Glycogen Storage Diseases

Abstract

Glycogen is a dense repository of energy which is present mostly in animal tissues; with its highly arborised structure, the glycogen dendrimer is a source of readily accessible glucose units at low osmotic cost. Access to, and accretion of glycogen is subject to fine metabolic and hormonal regulation; indeed, glycogen biosynthesis is driven by high‐energy phosphate‐bond energy, requiring also the participation of several unique protein complexes. Seminal research by Carl and Gerty Cori into the pathophysiology of glycogen metabolism opened up scientific universe of hormonal signalling, phosphorylation control and second messengers. That the glycogen storage disorder, Pompe disease, proved to be an inborn error affecting lysosome function demonstrated the crucial importance of lysosomal autophagy in cellular housekeeping. The polyglucosan body diseases, characterised by insoluble starch‐like deposits, reveal the critical role of macromolecular remodelling for the symmetrical compaction of branched glycogen structures to ensure that safe storage in the cytoplasm is combined with rapid metabolic access. Inherited defects in proteins which regulate glycogen metabolism, those which enact glycogenolysis and glycogen synthesis cause pathological glycogen accumulation – or prevent its formation. Defects in glycolysis also have consequential metabolic effects on glycogen storage. Latterly, at least eight human loci which harbour mutations associated with polyglucosan and Lafora body disease have been reported in these clinically diverse, but fatal, multisystem disorders. The principal defects identify pathways responsible for the unique control of glycogen metabolism in neurons; other conditions point to coregulation of glycogen metabolism and control of immune and inflammatory responses. Glycogen is an essential macromolecule, the adaptive advantages of which come at a cost. Disorders affecting the dynamic metabolism, regulation and maintenance of this vital energy source offer unique insights into a vast interactive network of molecular cell physiology. Key Concepts Glycogen is an essential intracellular macromolecule; its highly branched but compacted polymeric structure facilitates the rapid availability of glucose units for metabolic utilisation. With ≈55 000 linked glucose units, mature glycogen is a highly ordered sphere with a low intrinsic osmotic burden (molecular mass ≈ 10 7 Da). Glycogen is near ubiquitous in cells including neurons; but it is most abundant in muscle tissue, including cardiac muscle, and in the liver. Skeletal muscle provides the greatest net repository of glycogen for short‐lived bursts of ATP generation but the concentration in liver tissue is several‐fold greater. Liver glycogen is principally used to maintain interprandial glucose homeostasis. Appropriate molecular compaction of its symmetrical, highly branched structure maintains the solubility of glycogen in the cytoplasm – it also promotes access of metabolic enzymes, including complex protein assemblies which regulate the supply of glucose energy from its breakdown. To maintain optimal functional integrity, the branched structure of glycogen is constitutively remodelled by autophagy in the lysosomal compartment. With a short half‐life, glycogen undergoes dynamic interactions; its synthesis and degradation are subject to fine metabolic control. Inborn errors of biosynthesis and catabolism, including disorders of glycolysis, not only affect the abundance and availability of metabolic glucose released from intracellular glycogen but can also lead to altered glycogen storage and its macromolecular structure. Defects in proteins that regulate glycogen metabolism and transport, as well as those which catalyse its biosynthesis and breakdown, cause pathological – or defective – accumulation of glycogen in diverse tissues. Failure to synthesise glycogen and defective glycogenolysis lead to complex metabolic disturbances characterised by interprandial hypoglycaemia; accumulation of aberrant glycogen structures has additional pathological effects due to cellular toxicity. Glycogen storage disorders reveal much about the physiological biochemistry of glycogen and regulatory processes in the dynamic control of energy metabolism – including the special case of neuronal tissue.