Spinal muscular atrophy (SMA) is a hereditary condition that damages nerve cells in the spinal cord and brainstem. These specialized nerve cells, known as motor neurons, control voluntary muscle movements. As these neurons are lost, muscles progressively weaken and waste away in a process called atrophy, impacting a person’s ability to walk, swallow, and breathe.
The Genetic Cause of Spinal Muscular Atrophy
Spinal muscular atrophy arises from a deficiency of the survival motor neuron (SMN) protein, which is produced by the SMN1 gene and is necessary for motor neuron health. In most individuals with SMA, both copies of their SMN1 gene are mutated or missing. This condition is inherited in an autosomal recessive pattern, meaning an individual must inherit a faulty copy of the SMN1 gene from both parents.
The human body has a second gene, SMN2, which also produces SMN protein. However, due to a slight genetic difference, the SMN2 gene primarily produces a shorter, less stable version of the protein that is not fully functional. Only a small fraction of the protein made by SMN2 is the full-length, effective type.
While the SMN2 gene cannot completely compensate for non-functional SMN1 genes, it plays a role in the disease’s outcome. People can have multiple copies of the SMN2 gene, and a higher number of copies correlates with less severe symptoms. This is because more SMN2 copies lead to the production of more functional SMN protein, which can better support the survival of motor neurons.
Classifying the Types of SMA
Historically, SMA is categorized into five main types, from Type 0 to Type 4, based on the age when symptoms first appear and the highest physical milestone an individual achieves. While new treatments are changing historical outcomes, this classification system remains a useful reference.
Type 0 is the most severe and rarest form, with symptoms such as decreased fetal movement becoming apparent before birth. Newborns with Type 0 SMA have profound weakness and often require immediate respiratory support. They do not survive past early infancy due to respiratory failure.
SMA Type 1, also known as Werdnig-Hoffmann disease, is the most common form, with symptoms appearing before six months of age. Infants with this type experience significant muscle weakness, a weak cry, and have trouble with swallowing and breathing. They are unable to sit up without support.
SMA Type 2 is diagnosed between six and 18 months of age. Children with this type can sit independently but are unable to stand or walk on their own. They often experience tremors and a weak cough, and while life expectancy can be reduced, many live into adulthood.
SMA Type 3, or Kugelberg-Welander disease, has a later onset, with symptoms appearing after 18 months of age. Individuals with Type 3 are able to walk independently, although they may have difficulty with running or climbing stairs. Some may lose the ability to walk over time.
SMA Type 4 is the mildest form, with symptoms beginning in adulthood, after the age of 21. It involves mild to moderate muscle weakness, primarily in the legs, but individuals maintain their mobility and have a normal life expectancy.
Signs, Symptoms, and Diagnosis
The clinical presentation of SMA is characterized by progressive muscle weakness that is more pronounced in muscles closer to the body’s center, like the shoulders and hips. Common signs include poor muscle tone (“floppiness”), diminished reflexes, and muscle twitches. Infants may also present with a weak cry and poor head control.
As the disease progresses, individuals may develop joint problems and a curvature of the spine, known as scoliosis, due to the weakening of back muscles. The weakness of respiratory muscles is a serious aspect of SMA, as it can impair breathing and the ability to clear secretions from the airways. Sensation and intellectual ability are not impacted by the condition.
The diagnostic process for SMA begins with a physical examination and a review of the patient’s family history. If a provider suspects SMA, a definitive diagnosis is confirmed through genetic testing. A blood test can identify mutations or deletions in the SMN1 gene in about 95% of cases.
If genetic testing is inconclusive, other diagnostic tools may be used. An electromyography (EMG) measures the electrical activity of muscles to assess motor neuron function. A muscle biopsy, which involves examining a small sample of muscle tissue, can also reveal signs of nerve damage and muscle atrophy.
Modern Therapeutic Strategies
The management of SMA has been transformed by therapies that address its underlying genetic cause. These treatments include SMN-enhancing therapies and gene replacement therapy. SMN-enhancing drugs modify the SMN2 “backup” gene to increase its production of full-length, functional SMN protein.
Nusinersen is one such therapy, administered through an injection into the fluid surrounding the spinal cord. It targets the SMN2 gene, promoting the production of a more stable and effective SMN protein. Risdiplam is another SMN-enhancing therapy, but it is an oral medication that can be taken daily.
Gene replacement therapy offers a different approach by directly addressing the missing or non-functional SMN1 gene. Onasemnogene abeparvovec uses a modified, harmless virus to deliver a new, working copy of the SMN1 gene to motor neuron cells. This one-time intravenous infusion allows the cells to begin producing their own functional SMN protein. These treatments have shown significant benefits, especially when started early in life.
Alongside advanced therapies, comprehensive supportive care is fundamental. Physical and occupational therapy help maintain muscle strength and joint flexibility, while mobility aids assist with movement. Respiratory support, including exercises and ventilation machines, is often necessary. Nutritional support is also provided to manage swallowing difficulties and ensure adequate caloric intake.