Spinal muscular atrophy is a genetic disorder characterized by weakness and wasting (atrophy) in muscles used for movement (skeletal muscles). It is caused by a loss of specialized nerve cells, called motor neurons that control muscle movement. The weakness tends to be more severe in the muscles that are close to the center of the body (proximal) compared to muscles away from the body's center (distal). The muscle weakness usually worsens with age. There are many types of spinal muscular atrophy that are caused by changes in the same genes. The types differ in age of onset and severity of muscle weakness; however, there is overlap between the types. Other forms of spinal muscular atrophy and related motor neuron diseases, such as spinal muscular atrophy with progressive myoclonic epilepsy, spinal muscular atrophy with lower extremity predominance, X-linked infantile spinal muscular atrophy, and spinal muscular atrophy with respiratory distress type 1 are caused by mutations in other genes.

Spinal muscular atrophy type 0 is evident before birth and is the rarest and most severe form of the condition. Affected infants move less in the womb, and as a result they are often born with joint deformities (contractures). They have extremely weak muscle tone (hypotonia) at birth. Their respiratory muscles are very weak and they often do not survive past infancy due to respiratory failure. Some infants with spinal muscular atrophy type 0 also have heart defects that are present from birth (congenital).

Spinal muscular atrophy type I (also called Werdnig-Hoffmann disease) is the most common form of the condition. It is a severe form of the disorder with muscle weakness evident at birth or within the first few months of life. Most affected children cannot control their head movements or sit unassisted. Children with this type may have swallowing problems that can lead to difficulty feeding and poor growth. They can also have breathing problems due to weakness of respiratory muscles and an abnormally bell-shaped chest that prevents the lungs from fully expanding. Most children with spinal muscular atrophy type I do not survive past early childhood due to respiratory failure.

Spinal muscular atrophy type II (also called Dubowitz disease) is characterized by muscle weakness that develops in children between ages 6 and 12 months. Children with this type can sit without support, although they may need help getting to a seated position. However, as the muscle weakness worsens later in childhood, affected individuals may need support to sit. Individuals with spinal muscular atrophy type II cannot stand or walk unaided. They often have involuntary trembling (tremors) in their fingers, a spine that curves side-to-side (scoliosis), and respiratory muscle weakness that can be life-threatening. The life span of individuals with spinal muscular atrophy type II varies, but many people with this condition live into their twenties or thirties.

Spinal muscular atrophy type III (also called Kugelberg-Welander disease) typically causes muscle weakness after early childhood. Individuals with this condition can stand and walk unaided, but over time, walking and climbing stairs may become increasingly difficult. Many affected individuals require wheelchair assistance later in life. People with spinal muscular atrophy type III typically have a normal life expectancy.

Spinal muscular atrophy type IV is rare and often begins in early adulthood. Affected individuals usually experience mild to moderate muscle weakness, tremors, and mild breathing problems. People with spinal muscular atrophy type IV have a normal life expectancy.

Spinal muscular atrophy (SMA) is an inherited (genetic) condition that affects the nerve cells that carry messages from the brain to the muscles of the body.

The brain uses nerves called motor neurons to control muscle movement. Motor neurons need the survival motor neuron (SMN) protein to work correctly.

In SMA, your baby’s body cannot make enough SMN protein. When a baby cannot make enough SMN protein, motor neurons die, damaging the connection between the brain and the muscles. The brain will then have trouble telling the muscles to move, which causes the muscles to break down.

This results in muscle weakness and decreased muscle size (atrophy), which can cause breathing and swallowing difficulties. Loss of motor neurons also leads to other signs and symptoms of the condition.

There are several forms of SMA, and the severity of the condition depends on how much normal SMN protein your baby makes.

Hundreds of babies are born with this condition each year in the United States.

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.

Mutations in the SMN1 gene cause all types of spinal muscular atrophy described above. The number of copies of the SMN2 gene modifies the severity of the condition and helps determine which type develops.

The SMN1 and SMN2 genes both provide instructions for making a protein called the survival motor neuron (SMN) protein. Normally, most functional SMN protein is produced from the SMN1 gene, with a small amount produced from the SMN2 gene. Several different versions of the SMN protein are produced from the SMN2 gene, but only one version is functional; the other versions are smaller and quickly broken down. The SMN protein is one of a group of proteins called the SMN complex, which is important for the maintenance of motor neurons. Motor neurons transmit signals from the brain and spinal cord that tell skeletal muscles to tense (contract), which allows the body to move.

Most people with spinal muscular atrophy are missing a piece of the SMN1 gene, which impairs SMN protein production. A shortage of SMN protein leads to motor neuron death, and as a result, signals are not transmitted between the brain and muscles. Muscles cannot contract without receiving signals from the brain, so many skeletal muscles become weak and waste away, leading to the signs and symptoms of spinal muscular atrophy.

Typically, people have two copies of the SMN1 gene and one to two copies of the SMN2 gene in each cell. However, the number of copies of the SMN2 gene varies, with some people having up to eight copies. In people with spinal muscular atrophy, having multiple copies of the SMN2 gene is usually associated with less severe features of the condition that develop later in life. The SMN protein produced by the SMN2 genes can help make up for the protein deficiency caused by SMN1 gene mutations. People with spinal muscular atrophy type 0 usually have one copy of the SMN2 gene in each cell, while those with type I generally have one or two copies, those with type II usually have three copies, those with type III have three or four copies, and those with type IV have four or more copies. Other factors, many unknown, also contribute to the variable severity of spinal muscular atrophy.

Normal Function

The SMN1 gene provides instructions for making the survival motor neuron (SMN) protein. The SMN protein is found throughout the body, with highest levels in the spinal cord. This protein is one of a group of proteins called the SMN complex, which is important for the maintenance of specialized nerve cells called motor neurons. These cells are located in the spinal cord and the part of the brain that is connected to the spinal cord (the brainstem). Motor neurons transmit signals from the brain and spinal cord that tell skeletal muscles to tense (contract), which allows the body to move.

In cells, the SMN complex plays an important role in processing molecules called messenger RNA (mRNA), which serve as genetic blueprints for making proteins. Messenger RNA begins as a rough draft (pre-mRNA) and goes through several processing steps to become a final, mature form. The SMN complex helps to assemble the cellular machinery needed to process pre-mRNA. The SMN complex is also important for the development of specialized outgrowths from nerve cells called dendrites and axons. Dendrites and axons are required for the transmission of impulses between neurons and from neurons to muscles.

A small amount of SMN protein is produced from a gene similar to SMN1 called SMN2. Several different versions of the SMN protein are produced from the SMN2 gene, but only one version is functional; the other versions are smaller and quickly broken down.

Health Conditions Related to Genetic Changes

Amyotrophic lateral sclerosis

MedlinePlus Genetics provides information about Amyotrophic lateral sclerosis

Spinal muscular atrophy

Many mutations in the SMN1 gene have been found to cause spinal muscular atrophy. This condition is characterized by a loss of motor neurons that leads to weakness and wasting (atrophy) in muscles used for movement (skeletal muscles) that worsens with age. Spinal muscular atrophy has a wide range of severity. There are many types of spinal muscular atrophy that differ in age of onset and level of muscle functioning; however, there is overlap among the types. About 95 percent of individuals with spinal muscular atrophy have mutations that delete a piece of the SMN1 gene in both copies of the gene in each cell. As a result, SMN protein production is impaired. In about 5 percent of people with this disorder, one copy of the SMN1 gene is missing a section, and the other copy has a different kind of mutation that disrupts the production or function of the SMN protein.

Researchers suggest that a shortage of SMN protein leads to the inefficient assembly of the machinery needed to process pre-mRNA. A lack of mature mRNA, and subsequently the proteins needed for normal cell functioning, has damaging effects on motor neuron development and survival. The loss of motor neurons leads to the signs and symptoms of spinal muscular atrophy. However, it is unclear why these cells are particularly sensitive to a reduction in the amount of SMN protein. Some research findings indicate that a shortage of this protein impairs the formation and function of axons and dendrites, leading to the death of motor neurons.

Typically, people have two copies of the SMN1 gene and one to two copies of the SMN2 gene in each cell. However, the number of copies of the SMN2 gene varies, with some people having up to eight copies. Multiple copies of the SMN2 gene are usually associated with less severe features of the condition that develop later in life. The small amount of SMN protein produced by the SMN2 genes can help make up for the protein deficiency caused by SMN1 gene mutations. Other factors, many unknown, also contribute to the variable severity of spinal muscular atrophy.

Other Names for This Gene

• BCD541
• SMA1
• SMA2
• SMA3
• SMA4
• SMN_HUMAN
• SMNT
• T-BCD541
• telomeric SMN

Genomic Location

Normal Function

The SMN2 gene provides instructions for making the survival motor neuron (SMN) protein. The SMN protein is found throughout the body, with highest levels in the spinal cord. This protein is one of a group of proteins called the SMN complex, which is important for the maintenance of specialized nerve cells called motor neurons. These cells are located in the spinal cord and the part of the brain that is connected to the spinal cord (the brainstem). Motor neurons transmit signals from the brain and spinal cord that tell skeletal muscles to tense (contract), which allows the body to move.

Several different versions of the SMN protein are produced from the SMN2 gene, but only one version (called isoform d) is full size and functional. The other versions are smaller and quickly broken down. The full-size protein made from the SMN2 gene is identical to the protein made from a similar gene called SMN1; however, only 10 to 15 percent of all functional SMN protein is produced from the SMN2 gene (the rest is produced from the SMN1 gene). Typically, people have two copies of the SMN1 gene and one to two copies of the SMN2 gene in each cell. However, the number of copies of the SMN2 gene varies, with some people having up to eight copies. The more SMN2 gene copies a person has, the more SMN protein they produce.

In cells, the SMN complex plays an important role in processing molecules called messenger RNA (mRNA), which serve as genetic blueprints for making proteins. Messenger RNA begins as a rough draft (pre-mRNA) and goes through several processing steps to become a final, mature form. The SMN complex helps to assemble the cellular machinery needed to process pre-mRNA. The SMN complex is also important for the development of specialized outgrowths from nerve cells called dendrites and axons. Dendrites and axons are required for the transmission of impulses between neurons and from neurons to muscles.

Health Conditions Related to Genetic Changes

Spinal muscular atrophy

Extra copies of the SMN2 gene do not cause spinal muscular atrophy, but they modify the severity of the disorder. This condition is characterized by a loss of motor neurons that leads to weakness and wasting (atrophy) in muscles used for movement (skeletal muscles) that worsens with age. Spinal muscular atrophy has a wide range of severity. There are many types of spinal muscular atrophy that differ in age of onset and level of muscle functioning; however, there is overlap among the types. All individuals with spinal muscular atrophy have mutations in both copies of the SMN1 gene. As a result, little or no SMN protein is produced from this gene. The SMN2 gene can help replace some of the missing SMN protein. In people with spinal muscular atrophy, having multiple copies of the SMN2 gene is usually associated with less severe features of the condition that develop later in life. Affected individuals with one or two functional copies of the SMN2 gene generally have severe muscle weakness that begins at birth or in infancy. Affected individuals with four or more copies of the SMN2 gene typically have mild muscle weakness that may not become noticeable until adulthood. Other factors, many unknown, also contribute to the variable severity of spinal muscular atrophy.

Researchers suggest that a shortage of SMN protein leads to the inefficient assembly of the machinery needed to process pre-mRNA. A lack of mature mRNA and subsequently, the proteins needed for normal cell functioning, has damaging effects on motor neuron development and survival. The loss of motor neurons leads to the signs and symptoms of spinal muscular atrophy. However, it is unclear why these cells are particularly sensitive to a reduction in the amount of SMN protein. Some research findings indicate that a shortage of SMN protein impairs the formation and function of axons and dendrites, leading to the death of motor neurons. While the mechanism is not clear, it is apparent that increased SMN2 gene copy number leads to an increase in SMN protein production, which improves the function and survival of motor neurons and results in less severe disease.

Other Names for This Gene

• BCD541
• C-BCD541
• centromeric SMN
• SMN_HUMAN
• SMNC

Genomic Location

Spinal muscular atrophy is inherited in an autosomal recessive pattern, which means both copies of the SMN1 gene in each cell have mutations. In most cases, the parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition. In rare cases, a person with spinal muscular atrophy inherits an SMN1 gene mutation from one parent and acquires a new mutation in the other copy of the gene that occurs during the formation of reproductive cells (eggs or sperm) or in early embryonic development. In these cases, only one parent is a carrier of the SMN1 gene mutation.

Individuals who have more than the usual two copies of the SMN2 gene usually do not inherit the extra copies from a parent. They typically arise during a random error when making new copies of DNA (replication) in an egg or sperm cell or just after fertilization.

The main features of spinal muscular atrophy (SMA) include progressive muscle weakness and poor muscle tone (hypotonia), which may be present in a variety of conditions. The following conditions are part of the differential diagnosis for people with symptoms of SMA because they share similar features:

• Prader-Willi syndrome and other chromosome abnormalities
• Pompe disease
• Congenital myasthenia
• Congenital myopathies (such as nemaline myopathy, central core disease, and myotubular myopathy)
• Myotonic dystrophy
• Congenital muscular dystrophy
• Duchenne muscular dystrophy
• Becker muscular dystrophy
• Kennedy's disease
• Amyotrophic lateral sclerosis
• Zellweger syndrome spectrum
• Peripheral neuropathies, including Guillain-Barré syndrome
• Central nervous system abnormalities
• Trauma to the spinal cord

Newborn screening for SMA is done using a small amount of blood collected from your baby’s heel. During screening, a special machine looks for a specific change in the SMN1 gene in your baby’s blood. Babies with this specific change in the SMN1 gene might have SMA.

What Happens After an Out-of-Range Screening Result?

If your baby’s blood spot screening result for SMA is out-of-range, your baby’s health care provider will contact you. Together, you will discuss next steps and follow-up plans.

An out-of-range screening result does not mean that your baby definitely has the condition. It does mean that your baby needs more follow-up testing.

Your baby may need follow-up genetic testing after an out-of-range screening result.

You should complete any recommended follow-up testing as soon as possible. Babies with this condition can have serious health problems soon after birth if they are not diagnosed and treated quickly.

False-negative results may happen. Newborn screening only looks for one specific change in the SMN1 gene (the absence of exon 7). It is estimated that 2 to 5 percent of SMA cases are caused by a different genetic change that is not currently detected by newborn screening.

Newborn screening helps babies lead healthier lives. If your baby has an out-of-range result, follow up with your health care provider quickly. It is important to follow their instructions. Your baby may need to get treatment right away, even if they are not showing signs or symptoms. In some cases, your baby’s health care provider may decide it is best to watch (monitor) your baby to decide next steps. Careful monitoring and early treatment will help your baby stay as healthy as possible.

There are several newer treatments for SMA that include medications such as Spinraza, Nusinersen, and Evrysdi that can support the body to make more SMN protein. Gene therapy may be an option for some babies with SMA which can replace the nonworking SMN1 gene with a working copy. Additionally, several research based clinical trials may be available. It is important to talk to your health care provider about which treatment(s) are best for your baby. The goal of these treatments is to prevent muscle weakness and resulting health problems.

Some children with SMA will require other types of support that can include:

• Physical therapy
• Feeding support for babies who cannot swallow
• Breathing support

The outcomes of these treatments vary depending on the form and severity of the condition.

Spinal muscular atrophy affects 1 per 8,000 to 10,000 people worldwide. Spinal muscular atrophy type I is the most common type, accounting for about half of all cases. Types II and III are the next most common and types 0 and IV are rare.