Biochemical and clinical aspects of glycogen storage diseases

Abstract

The synthesis of glycogen represents a key pathway for the disposal of excess glucose while its degradation is crucial for providing energy during exercise and times of need. The importance of glycogen metabolism is also highlighted by human genetic disorders that are caused by mutations in the enzymes involved. In this review, we provide a basic summary on glycogen metabolism and some of the clinical aspects of the classical glycogen storage diseases. Disruptions in glycogen metabolism usually result in some level of dysfunction in the liver, muscle, heart, kidney and/or brain. Furthermore, the spectrum of symptoms observed is very broad, depending on the affected enzyme. Finally, we briefly discuss an aspect of glycogen metabolism related to the maintenance of its structure that seems to be gaining more recent attention. For example, in Lafora progressive myoclonus epilepsy, patients exhibit an accumulation of inclusion bodies in several tissues, containing glycogen with increased phosphorylation, longer chain lengths and irregular branch points. This abnormal structure is thought to make glycogen insoluble and resistant to degradation. Consequently, its accumulation becomes toxic to neurons, leading to cell death. Although the genes responsible have been identified, studies in the past two decades are only beginning to shed light into their molecular functions.

Keywords: diabetes; glycogen; metabolism; signal transduction.

Figure 1

Schematic of the enzymes involved in the priming, synthesis and breakdown of glycogen. Hexagons denote glucose monomers, with various colors added for clarity. Glycogen degradation occurs via distinct mechanisms in the cytosol (glycogenolysis) and lysosomes (glycophagy). Abbreviations: glycogen synthase (GS), glycogen phosphorylase (GP), acid alpha glucosidase (GAA).

Figure 2

Schematic of the pathways linked to glycogen metabolism. Glycogen breakdown produces glucose-1-phosphate (via glycogenolysis) and glucose (via glycophagy and debranching enzyme activity). Both products enter into the glycolytic pathway giving rise to pyruvate which acts as a key precursor for the TCA cycle, fatty acid synthesis and gluconeogenesis. The interconversion of pyruvate to lactate and alanine further integrate the metabolism of the liver and muscle tissues. Additionally, fructose-6-phosphate generated in glycolysis can also shunt to the pentose phosphate pathway for nucleotide synthesis.

Figure 3

Schematic of the enzymes involved in the branching and debranching of glycogen. Hexagons denote glucose monomers, with various colors added for clarity. For simplicity, glycogenin has been omitted in this figure. Abbreviations: glycogen branching enzyme 1 (GBE1), glycogen debranching enzyme (GDE).