Spinal Muscular Atrophy Type 3

Type 3 is a milder form of spinal muscular atrophy (SMA), a rare genetic disease characterized by the progressive loss of motor neurons, or nerve cells that control voluntary movement, leading to muscle weakness and wasting.

Along with the disease’s other four main types, SMA type 3 is caused by mutations in both copies of the SMN1 gene (one inherited from the mother and one from the father), which provides instructions to produce SMN, a protein essential for motor neuron and muscle health.

Symptoms

In type 3, also known as juvenile SMA or Kugelberg-Welander syndrome, symptoms usually appear in toddler-age children, but they can start at anytime before early adulthood, and are milder in severity relative to types 0, 1, and 2.

Notably, this type can be further broken down into two subgroups based on age of symptom onset: before age 3 (type 3a) and after age 3 (type 3b), which usually progresses more slowly.

Mild muscle weakness usually affects the legs more than the arms. While these patients can stand and walk independently, over time, they may experience difficulties in standing, running, or climbing stairs, and require aids later in life.

Poor balance, increased risk of falls, slight tremors in the fingers, and foot deformities are also common. About half of SMA type 3 patients will develop scoliosis, an abnormal and progressive sideways curvature of the spine caused by weakness in muscles of the back that support the spine’s position.

Most people with this milder SMA type do not have swallowing or breathing problems. If breathing difficulties occur, they are usually mild or only appear much later in life.

Cognitive function is not affected by the disease.

People with SMA type 3 generally have a normal life expectancy.

Diagnosis

When symptoms are present or if there is a family history of SMA, a diagnosis can be made through genetic testing that looks for disease-causing mutations in the SMN1 gene.

DNA testing, needing only a blood sample, can also be used to measure the number of copies of a “backup” SMN2 gene that influences disease severity. Typically, a higher number of SMN2 copies is associated with less severe SMA, and most type 3 patients carry three or four copies, relative to the two copies usually found in healthy people.

Combining these genetic results with age of symptom onset and symptom severity helps to confirm disease type.

Genetic testing can also be used to identify SMA carriers — individuals who will not develop SMA, but carry one mutated SMN1 copy and could pass it on to their children — as well as affected babies, either while still in the womb (prenatal screening), or shortly after birth (newborn screening).

If both parents carry one mutated copy of SMN1, they will have a 25% chance of having a biological child with any of the most common SMA types, and a 50% risk of each of their biological children being a carrier like them.

Further tests, such as an electromyogram or muscle biopsy, may be considered if uncertainty about the diagnosis remain, but they are not usually needed to confirm an SMA diagnosis.

Electromyography assesses the health of the muscles and motor neurons that control them by measuring muscles’ responses to electrical stimulations, via signals sent by motor neurons. In a muscle biopsy, a small section of muscle tissue is removed, usually from the upper thigh, and examined to see whether it has SMA-associated features.

Treatment

Currently, no cure exists for SMA, but three disease-modifying therapies have become available since 2016 that have the potential to slow or even prevent progression of the main types of the disease.

These include Biogen’s Spinraza (nusinersen), given directly into the spinal canal three times a year, Roche’s Evrysdi (risdiplam), taken daily as an oral solution, and Novartis’ gene therapy Zolgensma (onasemnogene abeparvovec-xioi), administered through a single into-the-vein (intravenous) injection.

Spinraza and Evrysdi work by increasing SMN protein production from the SMN2 gene, while Zolgensma uses a harmless virus to deliver a healthy copy of the SMN1 gene to cells, thereby restoring SMN levels.

In the U.S., Europe, and several other countries, people with a clinical or genetic diagnosis of SMA type 3 are eligible for treatment with Spinraza and Evrysdi; the latter only after 2 months of age.

Also, children with type 3 up to age 2 can be treated with Zolgensma in the U.S., and Japan. In Europe and Canada, the therapy is limited to certain children carrying up to three SMN2 copies, which excludes type 3 patients with four copies.

A multidisciplinary team of healthcare professionals is advised for managing the symptoms and care for a person with SMA type 3. The team may include specialists in neurology, genetics, respiratory medicine, physiotherapy, occupational therapy, orthopedics, and dietetics.

 

Last updated: Aug. 13, 2021

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