Type 4 is the mildest 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 other four main types of SMA, which are far more common, type 4 is caused by mutations in both copies of the SMN1 gene — one inherited from the mother and one from the father. That gene provides instructions to produce SMN, a protein essential for motor neuron and muscle health.
Also called adult-onset SMA, because it generally develops in early adulthood, Type 4 is very rare, accounting for less than 5% of all SMA cases.
Type 4 represents the mildest form of SMA, and features the slow progression of mild motor impairment.
While symptoms can appear as early as age 18, they usually begin after age 35, and commonly include mild muscle weakness in the legs and hips that may slowly progress to the arms and shoulders. Muscle twitching and aching, fatigue, numbness, cramping, and mild hand and finger tremors also are common.
Muscle weakness symptoms progress slowly, and most people with type 4 usually remain mobile into their 60s, after which they may require walking aids.
Contrary to the other four main types of SMA, type 4 rarely affects swallowing and breathing functions.
Cognition is not affected.
People with this type have a normal life expectancy.
Diagnosing SMA type 4 can take some time, given that the initial symptoms are typically mild and may resemble other neuromuscular conditions. If SMA is suspected and/or there is a history of SMA in the family, 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, also can be used to measure the number of copies a person has 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 4 patients carry four or more copies, relative to the two copies usually present in healthy people.
Combining these genetic results with the age of symptom onset and symptom severity helps to confirm the type of disease.
Genetic testing also can 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. It also will diagnose 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. There also is a 25% chance that their child could be born without the disease.
Further tests, such as an electromyogram or muscle biopsy, may be considered if there is any uncertainty about the diagnosis, but are usually not needed to confirm whether an individual has SMA.
Electromyography assesses the health of the muscles and motor neurons that control them by measuring muscles’ responses to electrical stimulations 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.
While no cure currently exists for SMA, 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 disorder.
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.
Access to treatments for those with SMA type 4 varies between countries, and the management and treatment of infants diagnosed with SMA through newborn screening who carry four SMN2 copies is currently under debate.
In the U.S., Europe, and several other countries, these patients may be eligible for treatment with Spinraza and Evrysdi. Children genetically diagnosed with type 4 up to age 2 may 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 most, if not all, type 4 patients.
A multidisciplinary team of healthcare professionals — such as specialists in neurology, genetics, physiotherapy, occupational therapy, and dietetics — may help to manage the symptoms of SMA type 4.
Last updated: Aug. 16, 2021
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