GSD type V (McArdle disease)

Pathophysiology - The Broken Engine

• Genetic Defect: Autosomal recessive deficiency of myophosphorylase (muscle glycogen phosphorylase) due to a mutation in the PYGM gene.
• Metabolic Block: Skeletal muscle is unable to perform glycogenolysis, failing to break down stored glycogen into glucose-1-phosphate.
• Consequences:
  • Glycogen accumulates in subsarcolemmal vacuoles.
  • Results in a critical lack of ATP substrate for glycolysis during strenuous anaerobic exercise.
  • Leads to a flat venous lactate curve with exercise.

⭐ The "second wind" phenomenon is a hallmark: after a few minutes of rest, increased circulation delivers blood glucose and free fatty acids to the muscle, providing an alternative energy source and allowing activity to resume.

Clinical Presentation - Exercise Gone Wrong

• Hallmark: Exercise intolerance with severe muscle cramps, pain, and fatigue appearing minutes into strenuous, anaerobic activity (e.g., sprinting, heavy lifting).
• "Second Wind" Phenomenon: A classic feature where symptoms subside after a brief rest, allowing activity to resume. This is due to a switch to alternative fuel sources like fatty acids.
• Rhabdomyolysis & Myoglobinuria: Intense exercise can cause muscle breakdown, leading to myoglobin release.
  • Results in dark, reddish-brown urine.
  • Risk of acute kidney injury.
• Onset: Typically presents in adolescence or early adulthood.

⭐ Despite dramatic muscle symptoms, serum lactate levels characteristically do not rise with ischemic exercise, a key diagnostic clue.

Diagnosis - Catching the Culprit

• Initial Workup:
  • Baseline serum Creatine Kinase (CK): Persistently elevated, typically >1,000 IU/L even at rest.
  • Urinalysis: Can reveal myoglobinuria (dark urine) after intense, anaerobic exercise.
• Provocative Testing:
  • Non-ischemic forearm exercise test (safer): Measures lactate and ammonia response to brief, maximal contractions.
  • Result: Shows a characteristic failure of venous lactate to rise, with an exaggerated ammonia response.

⭐ High-Yield: The hallmark of McArdle's is a flat venous lactate curve during an exercise test, distinguishing it from nearly all other causes of exertional rhabdomyolysis.

• Confirmatory Diagnosis:
  • Genetic Testing: PYGM gene mutation analysis is the definitive, non-invasive gold standard.
  • Muscle Biopsy (if genetics are ambiguous):
    • Histology: Shows subsarcolemmal vacuoles.
    • Stain: PAS-positive (glycogen).
    • Assay: Confirms absent myophosphorylase activity.

Management - Living with Limits

• Primary Goal: Avoid rhabdomyolysis & myoglobinuria by balancing activity and energy availability.
• Dietary Therapy:
  • Maintain a diet rich in complex carbohydrates.
  • Consume a sugary drink (e.g., 30-40g sucrose) 30-45 minutes before planned exercise to boost glucose supply.
• Exercise Prescription:
  • Avoid strenuous, anaerobic activities (sprinting, heavy lifting).
  • Engage in moderate-intensity aerobic exercise, recognizing personal limits.
  • Utilize the "second wind" phenomenon by warming up slowly.
• Supplementation:
  • Creatine monohydrate may ↑ exercise capacity.
  • Vitamin B6 (pyridoxine), a cofactor for myophosphorylase, is sometimes recommended.

⭐ The "second wind" phenomenon: After ~10 minutes of aerobic exercise, symptoms lessen as hepatic glucose release and lipolysis provide alternative fuels (free fatty acids), bypassing the muscle glycogenolysis block.

High-Yield Points - ⚡ Biggest Takeaways

• Autosomal recessive deficiency of myophosphorylase (muscle glycogen phosphorylase).
• Presents with exercise intolerance, muscle cramps, myalgia, and fatigue, typically in adolescence.
• Hallmark is the "second wind" phenomenon, where symptoms improve after a brief rest.
• Can cause rhabdomyolysis with strenuous exercise, leading to myoglobinuria (burgundy-colored urine).
• Flat venous lactate curve after forearm exercise is a key diagnostic finding.
• Muscle biopsy shows excess glycogen in subsarcolemmal deposits.