McArdle syndrome

Overview

McArdle syndrome, also known as Glycogen Storage Disease Type V (GSD V), is a rare inherited metabolic disorder that affects the skeletal muscles' ability to break down glycogen into glucose for energy during exercise. It is characterized by a deficiency of the enzyme myophosphorylase (also known as muscle phosphorylase), which is essential for glycogen breakdown in muscle tissue.

First described by British physician Brian McArdle in 1951, the condition leads to exercise intolerance, muscle pain, and cramps during physical activity. Though not life-threatening in most cases, it can significantly impact a person’s quality of life. With early diagnosis and proper management, many individuals with McArdle syndrome can lead active lives.

Causes

McArdle syndrome is caused by mutations in the PYGM gene, located on chromosome 11q13. This gene provides instructions for producing the enzyme myophosphorylase, which is necessary for initiating glycogenolysis — the process of breaking down glycogen into glucose within muscle cells.

The condition follows an autosomal recessive inheritance pattern, meaning an affected individual inherits two copies of the mutated gene (one from each parent). Carriers (with only one mutated copy) usually do not show symptoms.

Without functional myophosphorylase, muscle cells are unable to access stored glycogen for energy during anaerobic exertion, leading to the characteristic symptoms of the disorder.

Symptoms

Symptoms of McArdle syndrome usually begin in childhood or adolescence, although they may be misdiagnosed or attributed to other causes for years. The most common clinical features include:

• Exercise intolerance: Early fatigue during activities such as walking uphill, climbing stairs, or lifting heavy objects.

• Muscle pain and cramps: Especially during high-intensity or isometric exercises.

• Muscle stiffness: Often in the first few minutes of activity.

• Second-wind phenomenon: After a brief period of rest during exercise, many individuals experience an improvement in tolerance as the body switches to using other energy sources like fatty acids and blood glucose.

• Dark-colored urine (myoglobinuria): In severe cases, muscle breakdown releases myoglobin into the bloodstream, which is excreted in urine and may lead to kidney damage.

• Rhabdomyolysis: A serious complication involving severe muscle breakdown, which can lead to acute kidney failure if untreated.

Symptoms are often exacerbated by fasting, illness, cold temperatures, or sudden intense physical activity.

Diagnosis

Diagnosing McArdle syndrome involves clinical evaluation, laboratory testing, and genetic confirmation. Diagnostic steps include:

• Clinical history and physical examination: Noting early fatigue, muscle cramps, and the second-wind phenomenon during physical activity.

• Blood tests:

  • Elevated levels of creatine kinase (CK), especially after exercise

  • Detection of myoglobin in urine after physical exertion (suggestive of rhabdomyolysis)

• Forearm exercise test: Measures lactate and ammonia levels before and after handgrip exercises; a flat lactate curve supports the diagnosis.

• Muscle biopsy:

  • Shows excess glycogen in muscle fibers

  • Staining may reveal absent myophosphorylase activity

• Genetic testing: Identification of biallelic mutations in the PYGM gene confirms the diagnosis and can help with family counseling.

Early and accurate diagnosis is crucial to prevent unnecessary procedures and to initiate appropriate management strategies.

Treatment

There is currently no cure for McArdle syndrome, but symptoms can be managed effectively with lifestyle modifications and supportive care. Key treatment strategies include:

• Exercise management:

  • Avoid sudden, intense exercise or activities that cause muscle pain

  • Engage in regular, moderate aerobic activity (e.g., walking, swimming) to build endurance safely

  • Utilize the second-wind effect by gradually warming up before exercise

• Dietary interventions:

  • Pre-exercise consumption of simple carbohydrates (e.g., a small amount of fruit juice or glucose) may reduce symptoms

  • High-protein and complex-carbohydrate diets may be beneficial in some cases

• Avoid fasting: Regular meals prevent hypoglycemia and maintain stable energy availability for muscles.

• Emergency precautions:

  • Patients should be educated about signs of rhabdomyolysis

  • Carry medical identification and seek immediate care for severe muscle pain or dark urine

• Supplements and medications:

  • Creatine and branched-chain amino acids (BCAAs) have been explored, but results are mixed

  • Vitamin B6 supplementation may help in some individuals, though not universally effective

A multidisciplinary approach involving neurology, genetics, dietetics, and physical therapy can optimize care.

Prognosis

The long-term prognosis for individuals with McArdle syndrome is generally favorable, especially with proper management. Although the condition is chronic and lifelong, it does not typically reduce life expectancy.

With lifestyle adjustments, many patients can lead active and fulfilling lives. However, poorly managed cases may result in complications such as:

• Recurrent episodes of rhabdomyolysis

• Chronic muscle damage and weakness

• Acute kidney injury from myoglobinuria

Early diagnosis, patient education, and structured exercise programs can significantly improve quality of life and reduce the risk of complications.

Ongoing research into gene therapy and pharmacological treatments offers hope for more targeted therapies in the future.