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
The correct answer is- B), deficiency of debranching enzyme.
The child 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, 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 α (1- 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- The action of phosphorylase comes at a halt when at least 4 glucose residues are left on either side of the branch point. The glucosyl transferase component of debranching enzyme then transfers a trisaccharide to the linear polymer for the action of phosphorylase to continue. The resultant branch point is hydrolyzed by the (α 1, 6) glycosidase component of debranching enzyme releasing free glucose.
The debranching enzyme deficiency leads to liver disease, with subsequent hypoglycemia and seizure. Progressive muscle weakness also occurs. Diagnosis depends on patient’s history and physical examination, muscle biopsy, electromyelography, ischemic forearm test, and creatine kinase levels. In Cori disease, the ischemic forearm test result is positive.
Biochemical assay for enzyme activity is the method of definitive diagnosis. Unfortunately, no specific treatment or cure exists, although diet therapy may be highly effective at reducing clinical manifestations. Meticulous adherence to a dietary regimen may reduce liver size, prevent hypoglycemia, allow for reduction in symptoms, and allow for growth and development. In some cases, liver transplantation may abolish biochemical abnormalities. Active research continues.
As regards other options
Branching enzyme deficiency, Type IV GSD, also called Amylopectinosis or Andersen’s disease is manifested by- Hepatosplenomegaly; accumulation of polysaccharide with few branch points and death from heart or liver failure in first year of life
Glucose-6-phosphatase deficiency Type 1 GSD, also called -Von Gierke’s disease is similar in clinical manifestations to Cori’s disease but it is more severe in its course. It is manifested by glycogen accumulation in liver and renal tubule cells; hypoglycemia; lactic acidemia; ketosis and hyperlipemia.
Glycogen synthase deficiency, Type 0 GSD, is a fatal disease and is manifested by- Hypoglycemia; hyperketonemia and early death.
Muscle phosphorylase deficiency, Type V GSD, also called Myophosphorylase deficiency or McArdle’s syndrome, is manifested by- Poor exercise tolerance; abnormally high (2.5–4%) muscle glycogen content and a very low blood lactate level after exercise.Please help Biochemistry for Medics by "CLICKING ON THE ADVERTISEMENTS" every time you visit us. Thank you!