Spinal Muscular Atrophy (SMA) is a genetic disorder that affects the motor nerve cells in the spinal cord, leading to muscle weakness and atrophy. This comprehensive guide explores the causes, symptoms, progression, and current research surrounding SMA, providing a thorough understanding of this condition.
Understanding Spinal Muscular Atrophy
Spinal muscular atrophy (SMA) is a genetic disease impacting the central nervous system, peripheral nervous system, and voluntary muscle movement (skeletal muscle). The term “spinal” refers to the location of most motor nerve cells in the spinal cord. SMA is “muscular” because it primarily affects muscles, which don’t receive signals from these nerve cells. “Atrophy” denotes the shrinking of muscles due to lack of nerve stimulation. SMA is classified as a motor neuron disease due to the loss of these nerve cells.
The most common form of SMA, chromosome 5 SMA (also known as SMN-related SMA), exhibits significant variability in the age of onset, symptoms, and progression rate. This form is categorized into types 1 through 4, reflecting the differences in severity. Generally, an earlier onset of symptoms correlates with a greater impact on motor function. Infants displaying symptoms at birth or in early infancy typically have the lowest level of functioning (type 1), while later-onset SMA (types 2, 3, and 4) generally correlates with higher levels of motor function.
Causes of SMA
Chromosome 5 SMA arises from a deficiency in the survival motor neuron (SMN) protein, essential for normal motor neuron function. SMN plays a crucial role in gene expression within these cells. This deficiency stems from genetic mutations on chromosome 5 in the SMN1 gene. The most common mutation is the deletion of exon 7. SMN2 genes can partially compensate for the nonfunctional SMN1 genes due to their high degree of similarity. Other rarer forms of SMA (non-chromosome 5) are caused by mutations in other genes.
Symptoms of SMA
SMA symptoms vary widely, ranging from mild to severe.
The muscles closer to the center of the body (proximal muscles) are usually more affected in SMA than are the muscles farther from the center (distal muscles).
The primary symptom of chromosome 5-related SMA is weakness of voluntary muscles. Muscles closest to the body’s center, such as those in the shoulders, hips, thighs, and upper back, are most affected. The lower limbs are often more affected than the upper limbs, and deep tendon reflexes are decreased. Breathing and swallowing difficulties can arise if the related muscles are affected, and spinal curvatures can develop if the back muscles weaken. The age of onset and level of motor function achieved vary considerably and are roughly correlated with the amount of functional SMN protein present, which in turn depends on the number of SMN2 gene copies. Importantly, sensory, mental, and emotional functioning remain entirely normal in chromosome 5-SMA.
Some forms of SMA are not linked to chromosome 5 or SMN deficiency. These forms also vary greatly. While most forms primarily affect proximal muscles, some affect distal muscles more significantly, at least initially.
Progression of SMA
In chromosome 5-related SMA, the later the symptoms manifest and the more SMN protein available, the milder the disease course is likely to be. While historically, infants with SMA often did not survive beyond two years, SMA is now viewed as a continuum, and doctors generally avoid rigid predictions about life expectancy or weakness based solely on the age of onset. SMA remains the most common genetic cause of infant mortality.
Current Research and Treatments for SMA
Research efforts have concentrated on strategies to increase the body’s production of the SMN protein, deficient in chromosome 5-related SMA. This includes methods to support motor neuron survival. Significant advancements have been made in the treatment of SMA.
- Spinraza (nusinersen): Approved by the FDA in December 2016, Spinraza targets the underlying defect in SMA, potentially slowing, stopping, or reversing symptoms.
- Zolgensma (onasemnogene abeparvovac-xioi): Approved in May 2019, Zolgensma is the first gene-replacement therapy for a neuromuscular disease. It’s a one-time intravenous infusion for pediatric patients under 2 years old with SMA due to bi-allelic mutations in the SMN1 gene, including those who are presymptomatic.
- Evrysdi (risdiplam): Approved in August 2020 for adults and children two months and older, Evrysdi is an oral medication that increases SMN protein levels by enhancing production from the SMN2 “backup” gene. In May 2022, the FDA extended its approval for use in babies under two months, based on clinical trial data showing crucial motor milestone achievements in pre-symptomatic newborns.
The muscles closer to the center of the body (proximal muscles) are usually more affected in SMA than are the muscles farther from the center (distal muscles).
These therapeutic advancements have significantly improved the outlook for individuals with SMA.
Conclusion
Spinal Muscular Atrophy is a complex genetic disorder with a range of symptoms and progression rates. However, ongoing research and the development of new treatments offer hope for improved outcomes and quality of life for those affected by SMA. Early diagnosis and access to these treatments are crucial in managing the condition effectively.
References
- Ogino, S. & Wilson, R. B. Genetic testing and risk assessment for spinal muscular atrophy (SMA). Human Genetics (2002). doi:10.1007/s00439-002-0828-x
- Lefebvre, S. et al. Identification and characterization of a spinal muscular atrophy-determining gene. Cell (1995). doi:10.1016/0092-8674(95)90460-3
- Darras, B. T. Non-5q spinal muscular atrophies: The alphanumeric soup thickens. Neurology (2011). doi:10.1212/WNL.0b013e3182267bd8
- Arnold, W. D., Kassar, D. & Kissel, J. T. Spinal muscular atrophy: Diagnosis and management in a new therapeutic era. Muscle and Nerve (2015). doi:10.1002/mus.24497
