Spinal muscular atrophy(SMA) is one of many diseases that causes muscle weakness, typically in early childhood. It is one of the most common genetic (inherited) neuromuscular diseases affecting 1/8000 to 1/10 000 individuals.
Spinal muscular atrophy is caused by the loss of specialized nerve cells, called motor neurons that control muscle movement. Once these nerves die, the muscles become weak and atrophy (when muscles get smaller). SMA can affect a child’s ability to crawl, walk, sit up, and control head movements. Severe SMA can damage the muscles used for breathing and swallowing. Although most individuals with SMA present in infancy, the disease can also present in adulthood for the first time. SMA is caused by genetic faults in a gene called SMN1 (survival motor neuron 1)
Spinal muscular atrophy is inherited in what is termed an autosomal recessive pattern of inheritance.
This means that affected individuals have two faulty (missing) SMN1 genecopies, generally one inherited from each parent. Parents are not affected with SMA as their other SMN1 gene copy functions normally, but they are so-called carriers. When two carriers have children, each child has a ¼ or 25% of being affected a ½ or 50% chance of being a carrier and a ¼ or 25% chance of being unaffected. The chance for each child to be affected is independent.
Almost all individuals who have SMA have the identical genetic fault – both copies of the SMN1 gene are deleted (missing). It is not clear why there is then such variability in the age of onset. One partial explanation for the variability is that all individuals have another nearly identical gene to SMN1 called SMN2. This gene is not critical for nerve cell survival, but may be present in variable copy number in different individuals. As a broad principle, individuals with more SMN2 gene copies (2-3) have milder disease that people with less SMN2 (1 or 2 gene copies). This is because the SMN2 gene can partially compensate for the absence of SMN1 (although not entirely).
Importantly, one of the new therapies available for SMA, Nusinersen (Spinraza) is designed to cause the SMN2 genes to produce more of the missing SMN1 protein and thus make the disease less severe. The more SMN2 genes an individual has, the better the drug works. The number of SMN2 genes can be tested.
There have been some important and exciting recent new developments in the treatment of SMA. There are at least three new drugs to treat SMA: nusinersen (Spinraza), onasemnogene abeparvovec-xioi (Zolgensma) and risdiplam (Evrysdi). All are forms of gene therapy and are been shown to have very positive outcomes, especially when initiated early in the disease. Unfortunately, they are all very expensive and thus availability and accessibility remain challenging.