Is ME CFS Spinal Muscular Atrophy (SMA)?

After a 70-year journey filled with multiple incorrect diagnoses and just as many inappropriate treatments, I finally found an answer to my progressive muscle weakness. Throughout this time, I faced insults and was labeled lazy for my inability to walk long distances or up hills, climb steps, or carry heavy loads. I couldn't ride a bike because sitting on the saddle was impossible. My school grades suffered due to insufficient performance in sports.

Instead of receiving comfort from my parents, I was pushed into hard work to strengthen my muscles. Doctors also advised me to exercise my muscles. My life continued with reduced activity, as I had to avoid or quit jobs where standing for extended periods was required or where I couldn't support my skeletal muscle weakness by bracing my elbows. The most excruciatingly painful and weakest period, when I could barely walk, occurred at age 20, during pregnancy.

In 2008, an MRI referred by my endocrinologist for permanent adrenal insufficiency unexpectedly revealed Chiari Malformation II. However, the subsequent surgery in 2009 brought no improvement. A more relevant clue emerged in 2010 from a DNA test indicating a genetic marker in the ACTN3 gene. An MRI in 2015 showed ankylosing spondylitis, several Tarlov cysts, stenosis at L4 and L5, spinal canal stenosis, and multilevel degenerative changes. A surgery on L4 and L5 led to sepsis, resulting in weeks on a PICC line for vancomycin, which further weakened my muscles.

Shortly afterward, another neurologist diagnosed Myalgia, which increased muscle weakness and a possible ME/CFS. This MRI provided further insights for a later diagnosis. In 2021, another MRI revealed what appeared to be muscles protruding from under the scapula, yet no further examination was pursued.

Other diagnoses included Myasthenia Gravis (MG), though an EMG, despite being very painful, showed no abnormal findings. However, the last diagnosis in 2021 was Post Polio. 

After watching a presentation by Professor Laing from the University of Western Australia, a new and more fitting explanation for my muscle weakness began to emerge. I started to read all available papers and searched my DNA for the SMN1, SMN2, SMN3, and SMN4 genes.

However, a genetic analysis from 2021 showed the presence of the SMN1 gene in my DNA. A new DNA test is now needed to confirm if I have both copies of SMN1 and SMN2. While reviewing scientific papers, I remembered my brother, a year younger than me, who passed away in 2014 from Amyotrophic Lateral Sclerosis (ALS), which is related to the SMN1 gene.

My second brother, who was two years younger than me, had to give up his profession as a restaurant cook due to his inability to stand for long periods and skeletal muscle weakness. He passed away from a heart attack in 2021.

Tragically, two of my siblings died shortly after birth, and SMN1 could have been the cause. Both of my parents experienced muscle weakness and found it challenging to walk long distances or uphill. This condition is an inherited recessive disease linked to the SMN1 gene, identified as Spinal Muscular Atrophy.

SMN1, SMN2, and UBA1 genes primarily affect motor neuron function and health, but they can also have implications for brain function, though the effects are less direct compared to their impact on motor neurons and play significant roles in neuromuscular health, and mutations in these genes can lead to disorders affecting movement and energy levels. 

Here's how each of them impacts these aspects:

1. SMN1 and SMN2 (Survival Motor Neuron genes):

   • These genes are crucial for the production of the SMN protein, which is essential for the maintenance and function of motor neurons. Motor neurons are nerve cells that send signals from the spinal cord to muscles, enabling movement.
   • Mutations or deletions in the SMN1 gene lead to spinal muscular atrophy (SMA), a condition characterized by progressive muscle weakness and atrophy. The severity of SMA is often influenced by the number of copies of the SMN2 gene, which can partially compensate for the loss of function in SMN1.
   • In SMA, as motor neurons degenerate and die, the muscles they control become weak and atrophy (shrink). This leads to difficulties in movements such as crawling, walking, sitting up, and controlling head movement. In severe cases, it can affect breathing and swallowing muscles.
   • The energy levels in individuals with SMA may be impacted due to reduced muscle mass and strength, leading to increased fatigue during physical activities.

2. UBA1 (Ubiquitin-like modifier activating enzyme 1):

   • UBA1 is involved in the ubiquitin-proteasome pathway, a system that helps regulate protein degradation and turnover in cells.
   • Mutations in the UBA1 gene cause X-linked spinal muscular atrophy (XL-SMA). This condition disrupts normal protein degradation, particularly affecting motor neurons.
   • The impact on motor neurons leads to symptoms similar to those in SMA, including muscle weakness and reduced mobility. The muscles do not receive proper signals from the affected neurons, leading to reduced movement and strength.
   • Energy levels may also be affected in XL-SMA, as the body's ability to perform normal muscular functions efficiently is compromised. Fatigue and reduced stamina can be significant challenges.

SMN1 and SMN2 are directly involved in the health of motor neurons and thus impact movement through muscle weakness and atrophy. UBA1, through its role in protein degradation, also affects motor neurons and consequently influences movement and energy levels, albeit via a different cellular pathway. 

Many types of spinal muscular atrophy are caused by changes in the same genes.
Less common SMA forms are caused by changes in other genes including the:

• VAPB gene on chromosome 20
• DYNC1H1 gene on chromosome 14
• BICD2 gene on chromosome 9
• UBA1 gene on the X chromosome
  

 

How do you read SMA results?

Detection of 0 copies of SMN1 is consistent with a diagnosis of SMA. Detection of 1 copy of SMN1 is consistent with being a carrier for SMA. If 2 copies of SMN1 are detected and the g. 27134 T>G variant is present, the individual's chances of being a carrier may be increased.

What is the blood test for SMA?

A simple blood draw test can identify an estimated 95% of all SMA cases by testing for deletion or mutation of both SMN1 genes.

What are the methods of SMA testing?

Traditionally, SMA testing and carrier testing are done with polymerase chain reaction (PCR) based assays, such as quantitative PCR (qPCR),¹⁹ multiplex ligation-dependent probe amplification (MLPA),^20,21 and digital PCR. These methods primarily determine the copy number of SMN1 based on the c.
 

Physical test: Becker muscular dystrophy.

Muscle weakness of the lower body, including the legs and pelvis area, slowly gets worse, causing:

• Difficulty walking that gets worse over time; by age 25 to 30, the person is usually unable to walk.
• Frequent falls.
• Difficulty getting up from the floor and climbing stairs.
• Difficulty with running, hopping, and jumping.

Where is SMN protein expressed?

SMN is found in the cytoplasm and nucleus. The nuclear form is located in structures termed gems. Using a panel of anti-SMN antibodies, we demonstrate that the SMN protein is expressed from both the SMN^T and SMN^C genes

 

What is the difference between SMA and SMN?

Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder characterized by loss of motor neurons and muscle atrophy, generally presenting in childhood. SMA is caused by low levels of the survival motor neuron protein (SMN) due to inactivating mutations in the encoding gene SMN1.

In my chromosome 5 found: rs397514518  =  22323744 Genotype-phenotype relationship in 2 SMA III patients with novel mutations in the Tudor domain.

rs75030631, rs104893931, rs104893927, i500573, rs397514517, i500574, rs76163360

rs104893931, rs104893927, rs15580564
Molecular and functional analysis of intragenic SMN1 mutations in patients with spinal muscular atrophy. https://pubmed.ncbi.nlm.nih.gov/15580564/

9147655 Missense mutation clustering in the survival motor neuron gene: a role for a conserved tyrosine and glycine rich region of the protein in RNA metabolism? https://pubmed.ncbi.nlm.nih.gov/9147655/

9158159 Missense mutations in exon 6 of the survival motor neuron gene in patients with spinal muscular atrophy (SMA). https://pubmed.ncbi.nlm.nih.gov/9158159/

 Genotype-phenotype relationship in 2 SMA III patients with novel mutations in the Tudor domain
https://pubmed.ncbi.nlm.nih.gov/22323744/

Does everyone have SMN1?

Everybody has two copies of the SMN1 gene – one inherited from each parent. People with SMA have a gene change in both copies of the SMN1 gene. This is what is called an 'autosomal recessive' inheritance. The parents of a person with SMA each carry one copy of the changed SMN1 gene and are known as 'carriers'.

Is having 2 copies of SMN1 good?

Carrier screening results for SMA are reported as the number of healthy copies of SMN1 a person has: If you have two copies of the healthy gene, it means that you have a reduced risk of being a carrier. If you have one healthy copy of SMN1, it means the other copy is faulty and you are a carrier.

 

Why is SMN protein important?

SMN also plays an important role in DNA repair, transcription, pre-mRNA splicing, histone mRNA processing, translation, selenoprotein synthesis, macromolecular trafficking, stress granule formation, cell signaling and cytoskeleton maintenance.  Diverse role of Survival Motor Neuron Protein

 

AMPK is a highly conserved sensor of intracellular adenosine nucleotide levels that is activated when even modest decreases in ATP production result in relative increases in AMP or ADP. In response, AMPK promotes catabolic pathways to generate more ATP, and inhibits anabolic pathways.
See: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3249400/

Abnormalities of AMPK Activation and Glucose Uptake in Cultured Skeletal Muscle Cells from Individuals with Chronic Fatigue Syndrome: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0122982

Other Names for this gene: https://medlineplus.gov/genetics/gene/smn1/#synonyms

SMN1 and SMN2 Publication:

The Neuromuscular Junction with Dr. Tarnopolsky
https://www.youtube.com/@Dr.MarkTarnopolsky

Long-term efficacy and safety of nusinersen in adults with 5q spinal muscular atrophy: a prospective European multinational observational study
https://www.thelancet.com/journals/lanepe/article/PIIS2666-7762(24)00028-0/fulltext

Understanding Spinal Muscular Atrophy (SMA)
https://www.youtube.com/watch?v=5mI_ZsWkkc4&t=15s

Spinal Muscular Atrophy
https://www.youtube.com/watch?v=X6aVh7S5izg

Mechanism of Disease: SMA
https://www.youtube.com/watch?v=7HBTw9z4h4Q

Spinal Muscular Atrophy | Mechanism & Presentation
https://www.youtube.com/watch?v=7HBTw9z4h4Q

SMN1 gene
https://medlineplus.gov/genetics/gene/smn1/

Spinal muscular atrophy (Genetics)
https://medlineplus.gov/genetics/condition/spinal-muscular-atrophy/

Spinal Muscular Atrophy
https://www.ninds.nih.gov/health-information/disorders/spinal-muscular-atrophy

Spinal Muscular Atrophy (SMA)
https://www.cdc.gov/nceh/dls/nsmbb_sma.html

What is spinal muscular atrophy?
https://www.genome.gov/Genetic-Disorders/Spinal-Muscular-Atrophy

Infantile-onset X-linked spinal muscular atrophy
https://www.ncbi.nlm.nih.gov/medgen/C1844934

Dissecting the structural and functional impact of SNPs located in the spinal muscular atrophy associated gene SMN1 using in silico analysis:
https://www.sciencedirect.com/science/article/abs/pii/S2452014419300305

SURVIVAL OF MOTOR NEURON 1; SMN1:
https://omim.org/entry/600354#allelicVariants

Genetic test laboratories:  https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=6606[geneid]&_ga=2.154236664.1357313295.1706712152-765385979.1702538242

ClinVar: https://www.ncbi.nlm.nih.gov/clinvar?term=SMN1[gene]&_ga=2.250163270.1357313295.1706712152-765385979.1702538242

© 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