Types of spinal muscular atrophy

Last updated Feb. 2, 2023, by Marisa Wexler, MS
Fact-checked by Ana de Barros, PhD

Spinal muscular atrophy, or SMA, is a genetic disorder that is divided into five main types based on the age at which symptoms first appear.

These forms of SMA range from type 0, which occurs before birth, to type 4, in which symptoms do not start until adulthood. The more common types — 1, 2, and 3 — typically manifest in infancy, or in some cases, up through adolescence.

All of these main types are caused by mutations in the gene SMN1, which provides instructions for making a protein called SMN. As a result of these mutations, patients experience a progressive loss of motor neurons — the nerve cells controlling movement — that leads to a range of SMA symptoms, such as muscle weakness and wasting.

What are the different types of SMA?

SMA type 0

Type 0 is the rarest and most severe form of SMA. This form is also referred to as prenatal SMA because it’s defined by symptoms appearing in fetuses. Common symptoms include reduced or absent fetal movement in the prenatal stage, and after birth, issues such as:

• severe muscle weakness and low muscle tone, leading to floppy limbs
• contractures, where muscles become short and hardened
• heart disease to include congenital heart defects
• difficulty breathing and feeding.

Babies with type 0 SMA usually require medical interventions such as ventilation to keep them alive shortly after they are born. Most infants with this severe form of SMA do not live past 6 months of age.

SMA type 1

Type 1 is the most common form of SMA, accounting for about 60% of cases, and it also is one of the most severe. In this SMA type, symptoms are seen at birth or become apparent in early life, manifesting before 6 months of age. Common symptoms include:

• floppy limbs due to low muscle tone
• lack of reflexes
• failure to reach motor milestones, such as rolling over or sitting up
• weak cry and cough
• difficulty breathing and feeding
• scoliosis, or an abnormal curvature of the spine.

In the absence of treatment, children with SMA type 1 are generally not able to roll over or sit up unsupported, and most do not reach age 2. However, with modern therapies, children who start on treatment early in life have improved survival outcomes, and some can hit motor milestones such as walking that were not usually seen in the natural history of the disease. Overall, the most dramatic SMA treatment outcomes have been seen in children who are diagnosed genetically and start on therapy before the onset of symptoms.

SMA type 2

In SMA type 2, symptoms first become apparent between 6 and 18 months of age. This moderately severe form is the second most common type of SMA, affecting about a third of patients born with the disease. Among the symptoms of this type are:

• delays in hitting motor development milestones, such as standing or walking unaided
• floppy limbs, because of weak muscle tone
• a lack of reflexes
• scoliosis and contractures
• problems with breathing and eating.

Without treatment, most children with this form of SMA are able to sit up independently, but are unable to stand or walk on their own. Patients with SMA type 2 commonly survive into adulthood, though life expectancy is markedly reduced without treatment. Disease-modifying therapies can improve survival and motor function outcomes for type 2 patients.

SMA type 3

Type 3 SMA, also called juvenile SMA or Kugelberg-Welander syndrome, is a milder form of the disease defined by symptoms that appear between 18 months of age and the end of adolescence. Children with this disease type are able to walk as toddlers. However, as the disease progresses, some patients lose the ability to walk independently. Other symptoms of SMA type 3 include:

• muscle weakness, usually affecting the legs more than the arms
• poor balance and a higher risk of falls
• scoliosis and foot deformities.

Type 3 is considered a more mild form of SMA, and it affects about 10%–20% of people born with the disease. Life expectancy is usually not impacted even in the absence of treatment. Disease-modifying therapies can help slow disease progression to maintain motor function over time.

SMA type 4

Type 4 is the mildest form of the disease and is one of the rarest, affecting fewer than 1% of SMA patients. In this form, symptoms manifest in adulthood, usually after age 35. Common symptoms include:

• muscle weakness, which usually affects lower limbs more than upper limbs
• muscle twitching and aching
• fatigue, numbness, and cramping
• mild hand and finger tremors.

Life expectancy is usually unaffected in type 4 SMA, and even without treatment most patients do not lose the ability to walk. Some individuals may rely on aids like canes or walkers in later decades of life. Disease-modifying treatment can slow disease progression and may delay symptom onset.

Rarer types of SMA

In addition to the five main types of SMA that are caused by mutations in the SMN1 gene, there are several rare types of SMA that give rise to similar symptoms. These rarer types are caused by mutations in other genes and include:

• X-linked infantile SMA: Caused by gene mutations in UBA1, a gene present in the X chromosome, it mainly affects boys. This form of SMA is characterized by severe muscle weakness and breathing problems that usually are detectable at birth. Babies with this disease type often are born with contractures and/or bone fractures, and most children do not survive past early childhood.
• SMA with respiratory distress type 1 (SMARD1): SMARD1 is caused by mutations in the gene IGHMBP2. Babies with this form of disease usually experience difficulty breathing in the first months of life, with muscle weakness that progresses to all muscles during infancy, then stabilizes after about two years. Without mechanical ventilation, babies with SMARD1 usually die in the first year of life.
• SMA with lower extremity predominance (SMA-LED): This type, resulting from mutations in the genes DYNC1H1 or BICD2, is characterized by muscle weakness and atrophy that mainly affects the legs. Typically, symptoms appear in infancy or early childhood, though some patients don’t develop any signs of the disease until they reach adulthood. SMA-LED can cause difficulty walking, but lifespan is usually not affected.
• SMA with progressive myoclonic epilepsy (SMA-PME): Characterized by both progressive muscle weakness and seizures, this SMA type is caused by mutations in the ASAH1 gene. Symptoms usually manifest in childhood, and patients generally do not survive past early adulthood.
• Finkel type SMA (SMAFK): Known as SMAFK, this type is caused by mutations in the VAPB gene and characterized by progressive muscle weakness that develops in adulthood, usually after age 30. Here, weakness affects mainly the proximal muscles, or those close to the torso. Lifespan is usually unaffected in this form of SMA.
• Kennedy’s disease, also called spinal and bulbar muscular atrophy (SBMA): This type is caused by mutations in the AR gene, located in the X chromosome, and is more common in men than women, with symptoms usually starting between ages 20 and 50. The disease’s hallmark is progressive weakness and atrophy of the muscles closer to the trunk and those of the mouth and throat. This form of SMA can cause difficulty breathing, but most patients have a normal life expectancy.
• Distal spinal muscular atrophy (DSMA): DSMA is characterized by muscle weakness that mainly affects the hands and feet. Symptoms usually begin during adolescence, but onset can vary from infancy to about the mid-30s. This form of disease can be caused by mutations in several genes, including BSCL2, GARS1, and REEP1.

Does SMA type determine treatment?

There are three disease-modifying treatments approved to treat SMA types 0, 1, 2, 3, and 4 caused by mutations in the SMN1 gene.

In the U.S., these three medicines are approved for all of the five main types, but some therapies are only indicated for patients in specific age ranges.

• Spinraza (nusinersen), the first ever disease-modifying therapy available for SMA, is approved to treat patients of all ages. It is administered via injection into the spine every four months.
• Evrysdi (risdiplam) is a daily oral therapy approved to treat patients ages 2 months and older.
• Zolgensma (onasemnogene abeparvovec-xioi) is a one-time gene therapy approved to treat children ages 2 and younger.

These SMA treatments also are widely available outside the U.S., though specific indications — including approved types and age ranges — vary.

The three medicines work by boosting production of the SMN protein. As such, these treatments are used only for the five main types of SMA, which are caused by SMN deficiency due to SMN1 mutations.

There also are a number of symptom management and supportive interventions SMA patients can use, in addition to disease-modifying treatments, to maximize their ability to function in daily life. These supportive therapies can help in managing disease symptoms day to day, and include physiotherapy, respiratory and nutritional support, and speech and occupational therapy.

How is SMA type diagnosed?

The gold standard for diagnosing any form of SMA is genetic testing. Such testing can identify the disease-causing mutation in the SMN1 gene, or in other genes for the rarer types of SMA.

Genetic testing also can be used to identify the number of copies patients have of SMN2, another gene that acts as a “backup” to SMN1. Generally, SMA patients who have more copies of SMN2 have milder disease, whereas fewer copies of the gene are tied to severe disease. For example, most people with severe type 1 SMA have only two copies of the gene, whereas people with type 4 disease commonly have four or more copies.

Combining these genetic findings with clinical data on age of onset can be used to help confirm which type of SMA a person has.

For the main types of SMA, a person will only develop symptoms if both copies of SMN1 — one inherited from each biological parent — contain a disease-causing mutation. Someone with only one mutated copy of the gene is called an SMA carrier. That’s because such individuals will not develop the disease but may pass the mutated gene to their biological children.

Additional testing, such as electromyography (which measures electric activity in muscles) or muscle biopsy (taking a sample of muscle tissue for laboratory analysis) may be used if there is uncertainty about the diagnosis. But these measures usually are not needed to confirm a SMA diagnosis.

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