Inherited metabolic disorder characterized by hepatosplenomegaly and failure to thrive during the first year of life, followed by progressive liver cirrhosis with portal hypertension and death by 5 years of age. It is caused by an inborn error of metabolism resulting in a mutation in the GBE1 gene that causes a defect in the glycogen branching enzyme leading to accumulation of abnormal glycogen molecules particularly in cardiac and muscle cells. The severity of this disease varies on the amount of enzyme produced.
Amylopectinosis; Andersen Disease; Brancher Deficiency; Glycogenosis Type IV.
Also named Andersen Disease after the American pathologist and pediatrician Dorothy Hansine Andersen (1901-1963) who described the disease in 1938. She was also first to identify cystic fibrosis and describe the disease.
GSD IV accounts for only 3% of all glycogen storage diseases, which translates to an incidence of about 1:800,000 to 1,200,000 neonates worldwide.
Autosomal recessive. Both sexes are affected. The disease is caused by defects in the gene coding for the glycogen-branching enzyme located on chromosome 3p12.
Deficiency of amylo-1,4 to 1,6-transglucosidase (glycogen-branching enzyme), which results in production of abnormal glycogen with long, unbranched outer chains and decreased solubility (amylopectin-like). Tissue glycogen concentration is usually not increased, but the presence of insoluble glycogen induces foreign-body reactions, leading to cellular injury and organ dysfunction. Ultimately, patients develop terminal hepatic cirrhosis. In skeletal muscles, the presence of abnormal glycogen leads to weakness, exercise intolerance, and muscle atrophy. Cardiac involvement yields to dilated cardiomyopathy and progressive heart failure. In the nervous system, the presence of abnormal glycogen results in cognition disorders and both neuromuscular and neurovisceral dysfunction.
Clinical features. Diagnosis of GSD IV relies on demonstration of deficient glycogen-branching enzyme activity (1-10% of normal values) by an indirect enzyme assay. Heterozygotes display an intermediate reduction in enzyme activity. Definitive diagnosis may involve biopsy of the liver or other affected organs for microscopic examination and enzyme assay. Antenatal diagnosis consists of measuring the levels of glycogen-branching enzyme activity in cultured amniocytes and chorionic villi. Molecular diagnosis may be performed in selected cases.
Clinical heterogeneity with variable age of onset, specific organ involvement, and degree of accumulation of abnormal glycogen in different tissues. Typically, patients affected with a GSD IV present with hepatosplenomegaly and progressive development of cirrhosis and portal hypertension. Death commonly occurs before 5 years of age from hepatic failure. Liver transplant may stop disease progression in some patients. Liver disease may be associated with hypoalbuminemia, coagulopathy, and thrombocytopenia. Esophageal varices, ascites, splenomegaly, renal failure, and hepatic encephalopathy may complicate the clinical course. Associated features ...