Glycogen storage disease type III (GSD III) is characterized by variable liver, cardiac muscle, and skeletal muscle involvement. GSD IIIa, the most common subtype present in about 85% of affected individuals, 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 manifest as weakness is not usually evident in childhood, but slowly progresses, becoming prominent in the third to fourth decade.
Hepatomegaly, ketotic hypoglycemia with fasting, and elevated serum concentrations of transaminases and CK are the hallmark triad of GSD III. If serum CK is not elevated at the time of diagnostic work-up, absence of lactic acidosis and markedly elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) concentrations may provide a clue to diagnosis. Measurement of fasting serum concentration of glucose after glucagon administration can be used to support the diagnosis: the glucose concentration should not rise after a prolonged fast, but should rise after a fast of two hours or less. Molecular genetic testing of AGL, the only gene known to be associated with GSD III, allows confirmation of the diagnosis.
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 for pregnancies at increased risk are possible if the disease-causing mutations have been identified in the family.