Spinal Muscular Atrophy (SMA) is a progressive genetic disorder that affects the motor neurons in the spinal cord and brainstem, which control voluntary movement. The loss of these specialized nerve cells prevents signals from reaching the muscles, causing them to weaken and waste away (atrophy). This muscle weakness is typically more severe in the core muscles, such as those in the shoulders, hips, and back, and often includes the muscles used for breathing and swallowing. SMA severity varies widely, ranging from a severe form that is often the most common genetic cause of infant death to a milder, adult-onset presentation.
The Genetic Basis of SMA
Spinal Muscular Atrophy is primarily caused by mutations in the Survival Motor Neuron 1 (SMN1) gene, which is inherited in an autosomal recessive pattern. To develop the condition, an individual must inherit a mutated copy of the gene from both parents, who are typically carriers without symptoms. The SMN1 gene provides instructions for making the Survival Motor Neuron (SMN) protein, which is necessary for motor neuron survival.
A deficiency of the SMN protein causes motor neurons in the spinal cord to shrink and die. In most SMA cases, the SMN1 gene is deleted or mutated, resulting in little to no functional SMN protein production. Humans also possess a second, nearly identical gene called SMN2, which acts as a modifier of the disease’s severity and can be found in multiple copies.
The SMN2 gene is structurally similar to SMN1, but a minor change in its genetic code causes it to predominantly produce a shortened, non-functional version of the SMN protein. However, SMN2 still produces a small amount (roughly 10% to 15%) of the full-length, functional SMN protein. Individuals with a higher number of SMN2 gene copies generally have a milder form of SMA because they produce more of the necessary functional protein.
Classifying the Different Types of SMA
SMA is traditionally classified into four main types—Type 1 through Type 4—based on the age when symptoms first appear and the highest physical milestone achieved. The earlier the onset of symptoms, the greater the severity of muscle weakness and the poorer the long-term prognosis.
Type 1, historically known as Werdnig-Hoffmann disease, is the most common and severe form, accounting for about 60% of cases, with symptoms appearing before six months of age. Infants with Type 1 SMA never achieve the ability to sit without support. They experience severe generalized muscle weakness, poor head control, and difficulty breathing and swallowing. Without respiratory support, children with this type typically do not survive past two years of age.
Type 2 SMA, or intermediate SMA, is usually diagnosed between 6 and 18 months of age. Children with this form are able to sit independently but never gain the ability to stand or walk without assistance. Symptoms include progressive muscle weakness, often more pronounced in the legs, along with potential respiratory issues, involuntary hand tremors, and scoliosis. Most individuals with Type 2 SMA survive past age 25, often living into their 30s or beyond with supportive care.
Type 3 SMA, also called Kugelberg-Welander disease, is a milder form with onset after 18 months of age, sometimes presenting as late as early childhood. These individuals achieve the milestone of walking independently. However, they may experience progressive muscle weakness that leads to a loss of walking ability later in life. Symptoms often include difficulty running, climbing stairs, or rising from a chair, but respiratory weakness is usually minimal, and life expectancy is typically normal.
Type 4 is the mildest and rarest form, with symptoms not appearing until adulthood, usually after age 21. Individuals with Type 4 SMA experience mild to moderate muscle weakness, primarily in the legs, that progresses very slowly. They generally remain mobile and have a typical life expectancy.
Current Methods of Treatment and Care
The management of SMA has been revolutionized by disease-modifying therapies, although a comprehensive approach still includes supportive care. Early detection is paramount, increasingly accomplished through genetic testing and newborn screening programs. Identifying the condition before symptom onset allows for the immediate initiation of treatment, which dramatically improves outcomes.
Modern treatments address the underlying genetic deficit by increasing the amount of functional SMN protein.
Disease-Modifying Therapies
One approach involves antisense oligonucleotides (ASOs), which are short synthetic strands of genetic material that modify how the SMN2 gene is “read.” Drugs like nusinersen, the first approved treatment, are administered into the spinal fluid. This promotes the inclusion of a specific segment (exon) in the SMN2 gene’s messenger RNA, resulting in the production of more full-length, functional SMN protein.
Another therapeutic strategy is gene therapy, involving a one-time intravenous infusion of a harmless virus carrying a functional copy of the SMN1 gene. Onasemnogene abeparvovec is an example of this therapy, designed to deliver the correct genetic instructions directly to the motor neuron cells. A third type of treatment, such as the orally administered drug risdiplam, works by modifying the splicing of the SMN2 gene to increase SMN protein levels throughout the body.
Supportive care remains a fundamental part of management, working alongside targeted therapies to maintain function and quality of life. This includes physical and occupational therapy to manage muscle stiffness and maintain joint mobility. Nutritional support for feeding difficulties and respiratory support, such as non-invasive ventilation, are often necessary for individuals with more severe types to assist with breathing and prevent lung complications.