Spinal muscular atrophy (SMA) is an inherited neuromuscular disorder that causes muscle weakness and degeneration over time. There are five main types of SMA that account for 95 percent of cases – types 0, 1, 2, 3, and 4. Type 0 is the most severe form of SMA and begins before birth. Type 4 is the mildest and begins in adulthood. Depending on the type of SMA a person has, symptoms can include respiratory weakness, problems swallowing and chewing, lack of motor function, inability to walk, or mild muscle weakness.
Life expectancy is often reduced in more severe SMA types. The recent introduction of new therapies for SMA may influence the course of the disease, longevity, and disability.
For SMA types 0-4, a person must inherit a mutated survival motor neuron 1 gene (SMN1) from each parent. The SMN1 gene, located on chromosome 5, is responsible for the production of survival motor neuron (SMN) protein. SMN protein is essential for the function of motor neurons – nerve cells that send signals from the brain and spinal cord to the muscles. If motor neurons can’t signal the muscles, the muscles atrophy. Depending on the severity of the SMA type, muscle atrophy can lead to compromised respiratory and motor function.
The type of SMA a person develops can be influenced by a second gene on chromosome 5 called SMN2. The SMN2 gene produces some survival motor neuron protein, but not enough for normal muscle function. People without SMA usually have one or two copies of SMN2, though they may have more. Among people with SMA, having more copies of the SMN2 gene is associated with a less severe form of the condition.
Cases of SMA were first described in the early 1890s by Austrian scientist Guido Werdnig and German scientist Johan Hoffmann, leading to the name Werdnig-Hoffmann disease for what is now known as SMA type 1. The first cases of severe SMA in babies were identified around the same time, in 1899 and 1903. Milder forms of SMA, what might now be considered types 3 or 4, were first described in the 1950s. The classification system used today to describe SMA types 0-4 was developed in 1991.
Scientific understanding of SMA improved greatly in 1995 when researchers led by French geneticist Judith Melki discovered that 95 percent of all SMA cases are caused by a mutated or deleted SMN1 gene. The same research team discovered the SMN2 gene, which is sometimes referred to as the SMA “back-up gene.”
Discovering the role of the SMN genes opened the door for new diagnostic tools and research. Before identifying the SMN1 gene, SMA was diagnosed based on signs and symptoms of disease, rather than genetic testing that can confirm the presence of a genetic mutation.
The SMN gene breakthrough also allowed scientists to begin animal experiments to expand research on the genetic factors that influence SMA. Improved understanding of the genetic pathology of SMA opened the doors for clinical trials, which were rare before the 1990s.
Clinical trials for SMA have led to improvements in treatment options, including the first SMA treatment approved by the U.S. Food and Drug Administration (FDA) in 2016 – Spinraza (nusinersen). A second treatment for SMA in children under age 2, Zolgensma (onasemnogene abeparvovec-xioi), was approved in 2019.
SMA is a rare disease. It occurs in about 1 out of every 11,000 births in the United States. About 1 in 54 people in the U.S. is a carrier for SMA, though this rate varies by ethnic background. While SMA impacts a small number of people, it is the top genetic cause of infant mortality.
There are five main types of SMA – types 0,1,2,3, and 4 – that comprise 95 percent of SMA cases. These types of SMA are all caused by a mutation on the SMN1 gene. Types 0-4 are differentiated by age of onset and severity.
There are several other very rare types of SMA, including SMA with respiratory distress (SMARD) and distal SMA. Read more about types of spinal muscular atrophy.
Spinal muscular atrophy is usually diagnosed through genetic testing. The genetic test for SMA looks for mutations on the SMN1 gene on chromosome 5. Until recently, genetic testing was usually only conducted if a person showed symptoms of SMA or if there was a family history of the condition. Beginning in 2018, the United States Department of Health and Human Services added SMA to their list of conditions newborns should be screened for in their first 48 hours of life. As of January 2020, 17 states include SMA as part of routine newborn screening. Cure SMA offers resources for parents whose children were diagnosed through routine newborn screening.
Before genetic testing was available, SMA was diagnosed via a muscle biopsy. If SMA was suspected, doctors would remove a tiny piece of muscle tissue for evaluation in a lab and perform an electromyogram (EMG) to evaluate the electrical activity of muscles. Muscle biopsy and EMG may still be used on occasion if genetic testing is inconclusive.
Read more about genetic testing and spinal muscular atrophy diagnosis.
Muscle weakness (hypotonia) is the primary symptom of every type of SMA. Muscle weakness can impact several functions.
Difficulty sucking, chewing, and swallowing are most prevalent in babies and children with severe forms of SMA. Eating difficulties are the result of muscle weakness in the throat and mouth. A feeding tube may be necessary to ensure infants and children with SMA receive adequate nutrition.
Motor skill development and mobility is depending on SMA type. Babies and children with SMA type 0 and type 1 will never develop the ability to sit up unsupported. Children with type 2 may learn to sit up but may lose that ability as SMA progresses.
Occasionally, children with SMA type 2 develop the ability to stand. Depending on age of onset, those with SMA type 3 can develop the ability to stand and walk, though these abilities may be compromised over time. Adults with type 4 generally only experience muscle weakness that impacts mobility in their older age.
There are many other SMA symptoms that can impact function and quality of life. They include:
Learn more about symptoms of spinal muscular atrophy.
Depending on the type of SMA and symptoms, SMA can be treated with therapies that manage symptoms and disease-modifying therapies.
There are two disease-modifying therapies available for SMA — Spinraza (nusinersen) and Zolgensma (onasemnogene abeparvovec-xioi). The FDA approved Spinraza in 2016 and Zolgensma in 2019. Both drugs are forms of gene therapy. People with SMA may be eligible to participate in clinical trials to receive access to new treatments.
Breathing support can be critical for people with more severe forms of SMA. Breathing problems can be addressed with noninvasive or invasive ventilation support. Noninvasive forms of ventilation support are used as needed and can be removed. A bilevel positive airway pressure (BiPAP) machine is a noninvasive option often used for breathing support while sleeping.
Ventilation supports that penetrate the body are available if noninvasive options aren’t sufficient. Examples include an endotracheal tube (tube that goes through the trachea to the lung) that can be used short-term and a tracheostomy (surgical placement of a breathing tube in the trachea). In addition to breathing support machines, respiratory therapy can help strengthen weak intercostal muscles.
Feeding tubes may be necessary in cases where muscle weakness impacts a person’s ability to chew or swallow. Some feeding tubes are placed surgically through the skin and some are placed through the nose. They may go to the stomach or the small intestine.