Glycogen Storage Disease Type V

Clinical characteristics: Glycogen storage disease type V (GSDV, McArdle disease) is a metabolic myopathy characterized by exercise intolerance manifested by rapid fatigue, myalgia, and cramps in exercising muscles. Symptoms are usually precipitated by isometric exercise or sustained aerobic exercise. Most individuals improve their exercise tolerance by exploiting the "second-wind" phenomenon with relief of myalgia and fatigue after a few minutes of rest. Age of onset is frequently in the first decade of life but can vary; however, diagnosis is typically delayed as myalgia and fatigability are dismissed/overlooked. Fixed muscle weakness occurs in approximately 25% of affected individuals, is more likely to involve proximal muscles, and is more common in individuals of advanced age. Approximately 50% of affected individuals have recurrent episodes of myoglobinuria that can – on occasion – eventually result in acute renal failure.

Diagnosis/testing: The diagnosis of GSDV is established in a proband with suggestive findings and by identification of biallelic PYGM (encoding glycogen phosphorylase, muscle form) pathogenic variants on molecular genetic testing or – if genetic test results are not diagnostic – by assay of muscle myophosphorylase enzyme activity.

Management: Treatment of manifestations: Although no cure for GSDV is available, affected individuals benefit from moderate-intensity aerobic training (e.g., walking or brisk walking, bicycling) to increase cardiorespiratory fitness and muscle oxidative capacity. Pre-exercise ingestion of sports drinks containing simple carbohydrates improves exercise tolerance and may protect against exercise-induced rhabdomyolysis.

Surveillance: Annual routine physical examination and review of diet.

Agents/circumstances to avoid: To prevent occurrence of cramps and myoglobinuria, avoid intense isometric exercise and maximal aerobic exercise.

Evaluation of relatives at risk: When the family-specific PYGM pathogenic variants are known, early detection of GSDV in relatives at risk ensures proper management to prevent muscle injury leading to rhabdomyolysis and to improve long-term outcome, particularly by development of a healthy lifestyle (i.e., regular exercise such as brisk walking) in childhood.

Genetic counseling: GSDV is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier. Heterozygotes are asymptomatic. Once the pathogenic variants in the family are known, carrier testing for at-risk family members, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.