Progressive spinal muscular atrophy (SMA) is a rare genetic neuromuscular disorder characterized by the progressive loss of motor neurons. These specialized nerve cells in the brainstem and spinal cord control voluntary muscle movement. When motor neurons are lost, muscles do not receive signals, leading to muscle weakness and wasting, also known as atrophy.
Defining Progressive Spinal Muscular Atrophy and Its Types
Spinal muscular atrophy encompasses a spectrum of conditions, varying in age of onset and severity. The “progressive” nature means symptoms worsen over time, leading to increasing challenges in motor function. SMA is classified into several types, with Type 0 being the most severe and Type 4 the mildest.
SMA Type 0 is a severe form with symptoms appearing before birth, often resulting in decreased fetal movements. Infants with Type 0 experience profound muscle weakness and breathing difficulties, leading to a very short lifespan. SMA Type 1, also known as Werdnig-Hoffman disease, is the most common and severe form, with symptoms presenting within the first six months of life. Babies with Type 1 SMA often have severely low muscle tone, difficulty with head control, and challenges with breathing, sucking, and swallowing, with a life expectancy of less than two years without intervention.
SMA Type 2, or intermediate SMA, manifests between 6 and 18 months of age. Children with Type 2 can often sit independently but may not be able to stand or walk without assistance. Muscle weakness in Type 2 affects the legs more than the arms, and respiratory issues can arise.
SMA Type 3, known as Kugelberg-Welander disease, appears after 18 months of age, sometimes as late as early adulthood. Individuals with Type 3 can walk independently initially, but may experience progressive leg weakness, making activities like climbing stairs difficult, though their life expectancy is not affected. SMA Type 4, the mildest form, develops in adulthood, after age 21. Muscle weakness in Type 4 progresses slowly, primarily affecting the legs, and most individuals remain mobile with a normal life expectancy.
Genetic Origins
The underlying cause of progressive spinal muscular atrophy is a genetic change in the SMN1 gene. This gene provides instructions for producing the Survival Motor Neuron (SMN) protein, a substance found throughout the body with the highest concentrations in the spinal cord. The SMN protein is necessary for the proper maintenance and function of motor neurons.
In individuals with SMA, mutations or deletions in both copies of the SMN1 gene lead to an insufficient production of functional SMN protein. This deficiency causes motor neurons in the spinal cord to degenerate and die.
The SMN2 gene, a “backup” gene similar to SMN1, also produces SMN protein, though only a small percentage (about 10-20%) of it is fully functional. The number of copies of the SMN2 gene an individual possesses can influence the severity of SMA symptoms. More copies of the SMN2 gene are associated with higher levels of functional SMN protein and a milder disease course. For instance, individuals with SMA Type 1 have one or two SMN2 copies, while those with Type 4 may have three to five copies.
Recognizing Symptoms and Disease Progression
The symptoms of progressive spinal muscular atrophy involve muscle weakness. The weakness is more pronounced in muscles closer to the body’s center, such as those in the shoulders, hips, thighs, and upper back, and affects the legs more than the arms initially. This weakness can lead to difficulty with various motor skills, including crawling, sitting, standing, and walking.
Infants with Type 1 SMA may present as “floppy babies” due to severe muscle weakness and low muscle tone, making it impossible for them to raise their heads or sit without support. They may also have difficulty with sucking and swallowing, leading to feeding issues, and experience significant breathing problems due to weakened respiratory muscles. Children with Type 2 SMA may initially sit independently but might lose this ability as they enter their teens.
Progression in Type 3 SMA can involve increasing difficulty with walking, leading to frequent falls and challenges with stairs. While individuals with Type 3 have a lower risk of severe respiratory problems compared to earlier-onset types, muscle weakness can still affect breathing. A common issue across SMA types is scoliosis, a sideways curvature of the spine, which occurs due to the weakening of muscles supporting the spine.
Diagnosis and Identification
Diagnosing progressive spinal muscular atrophy begins with a clinical evaluation, where doctors observe symptoms and conduct a physical examination. As symptoms can overlap with other neuromuscular conditions, genetic testing is used to confirm the diagnosis. This testing focuses on identifying mutations or deletions in the SMN1 gene.
Genetic testing involves a blood sample and is the most accurate method for diagnosing SMA. In approximately 95% of SMA cases, diagnosis is confirmed by detecting a deletion of exon 7 in both copies of the SMN1 gene. If this initial test is negative or inconclusive, further DNA sequencing may be performed to identify other SMN1 gene mutations. While electromyography (EMG) or nerve conduction studies can support a diagnosis or rule out other conditions, genetic testing is definitive. Newborn screening for SMA is now widely implemented, aiding early identification.
Current Management and Therapeutic Strategies
Current management for progressive spinal muscular atrophy involves a multidisciplinary approach, combining disease-modifying therapies with supportive care to improve function, slow progression, and enhance quality of life. These therapies aim to increase the levels of functional SMN protein in the body.
Onasemnogene abeparvovec (Zolgensma) is a gene therapy administered as a one-time intravenous infusion for children under two years old. This therapy delivers a working copy of the SMN1 gene into the body’s cells, enabling them to produce the necessary SMN protein and preserve motor neuron function.
Nusinersen (Spinraza) is an antisense oligonucleotide that modifies the splicing of the SMN2 gene, leading to increased production of full-length SMN protein. Nusinersen is administered directly into the central nervous system through periodic intrathecal injections.
Risdiplam (Evrysdi) is an orally administered medication that also works by modifying the SMN2 gene’s splicing pattern to increase SMN protein levels.
Beyond these targeted therapies, supportive care plays an important role in managing SMA.
- Physical therapy helps maintain muscle strength and flexibility, improve motor function, and prevent contractures.
- Occupational therapy assists individuals in adapting to daily activities and using assistive devices to enhance independence.
- Respiratory support, including monitoring and interventions for breathing difficulties, is important for individuals with more severe forms of SMA, as respiratory complications are a major concern.
- Nutritional management ensures adequate intake for growth and overall health.
- Assistive devices such as wheelchairs, braces, or feeding tubes can improve mobility and quality of life.