How Many Known Illnesses Are Related to Muscle Weakness?

By SWA

There are hundreds of illnesses that can cause muscle weakness, involving genetic, epigenetic, autoimmune, metabolic, infectious, and toxic mechanisms.

1. Genetic Disorders (Inherited Conditions)

Genetic mutations directly impact muscle proteins, nerve function, or metabolic pathways, leading to muscle weakness.

Neuromuscular Disorders

Structural & Performance-Related Muscle Genes

  • ACTN3 Gene Deficiency (R577X Variant)
    • ACTN3 encodes α-actinin-3, a protein in fast-twitch muscle fibers used for power and speed.
    • The R577X mutation leads to α-actinin-3 deficiency, reducing fast-twitch muscle strength and potentially contributing to muscle weakness and endurance adaptations.
    • Individuals with two copies of the X allele (XX genotype) may experience:
      • Lower muscle power (e.g., reduced sprinting ability)
      • Increased muscle fatigue in high-intensity activities
      • Higher susceptibility to sarcopenia (age-related muscle loss)
    • This variant is common (~18% of people worldwide) but not typically disease-causing—it mainly influences muscle performance rather than leading to severe weakness.
      https://swaresearch.blogspot.com/2024/10/mitochondrial-hypertrophy-hyperfusion.html

Connective Tissue & Structural Disorders

  • Ehlers-Danlos Syndrome (EDS) – Collagen defects affecting muscle and joint stability
  • Marfan Syndrome – FBN1 gene mutation weakening connective tissue
  • Collagen VI-Related Myopathies – Ullrich congenital muscular dystrophy, Bethlem myopathy

2. Epigenetic Disorders (Gene Expression Dysregulation)

Epigenetic changes can alter gene expression without modifying the DNA sequence, leading to muscle weakness.

  • Facioscapulohumeral Muscular Dystrophy (FSHD) – Loss of DUX4 repression causing muscle degeneration
  • Beckwith-Wiedemann Syndrome (BWS) – IGF2/CDKN1C imprinting disorder affecting growth and muscle tone
  • Epigenetic Regulation in Myotonic Dystrophy (DM1, DM2) – Repeat expansions affecting RNA splicing

3. Autoimmune Diseases (Immune System Attacks on Muscles or Nerves)

The immune system mistakenly attacks muscles, nerves, or neuromuscular junctions, leading to weakness.

  • Myasthenia Gravis (MG) – Antibodies blocking acetylcholine receptors
  • Polymyositis (PM) – Inflammatory muscle disease
  • Dermatomyositis (DM) – Immune attack on muscles and skin
  • Inclusion Body Myositis (IBM) – Progressive inflammatory muscle degeneration
  • Multiple Sclerosis (MS) – Autoimmune attack on the nervous system

4. Metabolic and Endocrine Disorders (Impaired Energy Production)

Metabolic imbalances disrupt energy supply to muscles, leading to weakness.

  • Hypothyroidism & Hyperthyroidism – Thyroid hormone imbalances affecting muscle metabolism
  • Cushing’s Syndrome – Cortisol excess leading to muscle wasting
  • Diabetes (Type 1 & 2) – Neuropathy and glucose metabolism issues
  • Mitochondrial Myopathies – Mutations in mitochondrial DNA affecting energy production
  • Glycogen Storage Diseases (GSDs) – McArdle’s Disease (GSD V), Pompe Disease (GSD II)

5. Infectious Diseases (Viral, Bacterial, and Parasitic Infections)

Certain infections damage muscles or nerves, leading to long-term weakness.

  • Polio/Post-Polio Syndrome (PPS) – Poliovirus-induced motor neuron loss
  • Guillain-Barré Syndrome (GBS) – Autoimmune attack on peripheral nerves post-infection
  • HIV/AIDS – Muscle wasting and neuropathy
  • Lyme Disease – Bacterial infection causing fatigue and weakness
  • Botulism – Toxin blocking neuromuscular signals

6. Toxic and Drug-Induced Muscle Disorders

Certain substances damage muscles or interfere with neuromuscular function.

  • Statin-Induced Myopathy – Muscle pain and weakness from cholesterol-lowering drugs
  • Chronic Alcohol Myopathy – Muscle atrophy from long-term alcohol abuse
  • Steroid Myopathy – Muscle breakdown due to prolonged corticosteroid use
  • Chemotherapy-Induced Weakness – Neuromuscular side effects from cancer treatments
  • Heavy Metal Toxicity – Lead, mercury, arsenic poisoning affecting nerves and muscles

7. Neurological Disorders Affecting Muscle Control

Neurological damage impairs motor neuron signaling to muscles, leading to weakness.

  • Stroke – Muscle impairment due to brain damage
  • Parkinson’s Disease – Movement disorder causing rigidity and weakness
  • Cerebral Palsy (CP) – Muscle spasticity and weakness from brain injury at birth
  • Huntington’s Disease – Progressive neurodegeneration affecting movement
  • Test: Elevated Creatine Kinase in Patients with Peripheral Neuropathy (P3.4-021)
    https://www.nature.com/articles/s41598-022-27289-2

8. Other Conditions Contributing to Muscle Weakness

Some disorders cause generalized muscle weakness due to chronic fatigue, deconditioning, or systemic dysfunction.

  • Chronic Fatigue Syndrome (ME/CFS) – Persistent fatigue with muscle weakness

  • Key Pathophysiological Role of Skeletal Muscle Disturbance in Post COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Accumulated Evidence
    https://onlinelibrary.wiley.com/doi/10.1002/jcsm.13669

    Key Pathophysiological Role of Skeletal Muscle Disturbance in Post COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Accumulated Evidence
    https://pubmed.ncbi.nlm.nih.gov/39727052/     

  • Fibromyalgia – Widespread muscle pain and fatigue
  • Prolonged Bed Rest or Deconditioning – Muscle atrophy from inactivity

Conclusion

There are hundreds of conditions that contribute to muscle weakness, involving genetic mutations (like ACTN3 and DYSF), epigenetic changes, autoimmune reactions, metabolic imbalances, infections, toxins, and neurological dysfunctions.

  • ACTN3 gene deficiency (R577X variant) affects muscle power and endurance, making individuals more prone to fatigue, reduced fast-twitch muscle strength, and age-related sarcopenia.
  • If you're experiencing persistent muscle weakness, genetic testing, blood tests, EMG (electromyography), muscle biopsy, or MRI scans may help determine the cause.

© 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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