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

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My Journey Toward Understanding Spinal Muscular Atrophy (SMA)

Today, I better understand why Spinal Muscular Atrophy (SMA) received so little attention, particularly during the 1950s. This complex and debilitating genetic disorder was poorly understood, and patients’ symptoms could easily be minimized, misinterpreted, or dismissed.

Even today, SMA can present significant diagnostic challenges, particularly in adults with complex medical histories. In my own experience, comprehensive investigations into the underlying cause of progressive muscle weakness were not always pursued.

A Long and Complicated Diagnostic Journey

In 2008, while being investigated for permanent adrenal insufficiency, an MRI ordered by my endocrinologist unexpectedly revealed Chiari Malformation II.

 I underwent surgery in 2009, but unfortunately, my symptoms did not improve.

In 2010, a DNA test identified a genetic marker involving the ACTN3 gene. Further information about ACTN3 and its possible relationship to neuromuscular disorders can be explored here:

https://www.malacards.org/search/results?q=ACTN3%20gene%20and%20Spinal%20Muscular%20Atrophy%20(SMA)

A 2015 MRI revealed several additional abnormalities, including ankylosing spondylitis, multiple Tarlov cysts, stenosis at L4 and L5, narrowing of the spinal canal, and widespread degenerative changes.

I subsequently underwent surgery at L4 and L5. The procedure was complicated by sepsis, requiring weeks of treatment with vancomycin through a PICC line. My muscles became even weaker during this period, yet no additional investigation into the underlying muscle weakness was undertaken.

Shortly afterward, another neurologist diagnosed me with myalgia and possible ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome). Once again, no further investigations were pursued.

In 2021, another MRI showed what appeared to be muscles protruding from beneath my scapula. To me, this raised further concerns about significant skeletal muscle weakness, but no additional examination followed.

Subsequent diagnoses included Myasthenia Gravis (MG), although a painful EMG did not identify abnormal nerve activity. The most recent diagnosis, made in 2022, was Post-Polio Syndrome.
https://swaresearch.blogspot.com/2024/09/understanding-spinal-muscular-atrophy.html

Motor Neuron Loss and the Brain’s Ability to Compensate

An important area of research concerns the brain’s ability to compensate—or effectively “rewire” its motor networks—when motor neurons are lost. Researchers may be able to measure aspects of this compensation non-invasively, potentially providing useful information for understanding and monitoring disorders involving motor neuron loss, including SMA.

Researchers have studied adults who experienced polio during childhood because poliovirus can damage the same broad class of motor neurons that is affected in SMA.

In these studies, researchers simultaneously measured brain electrical activity using electroencephalography (EEG) and muscle activity using electromyography (EMG) while participants performed a simple finger-grip task.

They then calculated cortico-muscular coherence (CMC)—a measure of the synchronization between activity in the brain’s motor regions and the muscles those regions control.

Research of this kind may provide valuable insights into how the nervous system compensates for motor neuron loss and whether those compensatory mechanisms can be measured and monitored over time.

The Impact of COVID-19

COVID-19 in early 2021 significantly exacerbated my muscle weakness, particularly in my skeletal muscles. Lifting my arms became increasingly difficult, and walking became excruciatingly painful. Recovery after physical exertion could take nearly a week.

This deterioration prompted me to look more deeply into possible explanations for my longstanding symptoms.

Discovering a Possible Connection to SMA

After watching a presentation by Professor Laing from the University of Western Australia, I began reconsidering my family history and my own symptoms.

I remembered my brother, who died in 2014 from Amyotrophic Lateral Sclerosis (ALS). His illness, together with the history of muscle weakness in my family, led me to investigate inherited motor neuron and neuromuscular disorders more closely.

I began to suspect Spinal Muscular Atrophy (SMA) and immersed myself in the available research.

As part of that investigation, I analyzed my DNA for SMN1, SMN2, SMN3, and SMN4. A genetic test performed in 2021 indicated the presence of the SMN1 gene, but additional clinical genetic testing would be necessary to determine the precise SMN1/SMN2 copy number and whether other potentially relevant genetic variants are present.

A Family History of Muscle Weakness

My second brother also experienced significant muscle weakness. He eventually had to give up his profession as a restaurant cook because he could no longer tolerate standing for extended periods. He died from a heart attack in 2021.

Tragically, two of my siblings died shortly after birth. The causes remain uncertain.

Both of my parents also struggled with muscle weakness and found it difficult to walk long distances or uphill.

Taken together, this family history raises important questions about whether an inherited neuromuscular condition could have affected multiple generations of my family. Determining whether SMA or another genetic neuromuscular disorder is responsible, however, requires appropriate clinical and genetic testing.

What Is Spinal Muscular Atrophy?

Spinal Muscular Atrophy (SMA) is a genetic neuromuscular disorder characterized by progressive muscle weakness and wasting caused by the loss of motor neurons.

These motor neurons control voluntary muscles involved in functions such as walking, sitting, moving the arms, and controlling the head. Depending on the severity and form of the disease, muscles involved in breathing and swallowing can also be affected.

The most common form of SMA is associated with pathogenic changes affecting the SMN1 gene and is inherited in an autosomal recessive manner. The number of copies of the related SMN2 gene can modify disease severity, although it does not by itself determine an individual’s clinical course.

SMA encompasses a spectrum of disease. Historically, it has been classified into types according to the age at which symptoms begin and the highest motor milestones achieved.

The spectrum ranges from SMA type 0, which can become apparent before birth, to SMA type IV, which generally begins in adulthood and is usually milder.

There are also rarer SMA-like and inherited motor neuron disorders associated with other genes.

Symptoms can include:

  • Progressive muscle weakness and wasting

  • Difficulty sitting, standing, or walking

  • Poor head control

  • Scoliosis and other skeletal abnormalities

  • Joint contractures

  • Difficulty swallowing

  • Respiratory muscle weakness

  • Reduced endurance and mobility

Diagnosis is based on clinical evaluation and is generally confirmed through appropriate molecular genetic testing.

The progression and complications of SMA vary considerably between individuals. Fortunately, advances in targeted therapies have dramatically changed the treatment landscape for several forms of SMA.

Could ME/CFS, SMA, and Very Long-Chain Fatty Acids Be Connected?

An intriguing question is whether there could be an unexplored relationship between ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome), Spinal Muscular Atrophy (SMA), and Very Long-Chain Fatty Acids (VLCFAs).

At present, this appears to be an area in which substantially more research would be required before any direct relationship could be established.

Further discussion can be found here:

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 on Motor Neuron Function

The SMN1, SMN2, and UBA1 genes are associated with important cellular processes that can affect motor neuron and neuromuscular function.

SMN1 and SMN2 contribute to production of the survival motor neuron (SMN) protein. The SMN protein has an essential role in the assembly of small nuclear ribonucleoproteins (snRNPs), which are important for RNA processing and pre-mRNA splicing.

SMN also participates in processes important for neuronal development and maintenance, including the health and function of axons and other neuronal structures.

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

SMN1 and SMN2 — Survival Motor Neuron Genes

SMN1 and SMN2 are closely related genes involved in the production of SMN protein.

  • SMN1 normally produces most of the full-length, functional SMN protein.

  • Loss or pathogenic alteration of both functional copies of SMN1 is responsible for the vast majority of cases of 5q SMA.

  • SMN2 also produces SMN protein, but because of differences in RNA splicing, much of its transcript does not produce stable, full-length protein.

  • A higher SMN2 copy number is often associated with a less severe SMA phenotype, although the relationship is not absolute.

  • When SMN protein levels become insufficient, motor neurons are particularly vulnerable.

  • As motor neurons deteriorate, the muscles they control become progressively weaker and may eventually atrophy.

  • Depending on disease severity, this can affect sitting, standing, walking, arm movement, swallowing, and breathing.

Reduced muscle strength and endurance can also make physical activity substantially more demanding.

UBA1 — Ubiquitin-Like Modifier Activating Enzyme 1

UBA1 plays a fundamental role in the ubiquitin system, which helps regulate protein turnover and numerous other cellular processes.

Certain pathogenic variants involving UBA1 have been associated with a rare X-linked form of spinal muscular atrophy (XL-SMA).

Disruption of normal cellular protein regulation can have significant consequences for motor neuron health and neuromuscular function.

Affected individuals may experience symptoms including muscle weakness, reduced mobility, and other manifestations of motor neuron dysfunction.

Other Genes Associated With SMA-Like Disorders

Beyond SMN1 and SMN2, several rare hereditary motor neuron disorders and SMA phenotypes have been associated with other genes, including:

  • VAPB — chromosome 20

  • DYNC1H1 — chromosome 14

  • BICD2 — chromosome 9

  • UBA1 — X chromosome

Because different genetic disorders can produce overlapping symptoms, identifying the responsible gene can be important for establishing an accurate diagnosis.

Understanding SMA Genetic Testing

Genetic testing is central to diagnosing 5q SMA, but interpreting the results can be more complicated than simply determining whether an SMN1 gene is “present.”

Testing may examine the number of SMN1 exon 7 copies, identify deletions, and, when necessary, look for sequence variants that standard copy-number testing may not detect.

Common laboratory methods include:

  • Quantitative PCR (qPCR)

  • Multiplex ligation-dependent probe amplification (MLPA)

  • Digital PCR

  • DNA sequencing or other molecular methods when clinically indicated

A result showing zero functional SMN1 exon 7 copies is strongly associated with 5q SMA. A single copy generally indicates carrier status, while two or more copies substantially reduce carrier probability but do not always eliminate it because two copies can sometimes occur on the same chromosome.

For this reason, genetic results should ideally be interpreted by a neurologist, clinical geneticist, or genetic counselor familiar with SMA.

SMN Protein Expression and Function

SMN protein is found in both the cytoplasm and nucleus of cells. Within the nucleus, SMN is associated with structures known as gems.

Its best-established function involves the assembly of snRNP complexes required for RNA splicing, although research has identified additional roles for SMN in neuronal and cellular biology.

The particular vulnerability of motor neurons to insufficient SMN protein remains an important area of scientific investigation.

Distinguishing SMA From Other Neuromuscular Conditions

SMA belongs to a broad group of neuromuscular and motor neuron disorders. Symptoms such as progressive weakness, muscle wasting, fatigue, mobility difficulties, respiratory impairment, and reduced endurance can overlap with numerous other conditions.

For detailed research concerning SMN1 variants, see Molecular and functional analysis of intragenic SMN1 mutations on PubMed.

This overlap makes comprehensive neurological assessment and appropriate genetic testing particularly important, especially when symptoms begin in adulthood or when an individual has already received several different diagnoses.

Genotype–Phenotype Associations

Researchers continue to investigate how different SMN1 variants and other genetic modifiers influence SMA severity and clinical presentation.

Specific variants and single nucleotide polymorphisms have been investigated for possible genotype–phenotype relationships.

Additional studies can be found here and here.

Inheritance

Most people have two copies of SMN1, generally one inherited from each parent.

Classic 5q SMA follows an autosomal recessive inheritance pattern, meaning that disease usually develops when both inherited SMN1 copies are nonfunctional or otherwise unable to provide sufficient functional SMN protein.

A person with one nonfunctional SMN1 copy and one functional copy is generally considered a carrier.

Because SMN1 copy number and configuration can complicate carrier testing, professional interpretation of genetic results is particularly important when there is a strong family history of neuromuscular disease.

Why the SMN Protein Matters

The survival motor neuron protein is essential for normal cellular function and is particularly important for motor neuron survival.

Research into SMN biology has greatly expanded our understanding of SMA and has contributed directly to the development of treatments designed to increase functional SMN protein or compensate for the underlying genetic defect.

Conclusion

My own medical history, together with a family history of skeletal muscle weakness and Chiari I malformation, has taken me on a long and often difficult journey of questioning, searching for answers, and trying to understand how these pieces might fit together. Over time, this has led me to undertake extensive research and investigation in an effort to better understand both my own condition and the patterns that appear within my family.

The SMN1 and SMN2 genes are central to the biology of 5q Spinal Muscular Atrophy, while genes such as UBA1, VAPB, DYNC1H1, and BICD2 are associated with rarer inherited motor neuron and SMA-like disorders.

At the same time, symptoms such as muscle weakness, fatigue, reduced mobility, and exercise intolerance can occur in many different neurological, neuromuscular, metabolic, and systemic conditions. Personal DNA data can raise useful questions, but it cannot by itself establish an SMA diagnosis.

For individuals with progressive muscle weakness and a significant family history, comprehensive clinical genetic testing, neurological assessment, and specialist interpretation may provide a clearer answer than consumer or raw DNA analysis alone.

Continued research into motor neuron disorders, genetic modifiers, metabolic abnormalities, viral triggers, and mechanisms of neurological compensation may ultimately reveal connections that are not yet fully understood.

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:


Picture: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2853768/

© 2000-2030 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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