Is ME CFS connected to Spinal Muscular Atrophy (SMA)?

By SWA

Today, I understand why Spinal Muscular Atrophy (SMA) received little attention, particularly in the mid-50s. This complex and debilitating genetic illness was poorly understood, and patients' symptoms were often minimized or even dismissed.
For more information, please visit the Spinal Muscular Atrophy (SMA) page on MalaCards.

Even now, many neurologists lack detailed knowledge of SMA, and comprehensive examinations mentioned in research are rarely pursued. After a 70-year journey filled with misdiagnoses and ineffective treatments, I finally discovered the true cause of my progressive muscle weakness. Throughout this time, I endured insults and was labeled lazy because of my inability to walk long distances, climb stairs, or carry heavy loads. I couldn’t ride a bike because I couldn’t sit on the saddle, and my school performance suffered due to struggles in sports.

Instead of support, my parents urged me to work harder to strengthen my muscles, and doctors advised me to exercise more. Consequently, I led a restricted life, avoiding or leaving jobs that required prolonged standing or tasks that I couldn't perform due to my skeletal muscle weakness. The most challenging period was during my pregnancy at age 20 when I could barely walk.

In 2008, while investigating permanent adrenal insufficiency, an MRI ordered by my endocrinologist unexpectedly revealed Chiari Malformation II. However, surgery in 2009 brought no improvement. In 2010, a DNA test showed a genetic marker in the ACTN3 gene:
https://www.malacards.org/search/results?q=ACTN3%20gene%20and%20Spinal%20Muscular%20Atrophy%20(SMA)

A 2015 MRI revealed ankylosing spondylitis, multiple Tarlov cysts, stenosis at L4 and L5, spinal canal narrowing, and widespread degenerative changes. Surgery on L4 and L5 led to sepsis, requiring weeks of treatment with vancomycin via a PICC line, further weakening my muscles, yet no additional tests were conducted.

Shortly after, another neurologist diagnosed me with myalgia and possible ME/CFS, but no further investigations were pursued. In 2021, another MRI showed muscles appearing to protrude from under my scapula, a clear sign of skeletal muscle weakness, but again, no further examination followed.

Subsequent diagnoses included Myasthenia Gravis (MG), though a painful EMG found no abnormal nerve activity. The most recent diagnosis in 2021 was Post-Polio Syndrome.

COVID-19 in early 2021 exacerbated my muscle weakness, especially in my skeletal muscles, making it difficult to lift my arms. Walking became excruciatingly painful, and recovery took nearly a week.

After watching a presentation by Professor Laing from the University of Western Australia. The memory of my brother, who died in 2014 from Amyotrophic Lateral Sclerosis (ALS)—a condition related to the SMN1 gene—came to mind. So, I began to suspect Spinal Muscular Atrophy (SMA) and immersed myself in related research. I analyzed my DNA for the SMN1, SMN2, SMN3, and SMN4 genes. A genetic test from 2021 indicated the presence of the SMN1 gene, but a new DNA test is now needed to confirm if I have  in addition SMN3.

My second brother, who had to give up his profession as a restaurant cook due to his inability to stand for long periods and muscle weakness, died of a heart attack in 2021. Tragically, two of my siblings passed away shortly after birth, possibly due to SMN1-related complications. Both of my parents struggled with muscle weakness and found it difficult to walk long distances or uphill. SMA, an inherited recessive disorder linked to the SMN1 gene, had silently affected our family for generations.

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.

Has there been any research exploring a potential connection between ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome), Spinal Muscular Atrophy (SMA), and Very Long-Chain Fatty Acids (VLCFAs)?
So far, it seems this possibility has not been thoroughly investigated.

https://swaresearch.blogspot.com/2024/10/very-long-chain-fatty-acids-vlcfas-and.html

Unless current scientific research expands to include viral and pathogenic causes, the complexities of ME/CFS will continue to remain a mystery.

The Impact of SMN1, SMN2, and UBA1 Genes on Motor Neuron and Brain Function

The SMN1, SMN2, and UBA1 genes primarily affect motor neuron function and health, but they also have secondary effects on brain function, although these are less direct. These genes play critical roles in neuromuscular health, and mutations in them can lead to disorders affecting movement, muscle strength, and energy levels.

The SMN complex, involving SMN1 and SMN2, is vital for the assembly of cellular machinery needed for pre-mRNA processing and is essential for the development of specialized nerve cell outgrowths called dendrites and axons. These structures are crucial for transmitting signals between neurons and from neurons to muscles, facilitating movement.

For more information on SMN1, see the MedlinePlus Genetics SMN1 page.

Roles and Impacts of SMN1, SMN2, and UBA1:

The Impact of SMN1, SMN2, and UBA1 Genes on Motor Neuron and Brain Function

The SMN1, SMN2, and UBA1 genes primarily affect motor neuron function and health, but they also have secondary effects on brain function, although these are less direct. These genes play critical roles in neuromuscular health, and mutations in them can lead to disorders affecting movement, muscle strength, and energy levels.

The SMN complex, involving SMN1 and SMN2, is vital for the assembly of cellular machinery needed for pre-mRNA processing and is essential for the development of specialized nerve cell outgrowths called dendrites and axons. These structures are crucial for transmitting signals between neurons and from neurons to muscles, facilitating movement.

For more information on SMN1, see the MedlinePlus Genetics SMN1 page.

Roles and Impacts of SMN1, SMN2, and UBA1:

SMN1 and SMN2 (Survival Motor Neuron genes):

  • These genes are crucial for producing the SMN protein, which is essential for maintaining and functioning motor neurons that transmit signals from the spinal cord to muscles, enabling movement.
  • Mutations or deletions in the SMN1 gene cause Spinal Muscular Atrophy (SMA), characterized by progressive muscle weakness and atrophy. The severity of SMA often depends on the number of SMN2 copies, which can partially compensate for the loss of SMN1 function.
  • As motor neurons degenerate and die in SMA, the muscles they control become weaker and atrophy, leading to difficulties in movements such as crawling, walking, sitting up, and controlling head movement. In severe cases, it can affect breathing and swallowing muscles.
  • Individuals with SMA may experience reduced energy levels due to decreased muscle mass and strength, resulting in increased fatigue during physical activities.

UBA1 (Ubiquitin-like modifier activating enzyme 1):

  • UBA1 is a critical component of the ubiquitin-proteasome pathway, which regulates protein degradation and turnover in cells.
  • Mutations in the UBA1 gene lead to X-linked Spinal Muscular Atrophy (XL-SMA), disrupting normal protein degradation processes, particularly in motor neurons.
  • The impact on motor neurons results in symptoms similar to SMA, including muscle weakness and reduced mobility. Muscles do not receive adequate signals from affected neurons, leading to diminished movement and strength.
  • In XL-SMA, energy levels may be compromised due to impaired muscular function, leading to fatigue and decreased stamina.

Other SMA-Related Genes:

Beyond SMN1 and SMN2, less common forms of SMA are caused by mutations in other genes, including:

  • VAPB (chromosome 20)
  • DYNC1H1 (chromosome 14)
  • BICD2 (chromosome 9)
  • UBA1 (X chromosome)

Understanding SMA Genetic Testing:

  • Reading SMA Test Results: Detection of 0 copies of SMN1 confirms an SMA diagnosis, while 1 copy indicates carrier status. Detection of 2 SMN1 copies with the g.27134 T>G variant suggests an increased risk of being a carrier.
  • SMA Blood Test: A blood test can identify about 95% of SMA cases by detecting deletions or mutations in SMN1 genes.
  • Testing Methods: Common methods include quantitative PCR (qPCR), multiplex ligation-dependent probe amplification (MLPA), and digital PCR, which assess the copy number of SMN1.

SMN Protein Expression and Function:

  • SMN protein is expressed in both the cytoplasm and nucleus of cells, with the nuclear form found in structures called gems. SMN protein, expressed from SMN1 and SMN2, plays a critical role in DNA repair, transcription, pre-mRNA splicing, cell signaling, and cytoskeleton maintenance.

Distinguishing SMA from Other Conditions:

  • SMA is a neuromuscular disorder characterized by the loss of motor neurons and muscle atrophy, typically presenting in childhood, and is caused by insufficient SMN protein due to mutations in SMN1. For detailed research on SMN1 mutations, you can refer to the Molecular and functional analysis of intragenic SMN1 mutations on PubMed.

Genotype-Phenotype Associations:

  • Notable mutations identified in SMA patients include variations like rs397514518 and other single nucleotide polymorphisms, which can influence disease severity and phenotype. More details can be found in the studies here and here.

Inheritance Patterns:

  • Everyone typically has two copies of the SMN1 gene, one from each parent. SMA results from mutations in both SMN1 copies, following an autosomal recessive inheritance pattern. Parents who carry one mutated copy are known as carriers.

Significance of SMN Protein:

  • SMN protein is crucial for numerous cellular functions, including energy production and intracellular signaling. It plays a significant role in maintaining overall neuromuscular health.

Conclusion:

The SMN1, SMN2, and UBA1 genes are essential for motor neuron integrity and neuromuscular function, with mutations leading to conditions that severely impact movement and energy. Comprehensive genetic testing and understanding of these genes can aid in diagnosing and managing these complex disorders.

Learn About Spinal Muscular Atrophy 

Update:  Spinal muscular atrophy:
https://www.uptodate.com/contents/spinal-muscular-atrophy/print

The Survival Motor Neuron Protein in Spinal Muscular Atrophy
https://academic.oup.com/hmg/article-abstract/6/8/1205/2901201?redirectedFrom=fulltext

Understanding Spinal Muscular Atrophy (SMA)
https://www.youtube.com/watch?v=5mI_ZsWkkc4&t=33s

Spinal Muscular Atrophy (SMA) Overview
https://www.youtube.com/watch?v=4EPF8EBiQyI

Sebastian’s Story: Initial SMA Symptoms and Assessment
https://www.youtube.com/watch?v=6e_AYJhW9Xo

SMN1 and SMN2 Publications:

An external file that holds a picture, illustration, etc. Object name is nihms183674f1.jpg
Picture: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2853768/

© 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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