What is Spinal Muscular Atrophy?
SMA is a genetic disorder impacting the central nervous system, peripheral nervous system, and voluntary muscles responsible for movement. The nerve cells controlling muscles, primarily located in the spinal cord, become dysfunctional in SMA. As a result, the muscles fail to receive necessary signals, leading to their shrinkage or reduction in size, a process medically referred to as atrophy.
SMA is classified as a motor neuron disease because it involves the degeneration of motor neurons in the spinal cord. The most common form, chromosome 5 SMA (SMN-related SMA), varies significantly in its onset, symptoms, and progression. To account for these differences, chromosome 5 SMA is divided into types 1 through 4.
The severity of SMA is generally linked to the age at which symptoms begin. Infants or newborns showing signs of SMA (type 1) tend to have the most severe form and limited motor abilities. On the other hand, symptoms that develop later in childhood, adolescence, or adulthood (types 2, 3, and 4) are usually less severe, allowing for greater motor function.
What Causes SMA?
Chromosome 5 SMA results from a deficiency in a protein known as SMN (survival of motor neuron). This protein is essential for motor neuron health and function. The deficiency occurs due to genetic mutations in the SMN1 gene on chromosome 5. The most common mutation involves the deletion of exon 7.
A neighboring gene, SMN2, can partially compensate for the loss of SMN1, as it is nearly identical. The number of copies of the SMN2 gene a person has directly influences the amount of SMN protein their body can produce.
There are also less common forms of SMA caused by mutations in other genes, unrelated to SMN1.
Symptoms of SMA
Symptoms vary widely, ranging from mild to severe. In most cases, SMA primarily affects muscles near the center of the body (proximal muscles), such as the shoulders, hips, thighs, and upper back. Muscles farther from the body’s core (distal muscles) are less commonly impacted. The lower limbs are often more severely affected than the upper limbs, and reflexes in the affected areas are typically reduced.
In severe cases, complications can arise if the muscles involved in breathing or swallowing are impaired. Weakness in back muscles may also result in spinal curvature over time.
For chromosome 5 SMA, the degree of motor function and the age of symptom onset are closely tied to the amount of functional SMN protein available. Despite the impact on physical abilities, sensory, cognitive, and emotional functions remain entirely normal.
Some rare non-chromosome 5 forms of SMA primarily affect distal muscles and can exhibit different patterns of severity and progression.
How Does SMA Progress?
The progression of SMA depends on the type and the amount of SMN protein a person produces. In general, individuals with more SMN protein experience milder symptoms and later onset. Historically, infants with SMA often did not survive beyond two years, but advances in medical care have significantly improved outcomes.
SMA remains the most common genetic cause of infant mortality, though early intervention and new treatments have altered the outlook for many individuals.
Recent Advances in SMA Research
Research efforts focus on increasing the body’s ability to produce SMN protein in cases of chromosome 5 SMA. Scientists are also exploring ways to protect motor neurons from damage caused by the disease.
In December 2016, the U.S. Food and Drug Administration (FDA) approved Spinraza (nusinersen), a treatment that targets the genetic root of SMA. This medication helps slow, stop, or even reverse some of the disease’s effects.
In May 2019, the FDA approved Zolgensma (onasemnogene abeparvovec-xioi), the first gene replacement therapy for neuromuscular disorders. Administered as a single intravenous infusion, Zolgensma is specifically designed for children under two years of age with bi-allelic mutations in the SMN1 gene.
These groundbreaking therapies represent significant steps forward in the management of SMA, offering hope to affected individuals and families.