Spinal Muscular Atrophy (SMA) Type 1

Type 1 is the most common form of spinal muscular atrophy (SMA), a rare genetic disease characterized by the progressive loss of motor neurons, which are nerve cells that control voluntary movement, leading to muscle weakness and wasting.

Along with the other four main, more common types of SMA, type 1 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

SMA type 1, also called infantile-onset SMA or Werdnig-Hoffmann disease, is a severe form of SMA that accounts for 60% of cases. Symptoms usually begin in the first six months of life, but reduced fetal movements in later stages of pregnancy also may be detected in some cases.

Infants with this type typically show severe muscle weakness, floppy legs and arms, poor head control, weak cry and cough, lack of reflexes, and involuntary tongue movements. They usually fail to achieve certain developmental milestones such as raising their head, rolling over, or sitting without support.

Progressive weakness of the intercostal muscles (those supporting the chest wall) can cause severe breathing and coughing difficulties, which increase the risk of hypoventilation (shortness of oxygen and a carbon dioxide buildup) and of lung infections. These infants also commonly show an abnormally bell-shaped chest that prevents the lungs from expanding fully.

The disease also affects the muscles used for sucking, swallowing, and chewing, impairing feeding and normal growth. Feeding issues can increase the risk of small amounts of food or liquids entering the windpipe (aspiration), which can lead to several complications, such as breathing difficulties and aspiration pneumonia, which is a lung infection associated with aspiration.

Infants with type 1 may develop scoliosis, an abnormal and progressive sideways curvature of the spine caused by weakness in back muscles that support the spine’s position. Gastrointestinal and metabolic problems also are common.

Cognitive function is not affected by the disease.

If disease-modifying treatment is not initiated, most of these infants do not survive past age 2, usually due to respiratory failure.

Diagnosis

When symptoms are present 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, can 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 1 patients carry two copies, similar to healthy people.

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

Genetic testing may be used to identify SMA carriers — individuals who will not develop SMA, but carry one mutated SMN1 copy and could pass it 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 there is any uncertainty about the diagnosis, but usually are not 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 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, approved for all SMA types and most ages in the U.S., Europe, and several other countries, work by increasing the production of SMN protein from the SMN2 gene.

Zolgensma uses a harmless virus to deliver a healthy copy of the SMN1 gene to cells, thereby restoring SMN levels. The gene therapy is available for use in children up to age 2 in the U.S.Japan, and Canada. In Europe, it is approved for SMA patients with a clinical diagnosis of type 1 or carrying up to three SMN2 copies who weigh up to 21 kilograms (about 46 pounds), which could cover children up to age 5.

A multidisciplinary team of healthcare professionals is needed to manage the symptoms and care for an infant with SMA type 1. The team may include specialists in neurology, genetics, supportive care, respiratory medicine, physiotherapy, occupational therapy, speech and language therapy, and gastrointestinal tract/dietetics.

 

Last updated: Aug. 4, 2021

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