Epidemiology

• A very rare autosomal recessive disease, with heterozygotes usually being asymptomatic.
• The gene for myophosphorylase (PYGM) is on chromosome 11, and 33 distinct mutations have been identified in patients. Mutations are spread throughout the gene and there is no clear genotype:phenotype correlation.^[2]
• The incidence is estimated at 1 per 100,000 population. Only a few hundred cases have been reported but the disorder is probably underdiagnosed because of the mild symptoms in many patients.^[1] The overall incidence of all glycogen storage diseases is in the order of 2.3 children per 100,000 births per year.^[3]

Presentation

• The majority of patients with McArdle's disease present in the second or third decade of life. Symptoms are often reported retrospectively from childhood.
• The rare infantile form presents in the neonatal period with hypotonia, generalised muscle weakness and progressive respiratory distress.^[1]
• Clinical presentation and severity are variable but patients typically experience reversible exercise intolerance and acute crises (early fatigue and painful muscle cramps, sometimes with rhabdomyolysis and myoglobinuria) triggered by static muscle contractions (eg lifting weights) or dynamic exercise (eg climbing stairs or running).^[4]
• Following a short period of rest, most patients can resume exercise without difficulty.^[1]
• Mild proximal muscle weakness may occur, particularly in older patients.

Symptoms

• Diagnosis is suggested by the history.
• People with McArdle's disease develop severe muscle cramps and fatigue in the first few minutes of exercise.
• Because severity depends on enzyme activity, individual presentation is unique.
• Some adults develop a progressive proximal weakness.
• Some adults develop a fixed motor weakness.
• The so-called 'second wind' phenomenon (whereby patients can resume activity following a brief period of rest) is a pathognomonic feature of McArdle's disease that is reported by many but not all patients.^[1]
• Myoglobinuria (dark urine) occurs in about one third of patients following intense exercise.^[1]

Signs

• Clinical findings may be absent on physical examination. Muscle strength and reflexes may be normal.
• In later adult life, persistent proximal weakness and muscle wasting may be present.
• The fatal infantile form presents with hypotonia and reduced reflexes.^[1]
• Ischaemic forearm test: this is a traditional test but is painful and non-ischaemic exercise tests are now preferred.^[5]

Differential diagnosis

• Glucose intolerance.
• Glucose-6-phosphatase deficiency.
• Glucose-6-phosphate dehydrogenase deficiency.
• Other glycogen storage diseases.
• Liver failure.
• Hypoglycaemia.

Investigations

• Creatine kinase levels are elevated in more than 90% of patients with McArdle's disease at rest.
• There is no increase in venous lactic acid levels following exercise testing.
• Urine studies are indicated because myoglobinuria may occur in some patients. Myoglobinuria is found in 50% of patients after exercise.
• Phosphorous 31-nuclear magnetic resonance shows a lack of cytoplasmic acidification during exercise and an increased drop in recalculating Cr/inorganic phosphate (Pi) ratio.^[1]
• Electromyography: may show nonspecific myopathic changes or increased muscle irritability. Electrical activity may be absent during exercise-induced muscle cramps.^[1]
• The diagnosis is confirmed by a muscle biopsy, which shows an excess of glycogen and absence of the muscle enzyme phosphorylase.^[6]
• DNA testing is rarely helpful and often unavailable but in up to 85% of patients from northern Europe, an abnormality in the gene encoding for muscle phosphorylase (R50X) can be detected.^[6]

Management

• No specific treatment exists. There is no evidence of significant benefit from any specific nutritional or pharmacological treatment in McArdle's disease.
• Anaesthetists should be made aware of the diagnosis of McArdle's disease, and may choose to avoid certain anaesthetic agents.^[6]
• Tourniquets should not be used during operative procedures in patients with McArdle's disease.^[6]
• Advice to patients:
  • It is important to avoid strenuous (anaerobic or sustained) exercise, including lifting or pushing.^[7]
  • Patients should not continue to exercise in the presence of severe pain, as this may increase the risk of myoglobinuria and subsequent acute renal failure.^[4]
  • If an episode of myoglobinuria occurs, drink plenty of fluids.^[7]
  • The patient should seek medical attention immediately if they feel unwell or stop producing urine.^[7]
  • It is important to take regular gentle exercise, such as walking or cycling.^[2] Keeping physically fit is the most effective way of controlling the symptoms of McArdle's disease and improving quality of life.^[7]
  • Avoiding excessive weight gain is important, as increased weight lowers the aerobic threshold and increases the effort of exercise.^[7]
• High-protein diet may increase exercise tolerance but this is controversial.
• Although there is some evidence of benefit with creatine, oral sucrose, ramipril and a carbohydrate-rich diet, there is no strong evidence to indicate significant clinical benefit.^[8]
• There are some reports that that vitamin B6 may be beneficial.^[9]

Complications

• Severe myoglobinuria may lead to acute kidney injury.^[10] Progression to chronic kidney disease has not been described.
• Death may occur as a result of respiratory failure due to severe muscle weakness.
• Seizures may occur but are uncommon.
• Potential hyperuricaemia; overproduction of adenosine monophosphate (AMP), with accelerated liberation of hypoxanthine and xanthine into the blood, possibly leading to hyperuricaemia.^[4]

Prognosis

• McArdle's disease is a chronic but often relatively benign disorder.
• There does not seem to be any adverse effect on pregnancy and childbirth.
• Death may occur in infancy as a result of respiratory failure.^[1]

Prevention

• Genetic counselling is appropriate for all individuals with a genetic disorder.