highly sensitive to SMN deficiency, dying without it. Their loss results in the progressive muscle weakness and atrophy that marks SMA.
While a second SMN gene, called SMN2, is capable of producing SMN, a slight difference in its DNA sequence limits the amount of functional SMN it produces to 10–15%.
Typically, people have two SMN2 gene copies, and extra copies can help provide more SMN protein, with a higher number of copies being associated with less severe disease.
The most common types of SMA are inherited in an autosomal recessive manner, meaning a child must acquire two defective copies of SMN1 — one from the mother and one from the father — to develop the disorder.
People with only one mutated gene copy are typically healthy, but are considered to be carriers because they can still transmit the mutated gene to their children. If both parents are SMA carriers, each of their children have a 25% chance of inheriting two mutated SMN1 copies and developing the disease, and a 50% risk of being a carrier.
Rarer types of SMA
Rarer types of SMA are caused by mutations in genes other than SMN1.
Other autosomal recessive forms include SMA with respiratory distress 1 (SMARD1) and SMA with progressive myoclonic epilepsy (SMA-PME). SMARD1 is caused by changes in the IGHMBP2 gene, which provides instructions for making a protein that is involved in DNA replication, the process by which DNA makes a copy of itself during cell division. SMA-PME, also known as SMA plus, is linked to mutations in the ASAH1 gene, which contains the instructions for making an enzyme involved in fatty molecule breakdown inside cells.
Autosomal dominant forms, meaning that a single copy of the mutated disease-causing gene is sufficient to cause the disease, comprise Finkel type SMA and SMA with lower extremity predominance (SMA-LED). Finkel type SMA is associated with mutations in the VAPB gene, which 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 kills cells. SMA-LED is caused by changes in the DYNC1H1 or the BICD2 gene, which provide instructions for making proteins that are part of a complex involved in moving materials within cells. 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.
SMA’s X-linked recessive forms, or those associated with changes in genes located in the X chromosome, (one of the two sex chromosomes, the other being the Y chromosome), include Kennedy’s disease and X-linked infantile SMA. Kennedy’s disease, or spinal and bulbar muscular atrophy, is caused by mutations in the AR gene, which provides the instructions for making a protein receptor of androgens. Androgens are hormones (such as testosterone) important for normal male sexual development. X-linked infantile SMA is linked to changes in the UBA1 gene, which is involved in the process of breaking down proteins that are no longer needed inside cells.
Since men only have one X chromosome (inherited from the mother), those who inherit the mutated gene will develop these X-linked diseases. In women — who have two X chromosomes, one from the mother and one from the father — a healthy gene copy can compensate for the mutated copy, and they most likely will not show any symptoms. However, these carriers have a 50% chance of having a son with the disease, and 50% risk of having a daughter who will also be a carrier. Men with any of these conditions will 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.
Last updated: June 28, 2021
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