Clinical characteristics: Glycogen storage disease type III (GSD III) is characterized by variable liver, cardiac muscle, and skeletal muscle involvement. GSD IIIa is the most common subtype, present in about 85% of affected individuals; it manifests with liver and muscle involvement. GSD IIIb, with liver involvement only, comprises about 15% of all GSD III. In infancy and early childhood, liver involvement presents as ketotic hypoglycemia, hepatomegaly, hyperlipidemia, and elevated hepatic transaminases. In adolescence and adulthood, liver disease becomes less prominent. Hypertrophic cardiomyopathy develops in the majority of those with GSD IIIa, usually during childhood. Its clinical significance ranges from asymptomatic in the majority to severe cardiac dysfunction, congestive heart failure, and (rarely) sudden death. Skeletal myopathy manifesting as weakness is not usually evident in childhood, but slowly progresses, typically becoming prominent in the third to fourth decade.
Diagnosis/testing: Hepatomegaly, ketotic hypoglycemia with fasting, and elevated serum concentrations of transaminases and CK are the hallmarks of GSD III. The serum CK may not be elevated at the time of the diagnostic work up, but the absence of lactic acidosis and markedly elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) concentrations may provide clues to the diagnosis. Measurement of fasting serum concentration of glucose after glucagon administration can be used to support the diagnosis; glucagon administration should not cause the glucose concentration to rise following a prolonged fast, but should do so after a fast of two hours or less. The diagnosis is established by identification of biallelic pathogenic variants in AGL.
Management: Treatment of manifestations: A high-protein diet and frequent feeds (every 3-4 hours) to maintain euglycemia is the mainstay of management in infancy. Fructose and galactose can be used; special formulas are not required. Toward the end of the first year of life, one to three daily doses of 1 g/kg cornstarch can be used to avoid hypoglycemia. A protein intake of 3 g/kg is recommended. For those who cannot make it through the night on cornstarch and protein, Glycosade® extended-release cornstarch can be used. Liver transplantation is reserved for those with severe hepatic cirrhosis, liver dysfunction, and/or hepatocellular carcinoma. Liver transplantation may exacerbate myopathy and cardiomyopathy. Prevention of primary manifestations: See Treatment of manifestations. Prevention of secondary complications: Special precautions for persons undergoing surgery to avoid hypoglycemia. Surveillance: To identify periods of suboptimal metabolic control, blood glucose should be measured between 2 AM and 4 AM or urine ketones should be measured upon awakening at least several times per month. Annual: measurement of height and weight; liver ultrasound examination; laboratory studies (LFTs, CK, lipid profile); and echocardiogram. A bone density determination is recommended after growth is complete. Agents/circumstances to avoid: High simple sugar intake, steroid-based drugs, growth hormone replacement. Use with caution: hormonal contraceptives and statins for control of hyperlipidemia. Evaluation of relatives at risk: Diagnosis of at-risk sibs at birth allows for early dietary intervention to prevent hypoglycemia. Pregnancy management: Increased monitoring and support during pregnancy of women with GSD III because of increasing glucose needs during the course of pregnancy.
Genetic counseling: GSD III 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 an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing and preimplantation genetic testing for pregnancies at increased risk are possible if the pathogenic variants have been identified in the family.
Copyright © 1993-2020, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.