Principles of Biochemistry Volume 2 - A. Lehninger 1985

Bioenergetics and Metabolism
Biosynthesis of Carbohydrates in Animal Tissues
There are genetic disorders associated with impaired glycogen metabolism.

Several genetic diseases in humans are associated with impaired Glycogen synthesis or breakdown. One of the earliest cases described involved chronic hepatomegaly (enlarged Liver) in an 8-year-old girl who also exhibited various Metabolic Disorders. The girl died of Influenza. Autopsy revealed that her liver was 3 times the normal size and contained a massive amount of glycogen, accounting for nearly 40% of the organ's dry weight. Glycogen isolated from the liver appeared chemically normal; however, when a piece of the liver tissue was homogenized and incubated in a buffer, the glycogen remained intact—neither lactate nor glucose was produced. When a suspension prepared from normal liver tissue was added to the glycogen, it was rapidly degraded to glucose. Based on this biochemical test, the researchers concluded that the patient had a defect in glycogen breakdown (a condition often named von Gierke's disease after the physician who described it). Initially, glucose-6-phosphatase was suspected as the defective enzyme because the diseased liver failed to produce glucose; however, the absence of lactate formation indicated that the defect involved either Glycogen phosphorylase or the debranching enzyme [α(1→6)-glucosidase]. Later, researchers became convinced that α(1→6)-glucosidase was indeed the enzyme affected in this classic case. Consequently, only the outer side chains of the liver glycogen molecules could be cleaved to yield glucose or lactate, resulting in the accumulation of numerous glycogen molecules that could undergo no further breakdown. In essence, only the "core" (or "limit dextrin") of the molecule remained, which in this instance was unusually large.

Class="center">Table 20-3. Inborn errors of Glycogen METABOLISM and Gluconeogenesis in humans

At least 12 distinct types of inborn errors in glycogen synthesis or breakdown are currently known. Each of these cases involves a specific enzyme deficiency (Table 20-3). Particularly severe disorders, typically fatal, are associated with deficiencies of glucose-6-phosphatase, α(1→6)-glucosidase, and the branching enzyme. Genetic defects affecting pyruvate carboxylase and phosphoenolpyruvate carboxykinase—Enzymes that catalyze the early steps of gluconeogenesis—are also lethal.