Glycogen Storage Disease Type III

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 affected individuals. In infancy and early childhood, liver involvement presents as hepatomegaly and failure to thrive, with fasting ketotic hypoglycemia, hyperlipidemia, and elevated hepatic transaminases. In adolescence and adulthood, liver disease becomes less prominent. Most individuals develop cardiac involvement with cardiac hypertrophy and/or cardiomyopathy. Skeletal myopathy manifesting as weakness may be evident in childhood and slowly progresses, typically becoming prominent in the third to fourth decade. The overall prognosis is favorable but cannot be predicted on an individual basis. Long-term complications such as muscular and cardiac symptoms as well as liver fibrosis/cirrhosis and hepatocellular carcinoma may have a severe impact on prognosis and quality of life. To date, it is unknown if long-term complications can be alleviated and/or avoided by dietary interventions.

Diagnosis/testing: The diagnosis of GSD III is established in a proband by identification of biallelic pathogenic variants in AGL. If molecular genetic testing is inconclusive, debranching enzyme activity can be measured in either blood cells (leukocytes or erythrocytes), skin fibroblasts, or liver or muscle biopsy.

Management: Treatment of manifestations: Dietary management tailored to the individual patient remains the primary therapy. Frequent feeds (every 3-4 hours) are needed to maintain euglycemia in infancy. Toward the end of the first year of life, several doses per day (~1 g/kg) of cornstarch may be required to avoid hypoglycemia. Protein intake of 3 g/kg is recommended; extra protein supplementation may be needed. For those with night-time hypoglycemia, Glycosade^® extended-release cornstarch or continuous nocturnal drip-feeding can be used. Titration of dietary protein and cornstarch is based on self-monitored capillary blood glucose and ketone concentrations, to maintain euglycemia and to prevent ketosis, hypercholesterolemia, and hypertriglyceridemia. Maltodextrin or rapidly absorbable carbohydrates prior to exercise to prevent hypoglycemia during physical activity; oral fructose and sucrose ingestion to improve exercise tolerance. High-fat diet to reduce cardiomyopathy can be considered. Up-to-date individualized emergency letters; perioperative glucose infusion for surgeries to prevent hypoglycemia. Liver transplantation is reserved for those with severe hepatic cirrhosis, liver dysfunction, and/or hepatocellular carcinoma. Liver transplantation may exacerbate myopathy and cardiomyopathy. Vitamin D and calcium supplementation to prevent osteoporosis.

Surveillance: Aspartate aminotransferase, alanine transaminase, liver function as needed (e.g., albumin, bilirubin, ammonia, and clotting studies), creatine kinase (CK), lipid profile every six to 12 months, liver ultrasound every six to 12 months in children and every 12 to 24 months in adults, liver MRI as needed. To identify periods of suboptimal metabolic control, measured preprandial blood glucose and blood ketones or urine ketones on waking. Neurologic, physical therapy, and musculoskeletal assessments; NT-proBNP, CK-MB, electrocardiogram, and echocardiogram every 12 to 24 months in those with GSD IIIa, and every five years in those with GSD IIIb; measurement of height, weight, body mass index, head circumference, and assessment of diet and exercise as needed based on age; serum calcium and 25(OH)-vitamin D annually; regular bone density measurement is recommended.

Agents/circumstances to avoid: High carbohydrate intake, steroid-based drugs, growth hormone replacement therapy, medications that can cause rhabdomyolysis. Use with caution: hormonal contraceptives, statins for control of hyperlipidemia, and beta blockers.

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 increased glucose needs during pregnancy. Although gestational diabetes can occur, oral glucose tests are not indicated. Glucose infusion and regular monitoring of blood glucose, ketones, blood gases, and CK is necessary during labor and perinatally to prevent ketonuria and risk of hyperketosis, metabolic acidosis, and acute rhabdomyolysis. Glucose management requires balancing undertreatment against the risks assocated with overtreatment (e.g., fetal hyperinsulinemic hypoglycemia).

Genetic counseling: GSD III is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an AGL pathogenic variant, each sib of an affected individual has at conception a 25% chance of being affected with GSD III, a 50% chance of being an asymptomatic carrier, and a 25% chance of inheriting neither of the familial AGL pathogenic variants. Once the AGL pathogenic variants have been identified in an affected family member, carrier testing for at-risk family members and prenatal and preimplantation genetic testing for a pregnancy at increased risk are possible.