Glycogen Storage Diseases

Glycogen Synthesis

The synthesis of glycogen occurs mainly in the liver and muscle, where intracellular glucose is used to synthesize glycogen that is then stored to be used at times of need. The first step in glycogen synthesis is the phosphorylation of glucose into glucose-6-phosphate by the enzyme glucokinase in the liver and hexokinase in muscle. Next, phosphoglucomutase converts glucose-6-phosphate into glucose-1-phosphate, which then reacts with uridine triphosphate (UTP) to form the nucleotide sugar UDP-glucose. An autoglycosylating protein known as glycogenin then transfers the glucose from UDP-glucose to form an oligosaccharide primer chain, which is then used to form glycogen. Glycogen synthase, which is the primary regulatory enzyme in the synthesis of glycogen, and branching enzyme extend the oligosaccharide primer chain by adding more glucose molecules through α-1,4 and α-1,6 glycosidic bonds, respectively.

Glycogen Breakdown

Hepatic glycogenolysis (see Fig. 191-1 ) is activated by fasting, which leads to an increase of counter-regulatory hormones such as glucagon, cortisol, and adrenaline. In the muscle, the increase of cAMP during exercise stimulates the breakdown of glycogen. A small amount of glycogen is catabolized in the lysosomes, but the majority of catabolism occurs in the cytosol via a process called glycogenolysis. Glycogenolysis requires the coordinated action of phosphorylase kinase, phosphorylase, and debranching enzyme. Phosphorylase kinase is responsible for activating muscle and liver phosphorylase via phosphorylation. Next, activated phosphorylase releases glucose-1-phosphate from the glycogen branch. This process continues until there are four glucose residues from the α-1,6 branch point. At this point, the debranching enzyme continues the breakdown of glycogen through its two independent catalytic activities: amylo-1,6-glucosidase and 4-α-glucanotransferase. The 4-α-glucanotransferase catalyzes the transfer of three glycosyl residues from one outer branch to another, thereby exposing a single glucose residue that is linked by an α-1,6-glycosidic bond. The α-1,6-glucosidase breaks the α-1,6-glycosidic bond and releases a free glucose molecule.

More than 15 different enzymatic defects in the glycogen metabolic process correspond to the different glycogen storage diseases. Glycogen storage disorders are caused by homozygous, compound heterozygous, or hemizygous mutations in the target genes. Most glycogen storage diseases are inherited as autosomal recessive conditions. However, liver and muscle phosphorylase kinase deficiency, which are caused by mutations in PHKA2 and PHKA1 genes, and Danon disease are inherited as X-linked disorders. Some glycogen storage diseases also can be categorized as metabolic diseases; for example, Pompe disease can be categorized as a lysosomal storage disease, whereas phosphoglucomutase 1 (PGM1) deficiency can be classified as a congenital disorder of glycosylation.