Bethlem Myopathy and the Role of the Sarcolemma

By SWA

Introduction

Bethlem myopathy (BM) is a rare, inherited muscular disorder that primarily affects skeletal muscles and connective tissue. 

It is classified as a mild congenital muscular dystrophy, meaning it causes progressive muscle weakness and joint stiffness (contractures) but is generally less severe than other muscular dystrophies. A key aspect of this disease is the interaction between collagen and the sarcolemma (the muscle cell membrane), which plays a crucial role in muscle function and stability.

1. Causes & Genetics

Mutations in Collagen VI Genes

Bethlem myopathy is caused by mutations in the COL6A1, COL6A2, or COL6A3 genes, which encode Collagen Type VI. This type of collagen is essential for the stability and function of the extracellular matrix (ECM), which surrounds muscle fibers and connects them to the sarcolemma.

How Collagen VI Mutations Lead to Muscle Weakness

  • Defective Collagen VI production → Weakens the ECM, reducing mechanical support for the sarcolemma.
  • Weakened ECM-Sarcolemma Connection → Muscle fibers become more prone to stress and damage.
  • Disruption in Muscle Regeneration → Affects satellite cells (muscle stem cells), impairing muscle repair.

Inheritance Pattern

  • Autosomal Dominant (most common) – One mutated copy of COL6A1, COL6A2, or COL6A3 is enough to cause the disease.
  • Autosomal Recessive (rare) – Both copies of the gene must be mutated.

2. Symptoms & Progression

Bethlem myopathy symptoms vary in severity but typically appear in early childhood or adolescence. Some cases are so mild that symptoms are only noticed in adulthood.

Main Symptoms

✔ Muscle Weakness – Primarily affects proximal muscles (shoulders, upper arms, thighs, and calves).
✔ Joint Contractures (Stiffness & Limited Movement) – Often in the fingers, wrists, elbows, and ankles.
✔ Hyperelastic (Flexible) Skin – Some individuals have soft, velvety skin with excessive stretchiness.
✔ Mildly Delayed Motor Milestones – Some infants may take longer to walk.
✔ Slow Disease Progression – Weakness increases gradually, but mobility is usually preserved.
✔ Respiratory Issues (in severe cases) – Some individuals may develop breathing difficulties in adulthood.

Progression & Severity

  • Most people with Bethlem myopathy remain able to walk well into adulthood.
  • Some individuals may need a cane or wheelchair in later life, but severe disability is uncommon.

3. Diagnosis

Clinical Examination

Doctors assess muscle weakness, joint contractures, and skin changes.

Skin changes: can provide important diagnostic clues alongside muscle weakness and joint contractures. Individuals with BM often exhibit hyperelastic, velvety skin that may appear excessively soft or stretchy due to Collagen VI deficiencies affecting the extracellular matrix (ECM). This weakened ECM compromises the sarcolemma’s mechanical stability, making muscle fibers more vulnerable to stress and damage.

Genetic Testing

  • DNA sequencing identifies COL6A1, COL6A2, or COL6A3 mutations.

Muscle Biopsy (If Needed)

  • Staining for Collagen VI – Shows reduced or abnormal collagen in the ECM.

Other Tests

  • Electromyography (EMG) – May show mild myopathic changes.
  • Creatine Kinase (CK) Levels – Usually normal or slightly elevated.

4. Treatment & Management

There is no cure for Bethlem myopathy, but supportive treatments can improve quality of life.

Physical Therapy & Exercise

✔ Stretching & Range of Motion Exercises – Prevents worsening of joint contractures.
✔ Low-Impact Strength Training – Helps maintain muscle function.
✔ Aquatic Therapy (Swimming) – Reduces stress on joints and muscles.

Assistive Devices

✔ Braces & Splints – Helps with mobility and prevents contractures.
✔ Wheelchairs (If Needed in Later Life) – For severe cases.

Respiratory Support (For Severe Cases)

✔ Breathing Exercises & Non-Invasive Ventilation (e.g., CPAP/BiPAP) – If respiratory weakness develops.

Medications (Limited Use)

  • Pain Relievers – If joint stiffness causes discomfort.
  • Experimental Therapies – Research on gene therapy and collagen-modulating drugs is ongoing.

5. Bethlem Myopathy and the Sarcolemma

The sarcolemma is the plasma membrane that surrounds muscle fibers. It plays a key role in maintaining muscle integrity, transmitting signals, and protecting against mechanical stress.

How Bethlem Myopathy Affects the Sarcolemma

  1. Weakened ECM-Sarcolemma Connection → Reduces mechanical stability, making muscle fibers more vulnerable to damage and fatigue.
  2. Collagen VI Deficiency → Affects the dystrophin-glycoprotein complex (DGC), a key structure that stabilizes the sarcolemma.
  3. Muscle Regeneration Impairment → Slower healing and repair following muscle stress or injury.

Strengthening the Sarcolemma in Bethlem Myopathy

Although BM is a genetic disorder, certain lifestyle and therapeutic approaches can help support sarcolemma function.

1. Resistance Training & Exercise

✔ Progressive Overload – Engaging in strength training (e.g., weightlifting, bodyweight exercises) helps reinforce muscle fiber membranes.
✔ Eccentric Training – Exercises that emphasize lengthening under tension (e.g., slow negatives) promote adaptations in the sarcolemma and cytoskeletal proteins.

2. Proper Nutrition

✔ Protein Intake – Adequate protein (lean meats, fish, eggs, legumes) supports muscle repair.
✔ Omega-3 Fatty Acids – Found in fish, flaxseeds, and walnuts, these help reduce inflammation and support membrane flexibility.
✔ Antioxidants – Vitamins C & E (citrus fruits, nuts, seeds) reduce oxidative damage to muscle membranes.
✔ Creatine Supplementation – May support cell membrane stability and improve muscle recovery.

3. Cellular & Molecular Support

✔ Dystrophin & Cytoskeletal Proteins – Dystrophin helps stabilize the sarcolemma. Exercise and proper nutrition help maintain this protein.
✔ Collagen Production – Supports ECM integrity, which indirectly strengthens the sarcolemma. Bone broth, gelatin, and vitamin C help boost collagen.

4. Recovery & Injury Prevention

✔ Adequate Rest & Sleep – Muscle repair and membrane strengthening occur during deep sleep and recovery periods.
✔ Hydration – Proper fluid balance ensures optimal cell membrane function.
✔ Stretching & Mobility Work – Helps maintain muscle elasticity and reduce the risk of damage to the sarcolemma.

Conclusion

Bethlem myopathy is a slowly progressive muscle disorder caused by Collagen VI defects, leading to muscle weakness and joint stiffness. The sarcolemma, a crucial muscle membrane, is significantly affected in BM due to a weakened ECM-sarcolemma connection.

Although there is no cure, a combination of physical therapy, exercise, proper nutrition, and supportive treatments can help maintain muscle function and strengthen the sarcolemma. Ongoing research in gene therapy and collagen-modulating treatments provides hope for future interventions.

References Bethlem Myopathy

6 citations for rs121912938 https://www.ncbi.nlm.nih.gov/snp/rs121912938#publications


Position of glycine substitutions in the triple helix of COL6A1, COL6A2, and COL6A3 is correlated with severity and mode of inheritance in collagen VI myopathies
https://pmc.ncbi.nlm.nih.gov/articles/PMC4520221/

Genomewide linkage and linkage disequilibrium analyses identify COL6A1, on chromosome 21, as the locus for ossification of the posterior longitudinal ligament of the spine
https://pubmed.ncbi.nlm.nih.gov/12958705/

Association analysis and functional study of COL6A1 single nucleotide polymorphisms in thoracic ossification of the ligamentum flavum in the Chinese Han population
https://pubmed.ncbi.nlm.nih.gov/34287704/

© 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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