Glycogen Storage Disease Type IV (GSD IV)

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.

Amylopectinosis; Andersen Disease; Brancher Deficiency; Glycogenosis type IV.

Also named Anderson Disease after the American pathologist and pediatrician Dorothy Hansine Anderson (1901-1963) who described the disease in 1938.

GSD IV accounts for only 3% of all glycogen storage diseases, which translates to an incidence of about 1:800,000-1,200,000 neonates.

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, GSD IV patients 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 described in some patients include cardiomyopathy with congestive cardiac failure, peripheral neuropathy, and hypoglycemia. Prolongation of the QT interval on the ECG has been described and may predispose to arrhythmias. Several neuromuscular forms of GSD IV have been identified. A common variant consists of the development of myopathy or cardiomyopathy during childhood. A perinatal form is distinguished by severe neuromuscular involvement and death. Some patients with clinically diagnosed adult polyglucosan body disease have deficient glycogen-branching enzyme activity and diffuse neurologic (central and peripheral nervous system) dysfunction. After liver transplantation, some patients continue to have progressive accumulation of abnormal glycogen in other organs, ultimately leading to death.

Assess for signs and symptoms of cardiac failure. Obtain chest radiograph, ECG, and echocardiogram if indicated. Assess history for muscle weakness, perhaps periodic in nature. Assess for history of neuropathy. Check liver function, coagulation profile (major alterations are frequent), platelet count, and serum electrolytes and blood glucose levels. Ultrasonography may reveal the existence of portal hypertension, esophageal varices, and altered liver echogenicity; it allows determination of the portal vein diameter and blood flow directionality (important data when hepatic transplantation is considered).

Anesthetic management depends upon the severity of liver dysfunction and other manifestations of the disease. If heart failure is present, further depression of cardiac output by anesthetic agents should be avoided. Monitor ECG for arrhythmias. Regional techniques are contraindicated secondary to coagulopathy or neuropathy. Monitor serum potassium and blood glucose levels in perioperative period and administer intravenous fluids to maintain normal values. Nasoor orogastric tubes should be well lubricated and inserted very carefully in the presence of esophageal varices.

Avoid succinylcholine and reduce doses of nondepolarizing muscle relaxants if myopathy is present; cis-atracurium is the muscle relaxant of choice. Reduce doses of highly protein-bound drugs (e.g., thiopentone) if hypoalbuminemic. Liver failure may prolong the action of drugs eliminated by hepatic metabolism, for example, morphine. Preexisting renal failure and thrombocytopenia should preclude the use of nonsteroidal antiinflammatory drugs.

Other glycogen storage diseases.