X-linked infantile spinal muscular atrophy is a condition that affects only boys and is characterized by severe muscle weakness and absent reflexes (areflexia). Affected children often have multiple joint deformities (contractures) from birth that cause joint stiffness (arthrogryposis) and impair movement. In severe cases, affected infants are born with broken bones. The muscle weakness worsens over time; affected children reach some early motor developmental milestones, such as sitting unassisted, but these skills are often lost (developmental regression).

Additional features of X-linked infantile spinal muscular atrophy include an unusually small chin (micrognathia), abnormal curvature of the spine (scoliosis or kyphosis), and undescended testes (cryptorchidism).

Weakness of the chest muscles used for breathing often leads to life-threatening breathing problems. Children with X-linked infantile spinal muscular atrophy usually do not survive past early childhood due to respiratory failure, although, in rare cases, affected individuals can survive into adolescence.

Mutations in the UBA1 gene cause X-linked infantile spinal muscular atrophy. The UBA1 gene provides instructions for making the ubiquitin-activating enzyme E1. This enzyme is necessary for a process that targets damaged or unneeded proteins to be broken down (degraded) within cells. Protein degradation helps to maintain the proper balance of protein production and breakdown (protein homeostasis) that cells need to function and survive.

UBA1 gene mutations lead to a decrease in enzyme production or the production of an enzyme with reduced or abnormal function. As a result, damaged or unneeded proteins build up inside cells instead of being degraded, which may damage cells and contribute to cell death. This buildup also disrupts protein homeostasis. Old proteins must be removed before cells can make new proteins. If these damaged or unneeded proteins are not degraded, they can impair normal cell functions by stopping the production of new proteins. An imbalance in protein production and breakdown can ultimately lead to cell death. Specialized nerve cells that control muscle movement (motor neurons) are particularly susceptible to disruptions in cell function, likely due to their large size. Loss of these cells causes many of the signs and symptoms of X-linked infantile spinal muscular atrophy.

Normal Function

The UBA1 gene provides instructions for making the ubiquitin-activating enzyme E1. This enzyme is necessary for the ubiquitin-proteasome system, which targets damaged or unneeded proteins to be broken down (degraded) within cells. Protein degradation helps maintain the proper balance of protein production and breakdown (protein homeostasis). Old proteins need to be removed to make way for new proteins to allow cells to function and survive. The ubiquitin-proteasome system acts as the cell's quality control system by disposing of damaged, misshapen, and excess proteins.

Ubiquitin-activating enzyme E1 is responsible for the first step in the ubiquitin-proteasome system; it turns on (activates) a small protein called ubiquitin. With the assistance of other proteins, the active ubiquitin attaches to a protein that is to be broken down. When a chain of ubiquitin proteins is attached to a protein, the protein is recognized and destroyed by a complex of enzymes called a proteasome.

Health Conditions Related to Genetic Changes

VEXAS syndrome

Variants (also called mutations) in the UBA1 gene have been found to cause VEXAS syndrome. This condition is characterized by episodes of fever and abnormal inflammation affecting many parts of the body, particularly the skin, joints, and blood vessels. The UBA1 gene variants that cause VEXAS syndrome are somatic, which means that they occur after birth during a person's lifetime. These variants occur only in certain immune cells and blood-forming cells in the bone marrow.

Most cases of VEXAS syndrome are caused by genetic variants that change the protein building block (amino acid) methione at position 41 in the ubiquitin-activating enzyme E1 to another amino acid. These variants lead to the production of an abnormally short enzyme with reduced function. As a result, damaged or unneeded proteins build up inside cells instead of being broken down, which may contribute to abnormal activation of immune cells or cell damage and death. This protein buildup also disrupts protein homeostasis. Old proteins must be removed before cells can make new proteins. If these damaged or unneeded proteins are not broken down, they can impair normal cell functions by stopping the production of new proteins. When UBA1 gene variants occur in immune cells or blood cells, they lead to abnormal inflammation, impaired blood cell development, and other features of VEXAS syndrome.

X-linked infantile spinal muscular atrophy

Variants in the UBA1 gene have been reported to cause X-linked infantile spinal muscular atrophy. This condition is characterized by severe muscle weakness that begins at birth or in early infancy. Weakness in the chest muscles that control breathing often causes death from respiratory failure in early childhood.

UBA1 gene variants that cause X-linked infantile spinal muscular atrophy are inherited and present in all cells in the body. They all change one DNA building block (nucleotide) in an area of the gene known as exon 15. These variants reduce the activity, function, or production of the enzyme. This shortage of functional enzyme allows damaged or unneeded proteins to build up inside cells instead of being broken down, which may damage cells and contribute to cell death. This buildup also disrupts protein homeostasis. If damaged or unneeded proteins are not broken down, they can impair normal cell functions by stopping the production of new proteins. An imbalance in protein production and breakdown can ultimately lead to cell death. Specialized nerve cells that control muscle movement (motor neurons) are particularly susceptible to disruptions in cell function, likely due to their large size. Loss of these cells causes many of the signs and symptoms of X-linked infantile spinal muscular atrophy.

Other Names for This Gene

• GXP1
• SMAX2
• UBA1, ubiquitin-activating enzyme E1 homolog A
• UBA1_HUMAN
• UBA1A
• UBE1
• UBE1X
• ubiquitin-activating enzyme E1
• ubiquitin-like modifier activating enzyme 1

Genomic Location

This condition is inherited in an X-linked recessive pattern. The gene associated with this condition is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a mutation would have to occur in both copies of the gene to cause the disorder. Because it is unlikely that females will have two altered copies of this gene, males are affected by X-linked recessive disorders much more frequently than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

X-linked infantile spinal muscular atrophy is thought to be a rare condition; its prevalence is unknown.

What is spinal muscular atrophy?

Spinal muscular atrophy (SMA) refers to a group of hereditary diseases that can damage and kill specialized nerve cells in the brain and spinal cord (motor neurons). Motor neurons control movement in the arms, legs, face, chest, throat, and tongue, as well as skeletal muscle activity, such as speaking, walking, swallowing, and breathing.

The most common form of SMA is caused by a mutated or missing gene known as the survival motor neuron gene 1 (SMN1), which is typically responsible for the production of a protein essential to motor neurons. There are four types of this form of SMA:

1. Type l (also known as Werdnig-Hoffman disease or infantile-onset SMA) is usually evident before 6 months of age. The most severely affected children will have reduced movement and chronic shortening of muscles or tendons (contractures). Other children may have symptoms including reduced muscle tone, lack of tendon reflexes, twitching, skeletal abnormalities, and problems with swallowing and feeding. Without treatment, many affected children die before age 2.
2. SMA Type ll is usually first noticed between 6 and 18 months of age. Children can sit without support but are unable to stand or walk without help. Children may also have respiratory difficulties. Life expectancy is reduced but most individuals live into adolescence or young adulthood.
3. SMA Type lll (also known as Kugelberg-Welander disease) is seen after age 18 months. Children can walk independently but may have difficulty doing so or when running, rising from a chair, or climbing stairs. Other complications may include curvature of the spine, contractures, and respiratory infections. With treatment, most individuals can have an average lifespan.
4. SMA Type IV develops after 21 years of age, with mild to moderate leg muscle weakness and other symptoms.

Who is more likely to get spinal muscular atrophy?

The most common form of SMA is caused by a mutated or missing gene known as the survival motor neuron gene 1 (SMN1). The SMN1 gene is located on chromosome 5q and produces the survival motor neuron (SMN) protein which maintains the health and normal function of motor neurons.

People living with SMA have insufficient levels of the SMN protein, which leads to loss of motor neurons in the spinal cord and causes weakness and wasting of the skeletal muscles. The weakness is often more severe in the trunk (chest) and upper leg and arm muscles than in muscles of the hands and feet.

Many types of spinal muscular atrophy are caused by changes in the same genes. Less common SMA forms are caused by changes in other genes including the:

• VAPB gene on chromosome 20
• DYNC1H1 gene on chromosome 14
• BICD2 gene on chromosome 9
• UBA1 gene on the X chromosome

Except in rare cases, SMA is inherited in an autosomal recessive manner, meaning that the affected individual has two mutated genes, often inheriting one from each parent. Those who carry only one mutated gene are carriers of the disease who will not have any symptoms.

How is spinal muscular atrophy diagnosed and treated?

Diagnosing SMA

A blood test is available to look for mutations or deletions of the SMN1 gene. This test identifies at least 95 percent of SMA Types I, II, and III, and also may reveal if a person is a carrier. If the SMN1 gene is not found to be problematic or the individual's history and examination are not typical of SMA, other diagnostic tests may include:

• Electromyography to record the electrical activity of the muscles during contraction and at rest
• Nerve conduction velocity studies to measure the nerve's ability to send an electrical signal
• Muscle biopsy to diagnose many neuromuscular disorders
• Other blood tests

Treating SMA

There is no complete cure for SMA. Treatment consists of managing the symptoms and preventing complications.

Medications

• The U.S. Food and Drug Administration (FDA) approved nusinersen (Spinraza™) as the first drug approved to treat children and adults with SMA. The drug is designed to increase production of the SMN protein, which is critical for the maintenance of motor neurons.
• The FDA approved onasemnogene abeparovec-xioi (Zolgensma ™) gene therapy for children less than two years old who have infantile-onset SMA. A safe virus delivers a fully functional human SMN gene to the targeted motor neurons, which in turn improves muscle movement and function and survival.
• The FDA approved the orally-administered drug risdiplam (Evrysdi) to treat patients age two months of age and older with SMA.

Physical therapy, occupational therapy, and rehabilitation may help to improve posture, prevent joint immobility, and slow muscle weakness and atrophy. Stretching and strengthening exercises may help reduce contractures, increase range of motion, and keeps circulation flowing. Some individuals require additional therapy for speech and swallowing difficulties. Assistive devices such as supports or braces, orthotics, speech synthesizers, and wheelchairs may be helpful to improve functional independence.

Proper nutrition and calories are essential to maintaining weight and strength, while avoiding prolonged fasting. People who cannot chew or swallow may require insertion of a feeding tube. Non-invasive ventilation at night can improve breathing during sleep, and some individuals also may require assisted ventilation during the day due to muscle weakness in the neck, throat, and chest.

What are the latest updates on spinal muscular atrophy?

The National Institute of Neurological Disorders and Stroke (NINDS), a component of the National Institutes of Health (NIH), conducts basic, translational, and clinical research on SMA in laboratories at the NIH and also supports research through grants to major medical institutions across the country.

Scientists have developed model systems in animals and cells to study disease processes and speed up the testing of potential therapies, including the following:

• Gene therapy and specific drugs have been shown to halt motor neuron destruction and slow disease progression in mouse models and individuals with SMA. NINDS supports research to establish these methods and to provide a path toward clinical tests. Clinical trials for gene therapy in SMA are ongoing.
• Animal models of SMA represent critical tools in discovering and developing new therapies for SMA. Scientists developed zebrafish, mouse, and pig models, including models of less severe SMA types 2 and 3, which may greatly aid the identification of new therapeutic targets and candidate therapies.

Additionally, NIH-supported scientists have collected data on pre-symptomatic or recently diagnosed children with SMA types I, II, or III, and their healthy siblings. The goal of this study is to provide counselling and education to parents about possible clinical trial opportunities.

NINDS established the NeuroNext (NINDS Network for Excellence in Neuroscience Clinical Trials) clinical trials network to promote the rapid development and implementation of trials for neurological disorders that affect adults and/or children. The network is designed to develop early-phase trials aimed at identifying biomarkers—usually a physical trait or substance in the blood or other bodily fluids that can be measured to determine the presence and severity of a disease—and testing emerging therapies. One such project was to identify biomarkers for SMA and to understand the cause and mechanisms underlying the disease. Data gained through this study led to the approval decision for nusinersen (Spinraza™). Knowledge acquired from this study has also enhanced the design of additional clinical trials in SMA.