XL-SMA is caused by mutations in the ubiquitin-like modifier activating enzyme 1 (UBA1) gene. This gene encodes for a protein, called ubiquitin-activating enzyme E1, involved in breaking down proteins that are no longer needed inside cells.
Four mutations are currently known to cause XL-SMA, and all result in little or no enzyme being made. When there is not enough enzyme to break down unneeded proteins, they start to build up inside cells. This disrupts the normal workings of the cells and eventually causes their death. Motor neurons, which are the nerve cells that control voluntary muscles, are particularly vulnerable to this protein accumulation.
The UBA1 gene is located on the X chromosome. Women have two copies of the X chromosome, while men have one X chromosome and a Y chromosome.
As a result, if a male child inherits one mutated copy of the UBA1 gene, he will have XL-SMA. If a female inherits one mutated copy of the UBA1 gene, however, she has another X chromosome that will with a healthy copy of the gene. Her cells will produce enough of the enzyme to compensate, and she will generally not show any symptoms of XL-SMA. A woman with one mutated copy of the UBA1 gene is referred to as a carrier.
If a female carrier has children, there is a 50 percent risk that her sons will have the disease and a 50 percent risk that her daughters will also be a carrier.
The symptoms of XL-SMA closely resemble those of SMA type 0 or type 1. Like those two SMA types, symptoms can begin before or just after birth. XL-SMA is associated with severe and progressive muscle weakness, which especially affects the chest muscles and restricts patients’ ability to breathe.
One of the initial symptoms of the disease is misshapen joints (contractures) or, in more severe cases, being born with broken bones. This can affect the baby’s ability to move.
Affected babies will often not reach developmental milestones, such as being able to sit independently, and they likely will regress as the condition progresses.
XL-SMA may also cause scoliosis or kyphosis (an abnormally curved spine), micrognathia (a small chin), and cryptorchidism (testes that do not descend).
A diagnosis of XL-SMA can be confirmed through genetic testing that checks for mutations in the UBA1 gene.
The prognosis for patients with XL-SMA is currently poor and the majority of affected babies do not survive past early childhood. Respiratory failure is usually the cause of death at around 2 years old.
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