Spinal muscular atrophy (SMA) is a genetic disease that affects many families worldwide. This disease causes muscles to gradually weaken and atrophy, especially those responsible for movement, which are primarily controlled by motor neurons. Patients experience a persistent decline in motor neurons in the lower part of the spinal cord and brainstem. Affected individuals may have difficulty moving, and in severe cases, it can even affect eating and breathing.

Causes
The most common cause of spinal muscular atrophy (SMA) is a mutation or deletion of two survival motor neuron 1 (SMN1) genes located on chromosome 5 (5q13.2). In rare cases, SMA may also be caused by mutations in other genes, such as the VAPB gene on chromosome 20, the DYNC1H1 gene on chromosome 14, the BICD2 gene on chromosome 9, and the UBA1 gene on the X chromosome. Therefore, spinal muscular atrophy caused by mutations on chromosome 5 is called “5q spinal muscular atrophy”, while spinal muscular atrophy caused by other reasons is called “non-5q spinal muscular atrophy”.[2][3]
Motor neurons are nerve cells in the spinal cord responsible for transmitting the brain’s instructions to muscles, such as controlling the movement of arms, legs, face, chest, throat, and tongue. The motor neuron gene is responsible for producing survival motor neuron (SMN) protein, so this gene is very important for the function and survival of motor neurons. Most SMA patients have a deletion of the SMN1 gene (exon 7 of the SMN1 gene, or exon 7 and 8 are missing), resulting in reduced production or absence of SMN protein, leading to degeneration and loss of motor neurons that control muscle movement. All patients retain at least one copy of SMN2, generally 2-4 copies. The deletion of SMN1 is mainly responsible for the onset of SMA, while the severity is mainly related to the number of SMN2 copies. Most type I SMA patients have two SMN2 copies, type II SMA patients commonly have three SMN2 copies, while type III and IV patients generally have three or four SMN2 copies.

How is SMA inherited?
SMA is an autosomal recessive genetic disorder, which means that it requires both parents to pass on two problematic SMN1 gene copies to the next generation to develop the disease. Those who have one normal copy and one problematic copy are carriers, they will not develop SMA and will not show any symptoms related to SMA. [2]
Main types of SMA
SMA is divided into different types based on the age of onset and the severity of symptoms. There are four main types of SMA, classified by the age of onset and the severity of symptoms. The most severe type I usually shows symptoms shortly after birth, while types II and III patients may show symptoms when they are older, and type IV SMA appears in adulthood. [3][4]
● SMA Type I (Werdnig-Hoffman disease)
This is the most severe and most common form of SMA, accounting for 50-70% of childhood SMA. Infants usually show symptoms within 6 months after birth, including inability to sit independently, weak crying, difficulty swallowing and eating, etc. Patients have weak limbs and show general muscle relaxation. They can never sit, turn over or crawl independently, and have severe swallowing and breathing difficulties, and are prone to death due to lung infections. Most patients die within 2 years of birth, but the use of respiratory aids, gastric tube feeding and other support methods can extend their life to late childhood or even adulthood.
● SMA Type II (Dubowitz disease)
Patients usually show symptoms within 6-18 months. They can sit independently (some will gradually lose this ability), but cannot walk independently. Muscle reflexes are reduced or disappear, and there is hand tremor. Like type I, there are also lung and swallowing problems, scoliosis, but the condition is lighter than type I, the onset is slower, and the lifespan varies from childhood to adulthood.
● SMA Type III (Kugelberg-Welander disease)
The age of onset is between 18 months and 17 years. Patients can walk independently, but half of them will eventually lose their ability to walk. Most people have difficulty walking, are prone to falls, and have difficulty standing up. There is a slight tremor in the fingers, but there are few swallowing problems. The expected lifespan is no different from normal people.
● SMA Type IV
Most of them start after the age of 30, the symptoms are slower, the main symptoms are fatigue and muscle pain, usually first affecting the thighs and buttocks, then the upper limbs, breathing and swallowing are not affected, and the expected lifespan is normal.
What methods can be used to diagnose SMA?
Genetic Testing
Genetic testing is currently the most common and reliable method for diagnosing SMA, and it is usually the first choice for diagnosing SMA. By drawing blood or using a mouth swab to check the SMN1 gene, it is possible to analyze whether there are mutations or deletions, and determine the likelihood of having SMA. The SMN1 gene is responsible for the development of motor neurons, and genetic testing can directly analyze the sequence of the SMN1 gene to find defects in the SMN1 gene and check whether there is a deletion or mutation of the SMN1 gene in the patient. Through DNA sequence analysis, the status of the SMN1 gene can be determined very accurately, confirming the diagnosis of SMA. If both SMN1 genes are missing exon 7, the diagnosis of SMA is confirmed. If only one SMN1 gene is missing exon 7, then a full sequence analysis of the other SMN1 gene is needed to find point mutations in the gene. Variations in the SMN1 gene will lead to the degeneration of motor neurons and muscle atrophy, which is the direct cause of SMA, so genetic analysis is the most accurate diagnostic method. [2]

Electromyography (EMG) and Nerve Conduction Studies
Electromyography (EMG) and nerve conduction studies can also be used for the diagnosis of SMA. These tests can measure the electrical activity of muscles and nerves and detect abnormal muscle and nerve electrical activity. SMA is a motor neuron disease that leads to a gradual loss of muscle function. EMG and nerve conduction tests can observe reduced muscle contraction ability and nerve conduction disorders, thereby assisting in the diagnosis of SMA. EMG and nerve conduction tests help confirm the diagnosis of SMA and distinguish it from other neuromuscular diseases. The results of these tests can supplement genetic testing and provide doctors with a more comprehensive diagnostic basis.[2]
Muscle Biopsy
Muscle biopsy can directly observe changes in muscle tissue, but it is difficult to distinguish between SMA and other muscle diseases, so it is increasingly less used as the first choice for diagnosis. In addition, muscle biopsy requires a slice of muscle to be sampled, which causes some trauma to the patient, and the test results are also easily affected by other factors, so the accuracy is not as good as genetic testing. Therefore, although neurogenic muscle atrophy is a characteristic of SMA, muscle biopsy can check muscle tissue, but with the increasing popularity and reliability of genetic testing, muscle biopsy is less used in the diagnosis of SMA. [2]
If you suspect that you may be a potential SMA patient, or have a family history, it is recommended that you seek evaluation from a family doctor or neurologist as soon as possible. If necessary, they will arrange for you to undergo genetic testing for diagnosis.
Reference:
[3] D'Amico, A., Mercuri, E., Tiziano, F.D. et al. Spinal muscular atrophy. Orphanet J Rare Dis 6, 71 (2011). https://doi.org/10.1186/1750-1172-6-71
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