A female infant appeared normal at birth but developed signs of liver disease and muscular weakness at 3 months. She had periods of hypoglycemia, particularly on awakening. Examination revealed an enlarged liver. Laboratory analyses following fasting revealed ketoacidosis, blood pH 7.25, and elevations in both alanine transaminase (ALT) and aspartate transaminase (AST). Administration of glucagon following a carbohydrate meal elicited a normal rise in blood glucose, but glucose levels did not rise when glucagon was administered following an overnight fast. Liver biopsy revealed an increase in the glycogen content (6 percent of wet weight). In which of the following enzymes is a genetic deficiency most likely for this patient?
A. Branching enzyme
B. Debranching enzyme
D. Glycogen synthase
E. Muscle phosphorylase
Answer- The correct answer is- B.
The patient is suffering from Cori’s disease. GSD type III is also known as Forbes-Cori disease or limit dextrinosis. In contrast to GSD type I, liver and skeletal muscles are involved in GSD type III. Glycogen deposited in these organs has an abnormal structure. Differentiating patients with GSD type III from those with GSD type I solely on the basis of physical findings is not easy
Definitive diagnosis can be made from analysis of the glycogen structure and enzyme activities, but the hepatomegaly, increased liver glycogen content, fasting hypoglycemia, and muscle weakness are consistent with Cori disease. The increase in glycogen content results from an inability to degrade glycogen beyond the limit dextrin of phosphorylase. A deficiency in the debranching enzyme leaves glycogen with short outer branches.
Debranching enzyme has two independent active sites, consisting of residues in different segments of a single polypeptide chain that catalyze (α1, 6) glycosidase and Transferase (transglycosylase) reactions.
The Transferase of the debranching enzyme transfers three glucose residues from a 4-residue limit branch to the end of another branch, diminishing the limit branch to a single glucose residue.
The (α 1, 6) glycosidase moiety of the debranching enzyme then catalyzes hydrolysis of the (α 1, 6) linkage, yielding free glucose. This is a minor fraction of glucose released from glycogen (Figure)
Figure- Role of debranching enzyme in glycogen degradation
Branching enzyme deficiency is observed in Amylopectinosis or Andersen’s disease. Hepatosplenomegaly; accumulation of polysaccharide with few branch points; death from heart or liver failure in first year of life can be observed in affected patients.
Glucose-6-Phosphatase deficiency is observed in Von Gierke’s disease. Glycogen accumulation in liver and renal tubule cells and patients present with hypoglycemia; lactic acidemia; ketosis and hyperlipemia.
Glycogen synthase deficiency is observed in Glycogen storage disease type 0. Mostly patients present with hypoglycemia and hyperketonemia. Early death is observed in such patients.
Muscle phosphorylase deficiency is observed in Myophosphorylase deficiency, McArdle’s syndrome. The patients present with poor exercise tolerance; high muscle glycogen content and very low blood lactate after exercise .
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