Glycogen storage disease type 5 (GSDV), or McArdle disease, is a metabolic disorder characterized by onset of exercise intolerance, myalgia, painful muscle cramps, fatigue, and weakness in childhood or adolescence. In half of the patients, muscle exercise causes massive CK elevation and rhabdomyolysis with myoglobinuria (dark urine), potentially leading to acute kidney failure. Relief of myalgia and fatigue after a few minutes of rest is observed in many patients (“second wind” phenomenon). Few cases may have onset very early in life with hypotonia, generalized muscle weakness, and progressive respiratory failure. Later in adult life, there is persistent and progressive muscle weakness and atrophy with fatty replacement. The disease is caused by mutations in the PYGM gene, encoding the muscle glycogen phosphorylase (Table 49.1). The nonsense mutation p.R50X may account for 40–50 % of the alleles in Caucasian populations. The diagnosis is based on clinical features, the lack of lactate elevation in blood during ischemic forearm test, excess glycogen, and the deficient phosphorylase activity in the muscle biopsy.