Spinal muscular atrophy (SMA) is a rare inherited neuromuscular disorder caused by an inadequate level of the survivor motor neuron (SMN) protein due to mutations in the SMN1 gene. The SMN protein appears to play a role in regulating small nuclear ribonucleoproteins complexes, and while its exact function remains unclear, the absence of the SMN protein leads to cellular imbalances in motor neurons that in turn causes the motor neuron endplates to not properly connect to muscle and the motor neurons die.
Genetics and disease severity
SMA is an autosomal recessive disorder. Therefore, in order to show symptoms of the disease, the person received two mutant genes from their parents.
The predominate gene responsible for producing SMN protein is the SMN1 gene. There are numerous mutations in gene that can lead to SMA but most involve exon 7 or 8 of the SMN1 gene. A second gene, SMN2 gene, can also produce a form of SMN protein. The presence (or absence) of this second gene play an important role in both the severity of the SMA symptoms and in possible treatment options.
In SMA type 1 (the more severe form of the disease) babies can be further classified as having 2 or 3 copies of the SMN2 gene; the more copies the slower the disease progression (slightly). In a similar fashion, children with 4 copies of the SMN2 gene tend to have a latter onset of the condition (see Table 1).
Table 1: SMA Subtypes
|SMA type||Onset||Milestones achieved||Natural history||Number of SMN2 gene copies|
|0 (or 1A)||Prenatal||None||Death in weeks||1|
|1B||<3 months||Poor or absent head control||Death by second or third year of life||2|
|1C||>3 months||Cephalic control||Plateau in first two years||3|
|2||>6 months||Able to sit unaided||Survival to adolescence/adulthood||3|
|3A||18 – 36 months||Walking unaided||Early loss of ambulation|
|3B||>3 years||Walking unaided||Later loss of ambulation Normal lifespan||3-4|
SMA is a progressive disorder, meaning that symptoms worsen without proper treatment. Further compounding the problem is that symptoms do not appear until a significant amount of irreversible damage has been done to the muscle so even though treatment can reduce disease progression, it is likely that treatment will not help individuals improve – at least not significantly. Therefore, the sooner a person with SMA can be diagnosed, the better the chances they have of maintaining a certain level of activity and quality of life.
As members of the care team become more familiar with SMA, it is expected that delays in diagnosis can be reduced. A 2015 review looked at 21 studies involving SMA and calculated the delays in diagnosis.
The exact reasons for the delays in diagnosis are unclear. According to Lin et al, “It has been noted that the delays in diagnosis of SMA resulted from patient visits to multiple health care professionals to rule out the possibility of other illnesses before genetic testing for SMA was performed and a confirmed diagnosis was obtained.”
SMA type 1
- Symptoms of SMA type I include hypotonia (reduced muscle tone), diminished limb movements, lack of tendon reflexes, fasciculations, swallowing and feeding difficulties, and impaired breathing.
- These children also develop scoliosis (curvature of the spine) or other skeletal abnormalities as they get older. Without any treatment, affected children never sit or stand and the vast majority usually die of respiratory failure before the age of 2 years.
SMA type 2
- They are able to sit without support but are unable to stand or walk unaided, and some may lose the ability to stay seated independently over time without treatment.
- They may have respiratory difficulties including hypoventilation in sleep. The progression of disease is variable without treatment
SMA type 3
- They first show difficulty walking and running, climbing steps, or rising from a chair.
- The proximal leg muscles are most often affected first, with a tremor seen in the hands.
- Complications include scoliosis and joint contractures—chronic shortening of muscles or tendons around joints–caused by abnormal muscle tone and weakness, which prevents the joints from moving freely.
There are currently two treatments approved to treat SMA—one that can delay progression (nusinersen) and one that can possible stop progression (onasemnogene abeparvovec-xioi). There are also numerous other treatments in development (e.g., risdiplam).
Once a person has been diagnosed with SMA, a team approach to care is extremely important and numerous clinical professionals are required to manage the plethora of physical problems children with SMA must endure. This can include physical therapy, occupational therapy, respiratory care, gastrointestinal concerns, etc. Most people with SMA are seen by multiple medical professionals to help them manage their symptoms as the disease progresses.
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