Spinal Muscular Atrophy (SMA) is a severe, rare neuromuscular disease. This genetic disorder affects the motor nerve cells responsible for movement, leading to progressive muscle weakness and atrophy (wasting away of muscles). While SMA is the most common genetic cause of infant death, its severity exists on a wide spectrum, with some forms appearing later in childhood or even adulthood.
Defining Spinal Muscular Atrophy
Spinal Muscular Atrophy is characterized by the loss of specialized nerve cells called lower motor neurons, located in the spinal cord and brainstem. These motor neurons send signals from the central nervous system to the skeletal muscles, controlling voluntary movements like walking, breathing, and swallowing. When these cells die, the muscles they innervate no longer receive nerve signals, leading to progressive weakening and shrinking.
Muscle weakness in SMA tends to be more pronounced in the proximal muscles, which are those closest to the center of the body, such as the shoulders, hips, and upper back. A defining feature of SMA is that it affects motor function but typically spares cognitive function. Individuals with SMA usually have normal intelligence, which is an important distinction from some other neurological disorders. The progressive loss of motor neurons affects the body’s ability to move, but not the brain’s ability to think and learn.
The Genetic Basis of SMA
The primary cause of Spinal Muscular Atrophy is a mutation or deletion in the Survival Motor Neuron 1 (SMN1) gene, located on chromosome 5. This gene produces the Survival Motor Neuron (SMN) protein, which is necessary for the health and function of motor neurons. When SMN1 is mutated, the body cannot produce enough functional SMN protein, leading to the gradual death of motor neurons.
Humans also possess a second, nearly identical gene called SMN2, which acts as a backup. A slight structural difference means SMN2 only produces a small amount (typically 10–15%) of full-length, functional SMN protein. The number of SMN2 copies a person has strongly influences the disease’s severity. A higher copy number generally correlates with a milder disease course because it allows for greater production of the functional protein.
SMA is inherited in an autosomal recessive pattern. An individual must inherit a mutated copy of the SMN1 gene from both parents to develop the condition. If a person inherits only one mutated copy, they are considered a carrier and typically do not show symptoms. The variation in SMN2 copy number explains why SMA presents as a spectrum of severity rather than a single condition.
Classification and Symptoms
SMA is classified into four main types (Type 1 through 4) based on the age when symptoms first appear and the highest motor milestone an individual achieves. The earlier the age of onset, the more severe the symptoms tend to be. The most severe form, Type 1, also called Werdnig-Hoffman disease, is the most common, accounting for about 60% of cases.
Type 1 symptoms appear within the first six months of life; affected infants never achieve the ability to sit without support. They experience severe muscle weakness, poor head control, and difficulty with feeding and breathing. Respiratory complications are frequent and serious, often requiring ventilation. Type 2 SMA, or intermediate SMA, has an onset between 6 and 18 months. Children with Type 2 can learn to sit independently but cannot stand or walk without assistance.
Type 3 SMA, sometimes called Kugelberg-Welander disease, appears after 18 months of age, sometimes as late as adolescence. Individuals with Type 3 achieve independent walking but may later experience difficulty running, climbing stairs, or rising from a chair. Muscle weakness remains primarily in the legs and proximal muscles, and some may lose the ability to walk later in life. Type 4 is the mildest form, considered adult-onset, with symptoms typically appearing after age 35. Symptoms are generally mild to moderate, involving gradual leg muscle weakness, and the disease progresses very slowly.
Modern Therapeutic Approaches
The understanding of SMA’s genetic basis has led to the development of revolutionary disease-modifying therapies. These treatments target the underlying genetic deficiency rather than just managing symptoms. Before these advances, care was limited to supportive measures like physical therapy and respiratory support.
One therapeutic approach involves drugs that modify the splicing of the SMN2 gene to increase functional SMN protein production. Nusinersen (Spinraza), the first approved drug, is an antisense oligonucleotide (ASO) delivered into the fluid surrounding the spinal cord. It works by binding to the SMN2 pre-mRNA, promoting the inclusion of Exon 7, which creates more full-length SMN protein. Another drug, Risdiplam (Evrysdi), is an oral small molecule that also acts as an SMN2 splicing modifier. Because it is taken by mouth, it increases SMN protein levels systemically in both the central nervous system and peripheral tissues.
A separate therapeutic strategy is gene therapy, exemplified by onasemnogene abeparvovec (Zolgensma). This therapy uses a single intravenous infusion of a harmless adeno-associated virus vector (AAV9) to deliver a functional copy of the SMN1 gene. The goal is to provide motor neurons with a permanent source of the SMN protein. These treatments have fundamentally changed the prognosis for many patients, especially when administered early, allowing some infants to reach motor milestones previously considered unattainable.