Understanding Spinal Muscular Atrophy (SMA) and the related SNM Protein

By SWA

Spinal Muscular Atrophy (SMA) is a genetic neuromuscular disorder characterized by the progressive weakening and wasting of voluntary muscles due to the loss of motor neurons. This condition primarily affects muscles involved in movement, including those used for walking, sitting, arm movement, and head control, and can also impact breathing and swallowing. SMA is most commonly caused by mutations in the SMN1 gene and is inherited in an autosomal recessive manner. The severity of SMA can be modified by the number of copies of the SMN2 gene.

SMA presents in several types, which vary based on the age of onset and severity of symptoms. The condition can manifest from infancy to adulthood, with SMA type 0 being the most severe form, apparent before birth, and SMA type IV being a milder form beginning in early adulthood. Additional variants like SMA-PME and SMARD1 are linked to changes in other genes. Symptoms include poor head control, scoliosis, joint contractures, and difficulties in swallowing and breathing.

Diagnosis is primarily based on clinical symptoms and confirmed through genetic testing. The disease's progression leads to significant complications such as restrictive lung disease, poor weight gain, and skeletal deformities. However, recent advances in targeted treatments are altering the natural progression of SMA, offering hope for improved outcomes.

For more information, please visit the Spinal Muscular Atrophy (SMA) page on MalaCards.

Introduction to Spinal Muscular Atrophy (SMA) and the SMN Genes

Spinal Muscular Atrophy (SMA) is a rare genetic disorder that primarily targets motor neurons—the nerve cells within the spinal cord responsible for controlling muscle movements. While SMA does not affect cognitive abilities, it severely impacts basic physical functions such as walking, breathing, and swallowing. A comprehensive understanding of SMA involves recognizing how the brain, nerves, and muscles interact, as well as the critical role of the SMN (Survival Motor Neuron) protein and its related genes, SMN1, SMN2, SMN3, and SMN4.

The Role of Motor Neurons and the SMN Protein

The brain communicates with muscles through motor neurons, which relay movement signals that dictate muscle contractions. The SMN protein is vital in maintaining the health of these motor neurons. The SMN protein is part of a complex involved in processing molecules called messenger RNA (mRNA), which are the genetic blueprints for protein production within cells. Proper mRNA processing is crucial because it ensures that proteins, including those necessary for motor neuron function, are correctly synthesized. Without sufficient SMN protein, motor neurons begin to deteriorate and die, leading to muscle weakening and atrophy due to lack of use. Learn more about the function of SMN protein.

Genetic Mutations Behind SMA

SMA is primarily caused by a genetic mutation in the SMN1 gene, which is crucial for producing the majority of the SMN protein. Mutations in this gene lead to a severe reduction in functional SMN protein, critical for motor neuron survival. In addition to SMN1, most people with SMA have one or more copies of a nearly identical backup gene known as SMN2. However, due to subtle differences in the gene, SMN2 produces the SMN protein with much less efficiency. The severity of SMA symptoms is often influenced by the number of SMN2 gene copies: more copies generally result in higher levels of SMN protein and thus milder symptoms.

The zinc finger protein ZPR1 is a potential modifier of spinal muscular atrophy 

We report that the reduced ZPR1 expression causes increase in the loss of motor neurons, hypermyelination in phrenic nerves, increase in respiratory distress and disease severity and reduces the lifespan of SMA mice.
 
Zinc level Test:
  1. Serum or Plasma Zinc Test,
  2. Urine Zinc Test,
  3. Hair or Nail Zinc Test,
  4. Zinc Taste Test (Zinc Tally Test).
Testing your zinc levels can help ensure that you are maintaining an appropriate balance, which is critical for overall health and well-being.
Gene dbSNP 133 citations for rs964184: https://www.ncbi.nlm.nih.gov/snp/rs964184#publications

Function of the SMN Protein

Within cells, the SMN protein plays a crucial role in the formation and maintenance of motor neurons. It is particularly involved in processing pre-mRNA, the initial form of mRNA that undergoes several modifications to become fully functional. This process is essential in neurons, where rapid and accurate mRNA processing is required for the maintenance of cellular health. A deficiency in SMN protein disrupts these processes, causing motor neuron degeneration and subsequent muscle weakness. Explore more about the function of SMN protein.

Types of SMA and Disease Severity

SMA presents in various forms, categorized into four primary types based on the age at which symptoms first appear and the highest motor abilities achieved. The severity of each type is linked to the number of SMN2 gene copies, as these copies influence the level of SMN protein production:

  1. Type 1 (Severe SMA): Symptoms usually manifest within the first six months of life. Infants with Type 1 SMA often cannot sit independently and have significant respiratory and feeding challenges. 

  2. Type 2 (Intermediate SMA): Symptoms typically appear between 6 and 18 months of age. Individuals with Type 2 SMA can sit without support but are unable to walk independently.

  3. Type 3 (Mild SMA): Known as Kugelberg-Welander disease, symptoms appear after 18 months, often during childhood or adolescence. People with Type 3 SMA can walk but may lose this ability over time. 

  4. Type 4 (Adult-Onset SMA): The mildest form of SMA, with symptoms typically emerging in adulthood. Individuals with Type 4 SMA experience mild motor impairments and can often maintain mobility throughout life. 

The number of SMN2 gene copies plays a critical role in determining disease severity; more SMN2 copies generally correlate with milder symptoms and a later onset of the disease.

Respiratory Challenges in SMA

SMA can severely affect respiratory function due to weakened intercostal muscles, which are critical for normal breathing. This muscle weakness disrupts regular breathing patterns, leading to complications such as underdeveloped lungs and weakened respiratory muscles. Patients with SMA often require respiratory support, including non-invasive ventilation, to manage these challenges. Learn more about how SMA affects the lungs.

The Two-Neuron Pathway in Movement

Movement in the body involves a two-neuron pathway comprising upper and lower motor neurons. Upper motor neurons originate in the brain and communicate using glutamate, a neurotransmitter that activates lower motor neurons located in the spinal cord and brainstem. Lower motor neurons, which use the neurotransmitter acetylcholine, then relay signals to muscles, causing them to contract and produce movement. There are three main types of lower motor neurons: somatic motor neurons (responsible for voluntary movements), special visceral efferent neurons (controlling muscles involved in chewing and facial expressions), and general visceral motor neurons (regulating involuntary muscle control).
Read more on the function of motor neurons.

What is SMN gene test?
Quantitative SMN1 gene dosage analysis is used to identify carriers with one copy of SMN1 from non-carrier individuals with 2 or more copies of SMN1. Carrier testing has been valuable to families with a history of SMA who are at risk of having affected offspring.

Spinal Muscular Atrophy: Mutations, Testing, and Clinical Relevance
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846873/

Muscle Disorder https://www.sciencedirect.com/topics/neuroscience/muscle-disorder

Advances in Treatments in Muscular Dystrophies and Motor Neuron Disorders
https://www.sciencedirect.com/science/article/abs/pii/S0733861920300724

Impact and Hope for the Future

Living with SMA presents significant challenges, not only for individuals with the condition but also for their families and caregivers. SMA requires a comprehensive, multidisciplinary approach to manage mobility, respiratory function, nutrition, and overall quality of life. However, advancements in genetic research, including gene therapy, SMN-enhancing drugs, and novel supportive care strategies, have brought new hope. These emerging treatments are transforming the outlook for those with SMA, providing improved outcomes and enhancing the quality of life for patients.

With ongoing research and better understanding of SMA’s genetic mechanisms, there is growing potential for more effective treatments. By raising awareness, supporting research, and advocating for innovative therapies, we can make a meaningful difference in the lives of those affected by this complex and life-altering condition.

News: 

Rare genetic disorder treated in womb for the first time
https://www.nature.com/articles/d41586-025-00534-0?linkId=13041268

First-in-human study of epidural spinal cord stimulation in individuals with spinal muscular atrophy https://www.nature.com/articles/s41591-024-03484-8

Learn About Spinal Muscular Atrophy

Spinal Muscular Atrophy 2019: Later Onset Spinal Muscular Atrophy
https://www.youtube.com/watch?v=W3MJq9IzSFc

Explore more about SMA and discover how ongoing research continues to pave the way for new treatments and hope for the future.

Improving Outcomes in Spinal Muscular Atrophy:
https://www.youtube.com/watch?v=xNZs7b1_XDk

My personal experience with SMA:
https://swaresearch.blogspot.com/2024/01/is-me-cfs-spinal-muscular-atrophy.html


© 2000-2025 Sieglinde W. Alexander. All writings by Sieglinde W. Alexander have a fife year copy right.
Library of Congress Card Number: LCN 00-192742 ISBN: 0-9703195-0-9

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