Spinal muscular atrophy (SMA) is a rare genetic condition characterized by progressive muscle weakness and atrophy, mainly affecting motor function, but often also causing speaking, swallowing, and breathing problems, along with other symptoms.
It is the leading genetic cause of death in infants and toddlers, and is estimated to affect 1 in every 6,000 to 10,000 live births and to have a carrier frequency of 1 in 40–60 people. Carriers are typically healthy people who have the mutated disease-causing gene and can transmit it to their children.
The disease is divided into five main types — 0, 1, 2, 3, and 4 — based on the age of symptom onset and the highest motor milestone achieved. Type 0 is the most severe form of the disease, with an onset before birth, while type 4 is its mildest form, with an adult onset. Life expectancy also depends on the disease type, with the most severe forms being associated with a shorter lifespan and milder types with a normal life expectancy.
Nearly all cases (95%) of the main types of SMA are caused by mutations in the SMN1 gene, which impair the production of survival motor neuron (SMN). SMN is a protein present in virtually every cell in the body and involved in maintaining protein balance.
Motor neurons, the specialized nerve cells that control voluntary muscle movement, appear to be particularly vulnerable to SMN deficiency, dying without it. The progressive loss of motor neurons leads to the muscle weakness and wasting that characterizes SMA.
To develop any of SMA’s main types, a child has to inherit two mutated copies of SMN1, one from the mother and one from the father. Disease severity is mostly determined by the number of copies a patient has of the “backup” SMN2 gene, which can partly compensate for the loss of SMN1-produced SMN. Typically, the more SMN2 gene copies a patient has, the less severe the disease.
People with only one defective SMN1 copy will not develop SMA, but will be carriers, meaning they can pass the mutated gene to their children. If both parents are SMA carriers, they will have a 25% chance of transmitting two mutated SMN1 copies — and thereby the disease — to each of their children, and a 50% risk of each of their biological children being a carrier.
Other, rarer types of spinal muscular atrophy are linked to mutations in genes other than SMN1. These include Finkel type SMA, SMA with respiratory distress 1, SMA with lower extremity predominance, Kennedy’s disease, X-linked infantile SMA, and SMA with progressive myoclonic epilepsy.
Symptoms of SMA differ in age of onset, severity, and occurrence across the different disease types. Some first appear before birth, while still in the womb — in type 0 — while others start in the first year of life. In type 1, symptoms usually begin in the first six months of life, while onset is between six and 18 months in type 2. Symptoms in type 3 usually appear between 1.5 and 3 years of age, while those in type 4 start during adulthood, usually after age 35. Notably, later symptom onset is associated with milder severity.
The most common symptoms include progressive muscle weakness and poor muscle tone and control, which impair patients’ motor development and/or future mobility. The proximal muscles, or those closer to the center of the body, such as those of the shoulders and upper arms and legs, are more severely affected than the most distant muscles, such as those in the hands and feet. Patients may never acquire or may gradually lose the ability to sit, walk, or move.
Breathing difficulties, problems with feeding and swallowing, and scoliosis (a sideways curvature of the spine) — associated with weakness in the muscles supporting these regions — also are common in both children and adults with SMA. Patients have an increased risk of lung infections, including aspiration pneumonia, which is a lung infection that develops due to food or liquid being aspirated into the lungs.
People with SMA often experience tremors, muscle fatigue, joint contractures, and gastrointestinal problems, such as diarrhea, bloating, vomiting, and abdominal distention.
Increasing evidence suggests that spinal muscular atrophy also affects bones, the liver, heart, and pancreas, and the vascular and immune systems.
When symptoms are present and/or there is a history of SMA in the family, a diagnosis can be made through genetic testing. Such testing identifies disease-causing mutations in a person’s copies of the SMN1 gene. The number of SMN2 gene copies also can be measured in a genetic test, which may help to confirm or predict the type of disease.
DNA testing also is highly reliable in identifying carriers — which can help to estimate a person’s chances of having a child affected by the disease — as well as affected babies, either while still in the womb (prenatal screening), or shortly after birth (newborn screening).
SMA screening is available in several states in the U.S., and other countries also have implemented or are in the process of introducing spinal muscle atrophy to the list of diseases screened at birth for free.
Rare mutations in the SMN1 gene or in other genes causing rarer types of spinal muscular atrophy are not part of standard SMA genetic tests, but may be requested if a diagnosis is strongly suspected and initial DNA testing is negative. Such inconclusive scenarios also may prompt other types of tests, such as electromyography and muscle biopsy.
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.
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, and in those with most types who weigh up to 21 kilograms (about 46 pounds) in Europe, which could cover children up to age 5.
Due to the progressive nature of spinal muscular atrophy, early intervention with these targeted therapies is particularly important.
General care of SMA includes physical, occupational, and rehabilitation therapy to help improve posture, joint mobility, and quality of life. These therapies also may help to maintain blood flow and slow muscle weakness and atrophy. These types of interventions also may be used to manage speech, chewing, and swallowing problems.
Assistive devices such as supports or braces, speech synthesizers, and wheelchairs are often used to help patients stay more independent. Non-invasive ventilation at night can improve breathing during sleep, and some patients with greater breathing difficulties also may need assisted ventilation during the day.
Proper nutrition also is essential to maintain patients’ weight and strength, and those who cannot chew or swallow may require the insertion of a feeding tube to get the nutrition they need.
Muscle relaxants, and medications to reduce muscle spasms and drooling, also are commonly used to ease SMA symptoms.
A number of experimental therapies also are currently being tested as potential treatments for SMA.
Last updated: July 1, 2021
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