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INTRODUCTION

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The glycogen storage diseases (GSD) comprise several inherited diseases caused by abnormalities of the enzymes that regulate glycogen synthesis and degradation.1,2 Glycogen is stored principally in liver and muscle. Muscle lacks glucose-6-phosphatase (G6Pase) and therefore is unable to release glucose for systemic use. Hypoglycemia is the primary manifestation of the hepatic glycogenoses, whereas weakness and muscle cramps are the predominant features of the muscle glycogenoses. After a meal, glucose is stored as glycogen, a complex, insoluble, highly branched polymer that allows efficient storage and release of glucose. The liver is freely permeable to glucose, which is rapidly phosphorylated by glucokinase to form glucose-6-phosphate. Glucose-6-phosphate is subsequently converted to glucose-1-phosphate, the starting point for glycogen synthesis. Glycogen synthase creates chains of glucose molecules by catalyzing the formation of α-1,4-linkages. A branching enzyme forms α-1,6-linkages approximately every 10 glucose units along the chain. In between meals, glycogen is degraded by the sequential action of two enzymes: hepatic glycogen phosphorylase and debranching enzyme. Debranching enzyme has two enzymatic activities: transferase and amylo-1,6-glucosidase activity. Glycogen phosphorylase is the rate-limiting enzyme in glycogenolysis, which hydrolyzes the α-1,4-linkages from the outer branches of glycogen until only four glucosyl units remain distal to the α-1,6 branch point. Then the debranching enzyme through its transferase activity transfers three of the glucosyl residues to the outer end of an adjacent chain and through its amylo-1,6-glucosidase activity hydrolyses the branch point glucose residue (Figure 5-1). The main physiological functions of glycogen in skeletal muscle is providing substrate for glycolysis. At the start of exercise and during high-intensity exercise, the muscle depends solely on muscle glycogen breakdown. Intact metabolic pathways in glycogen and glucose breakdown are consequently essential for preserving aerobic power to fuel muscles on the move. There are two central forms of clinical presentation of muscular glycogen storage diseases, those with static muscle wasting and weakness, and those with dynamic, exercise-induced symptoms. Sometimes both presentations may overlap.

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FIGURE 5-1.

Schematic representation of glycogen degradation. 1. Phosphorylase catalyzes the cleavage of glucosyl units from 1,4 glucosyl-linked chains of glycogen until only four glucosyl units remain before a 1,6 branch point. 2. The branching enzyme transfers three glucose molecules from the short branch to the end of another branch through its transferase activity. 3. The branching enzyme hydrolyzes the remaining glucosyl unit at the 1,6 branch points through its 1,6 glucosidase activity.

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The discussion of the muscular glycogen storage diseases are in the latter part of the chapter.

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G6Pase catalyzes the terminal reaction of glycogenolysis and gluconeogenesis, the hydrolysis of glucose-6-phosphate to glucose and inorganic phosphate in hepatocytes and renal epithelial cells, allowing glucose to be released into the systemic circulation.

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HEPATIC GLYCOGEN SYNTHASE DEFICIENCY (TYPE 0 GSD)

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Etiology and Pathophysiology
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Type 0 glycogen storage ...

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