Snapshot A 16-year-old boy presents to his primary care physician with a complaint of fatigue and muscle cramps. He recently tried out for his high school basketball team and found himself exhausted and unable to run after performing a set of high intensity sprints. He notes that after resting briefly, he is able to get a “second wind.” After practice, he noticed that his urine was a brown color. Laboratory results are significant for an elevated creatine kinase level of 1,423 U/L (normal < 200 U/L). There was no elevation of lactate levels on forearm nonischemic testing. (McArdle disease) Introduction Overview glycogen storage disorders (GSD) result from errors of glycogen metabolism caused by mutations in genes for enzymes involved in glycogen synthesis and degradation Glycogen Storage DiseasesGSDDefective EnzymeCharacteristicsVon Gierke disease (type 1)Hepatic glucose-6-phosphataseAutosomal recessiveUsually presenting at 3-6 months of ageHepatomegalySigns of hypoglycemiaseizure"Doll-like" facePoor growth↑ uric aciddue to impaired renal clearance and increased productiongout↑ lactic acid↑ triglyceridesxanthomaspancreatitisPompe disease (type 2)Lysosomal α(1,4)-glucosidaseAutosomal recessiveInfantile formcardiomegalygeneralized muscle hypotoniarespiratory distressJuvenile and adult formskeletal myopathydelayed-gross motor developmentlimb-girdle weaknessrespiratory issuesCori disease (type 3) Glycogen debranching enzymeAutosomal recessiveMost cases involve the muscle and liverHepatomegalyMild hypoglycemiaintact gluconeogenesisMcArdle disease (type 5)Muscle glycogen phosphorylaseAutosomal recessiveAffects theskeletal muscleNo elevation of blood lactate during forearm exercise test↑ creatine kinaseMuscle cramp, fatigue, myalgias, and myoglobinuria"Second wind" phenomenomrapid relief of fatigue and myalgiasecondary to increase blood flow, improved free fatty acid delivery, and liver glucose utilization Epidemiology Incidence overall incidence of all forms of glycogen storage diseases in the US, Europe, and Canada is approximately 1 in 20,000-40,000 von Gierke disease (GSD type 1) most common type ~25% of all patients with GSD Demographics age of onset may range from the first months of life to later decades of life highest incidence of Cori disease (GSD type 3) in non-Ashkenazi Jews in northern Africa ETIOLOGY Pathophysiology glycogen storage disorders result from abnormal glycogen metabolism and accumulation of glycogen within cells of certain tissues (i.e., liver and skeletal muscle) Genetics inheritance pattern autosomal recessive Studies Von Gierke disease (type 1) serum glucose and electrolyte levels fasting hypoglycemia (serum glucose < 2.5 mmol/L) serum uric acid level hyperuricemia (uric acid > 5.0 mg/dL) serum triglyceride level hypertriglyceridemia (triglyceride level > 250 mg/dL) serum cholesterol level hypercholesterolemia (cholesterol level > 200 mg/dL) Pompe disease (type 2) acid α-glucosidase testing initial test gives definitive diagnosis laboratory testing ↑ creatine kinase, lactic acid, and aspartate aminotransferase Cori disease (type 3) serum glucose and electrolyte levels fasting hypoglycemia (serum glucose < 2.5 mmol/L) laboratory testing ↑ creatine kinase and aspartate aminotransferase McArdle disease (type 5) serum creatine kinase levels ↑ serum CK at rest further ↑ in CK after intensive exercise myophosphorylase enzyme activity assay ↓↓ myophosphorylase levels genetic testing identification of pathogenic variants in the PYGM gene gives definitive diagnosis Treatment Von Gierke disease (type 1) dietary management frequent oral glucose/cornstarch consumption avoid fructose and galactose prevent lactic acidosis Pompe disease (type 2) enzyme replacement therapy alglucosidase alfa Cori disease (type 3) symptomatic treatment McArdle disease (type 5) sucrose consumption before exercise may improve symptoms Prognosis GSD type 1 good when dietary and medical treatments are implemented GSD type 2 poor prognosis without treatment GSD type 3 good prognosis with many patients surviving into adulthood GSD type 5 variable prognosis