X-linked infantile spinal muscular atrophy
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X-linked infantile spinal muscular atrophy (XL-SMA) is a rare and severe type of spinal muscular atrophy (SMA), which usually is diagnosed in male infants at birth or shortly after. Life expectancy is considerably shorter for male infants with XL-SMA, with most not surviving past childhood.
XL-SMA also can be referred to as SMAX2.
Other forms of SMA, which are caused by mutations in the SMN1 gene, are divided into five main types — 0, 1, 2, 3, and 4. XL-SMA is one of the rare SMA types. Other rare types include lower extremity dominant (SMA-LED), SMARD1, Finkel type, and Kennedy’s disease.
What causes XL-SMA?
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, which is involved in breaking down proteins no longer needed inside cells.
Mutations in the UBA1 gene associated with XL-SMA typically lead to a decrease in the production of ubiquitin-activating enzyme E1 protein or to the production of an enzyme with abnormal function. When this enzyme is defective, old or damaged proteins (unwanted proteins) start to build up inside cells as they are not being properly broken down or degraded. Such protein accumulation impairs cells’ functioning and can eventually lead to their death.
Motor neurons, which are specialized nerve cells that control muscle movements, are particularly vulnerable to this protein build up. The death of the motor neurons results in the disease’s symptoms.
XL-SMA differs from another X-linked SMA type, Kennedy’s disease, where a mutation on the androgen receptor encoding gene causes the condition.
How is XL-SMA inherited?
Male infants are more likely to be affected by XL-SMA. Female babies can carry a mutated UBA1 gene, but generally don’t have symptoms of XL-SMA. This is because the UBA1 gene is located on the X chromosome. Females have two copies of the X chromosome, while males have one X chromosome and one Y chromosome.
As a result, if a male child inherits a mutated copy of the UBA1 gene, he will have XL-SMA. A female child who inherits a mutated copy of the UBA1 gene has another X chromosome with a healthy copy of the gene. It is unusual for a woman to inherit two copies of the mutated gene, one from each parent.
A female infant who inherits one mutated copy 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 a male child, there is a 50% risk that they will have the disease. If a female carrier has a female child, there is a 50% risk that they will also be carriers of a mutated UAB1 gene copy.
What are the symptoms of XL-SMA?
The symptoms of XL-SMA closely resemble those of SMA types 0 or 1. Like those two SMA types, symptoms can begin before or just after birth. XL-SMA symptoms can include:
- hypotonia (low muscle tone) to severe muscle weakness that progressively worsens
- weakness affecting the chest muscles that restricts the infant’s ability to breathe
- misshapen joints (contractures) and joint stiffness
- being born with broken bones in severe cases.
All of these affect the infant’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, a phenomenon known as developmental regression.
XL-SMA may also cause scoliosis or kyphosis (an abnormally curved spine), micrognathia (a small chin), and cryptorchidism (testes that do not descend).
How is XL-SMA diagnosed?
Diagnosis of XL-SMA includes physical examination of the infant, reviewing the family history for any X-linked inherited disorders, along with tests including imaging and blood work for genetic testing.
An MRI may be done of the infant’s spine, looking for degeneration.
An XL-SMA diagnosis can be confirmed through genetic testing that checks for mutations in the UBA1 gene. A multigene panel can be used to identify mutations in the UBA1 gene and to rule out other genetic variants.
What treatment options are available for XL-SMA?
At this point in time, there is no cure or gene therapy for XL-SMA. Instead, treatment is supportive and may include counseling for end of life care.
The healthcare team will discuss supportive therapies such as:
- physiotherapy and occupational therapy to manage contractures and scoliosis
- respiratory care, including airway clearance, and noninvasive ventilatory support
- possible tracheostomy: a surgically created opening through the neck into the trachea to aid breathing
- mechanical ventilation
- dietary modifications to manage adequate nutrition, and decrease constipation
- gastronomy tube for feeding
- management of gastroesophageal reflux.
Like other fatal forms of SMA, respiratory failure is a common cause of death for infants with XL-SMA. The medical team may discuss a do not resuscitate order prior to respiratory failure. Genetic counseling may be offered to the parents, as well as a connection to family support services.
What is the life expectancy for people with XL-SMA?
The life expectancy for male infants with XL-SMA is low and the majority of affected babies do not survive past early childhood. Some may survive into adolescence, but these are rare cases and they rely heavily on supportive devices and therapies. Respiratory failure is usually the cause of death at around the age of 2 years.
SMA News Today is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.
FAQs about X-linked infantile spinal muscular atrophy
X-linked infantile spinal muscular atrophy (XL-SMA) is a rare form of spinal muscular atrophy that occurs only in male infants, and is generally fatal before the age of 2 years. It is characterized by muscle weakness, difficulty breathing, misshapen joints, and broken bones, often before birth.
Due to the way XL-SMA is inherited, girls do not show symptoms but are genetic carriers of the mutated gene which causes the condition.
At this point, there is no cure for XL-SMA. Instead, treatment is supportive.
A child with XL-SMA will be born with certain characteristics, which may include misshapen joints and broken bones, along with muscle weakness and difficulty breathing. Diagnosis includes a physical examination of the infant after birth, a family history of any X-linked inherited disorders, and tests including imaging and a blood test for genetic testing.
No, adults cannot develop XL-SMA. Only male infants with a mutated ubiquitin-like modifier activating enzyme 1 (UBA1) gene can have the condition, and the life expectancy sees most male children with the condition die before the age of 2 years.
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