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 ≈ 107 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.

Keywords: glycogen; glucose units; storage; metabolism; muscle; liver; starvation; hypoglycaemia; glycogenolysis; polyglucosan

References

Akman HO, Sampayo JN, Ross FA, et al. (2007) Fatal infantile cardiac glycogenosis with phosphorylase kinase deficiency and a mutation in the gamma2‐subunit of AMP‐activated protein kinase. Pediatric Research 62: 499–504.

de Barsy T and Hers H‐G (1990) Normal metabolism and disorders of carbohydrate metabolism. Baillière's Clinical Endocrinology and Metabolism 4: 499–522.

Boisson B, Laplantine E, Prando C, et al. (2012) Immunodeficiency, autoinflammation and amylopectinosis in humans with inherited HOIL‐1 and LUBAC deficiency. Nature Immunology 13: 1178–1186.

Byrne BJ, Falk DJ, Pacak CA, et al. (2011) Pompe disease gene therapy. Human Molecular Genetics 20(R1): R61–R68.

Bresolin N, Ro YI, Reyes M, Miranda AF and DiMauro S (1983) Muscle phosphoglycerate mutase (PGAM) deficiency: a second case. Neurology 33: 1049–1053.

Chen Y‐T (2001) Glycogen storage diseases. In: Scriver CR, Beaudet A, Valle D and Sly WS (eds) The Metabolic and Molecular Bases of Inherited Disease, vol. III, pp. 1521–1552. New York, NY: McGraw‐Hill.

Chen Y‐T, Kishani PS and Koeberl D (2013) Glycogen storage diseases. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarkis SE and Ballabio A (eds) The Online Metabolic and Molecular Bases of Inherited Disease. New York, NY: The McGraw‐Hill Companies, Inc.. OMMBID Available at www.ommbid.com.

Chien YH, Lee NC, Chen CA, et al. (2015) Long‐term prognosis of patients with infantile‐onset Pompe disease diagnosed by newborn screening and treated since birth. Journal of Pediatrics 166: 985–991.

Chou JY and Mansfield BC (1999) Molecular genetics of type I glycogen storage diseases. Trends in Endocrinology and Metabolism 10: 104–113.

Chou JY, Jun HS and Mansfield BC (2015) Type I glycogen storage diseases: disorders of the glucose‐6‐phosphatase/glucose‐6‐phosphate transporter complexes. Journal of Inherited Metabolic Disease 38: 511–519.

Comi GP, Fortunato F, Lucchiari S, et al. (2001) Beta‐enolase deficiency, a new metabolic myopathy of distal glycolysis. Annals of Neurology 50: 202–207.

Conlon TJ, Mah CS, Pacak CA, (2016) Transfer of Therapeutic Genes into Fetal Rhesus Monkeys Using Recombinant Adeno-Associated Type I Viral Vectors. Human Gene Therapy Clinical Development 4: 152–159.

Cori GT and Cori CF (1952) Glucose‐6‐phosphatase of the liver in glycogen storage disease. Journal of Biological Chemistry 199: 661–667.

Cori GT (1954) Glycogen structure and enzyme deficiencies in glycogen storage disease. Harvey Lectures 48: 145–171.

Cori GT (1957) Biochemical aspects of glycogen deposition diseases. Modern Problems in Paediatrics 3: 344–358.

Devos P and Hers HG (1980) Random, presumably hydrolytic, and lysosomal glycogenolysis in the livers of rats treated with phlorizin and of newborn rats. Biochemical Journal 192: 177–181.

DiMauro S and Spiegel R (2011) Progress and problems in muscle glycogenoses. Acta Myologica 30: 96–102.

D'souza RS, Levandowski C, Slavov D, et al. (2014) Danon disease: clinical features, evaluation, and management. Circulation, Heart Failure 7: 843–849.

Endo Y, Furuta A and Nishino I (2015) Danon disease: a phenotypic expression of LAMP‐2 deficiency. Acta Neuropathologica 129: 391–398.

Fratantoni JC, Hall CW and Neufeld EF (1968) Hurler and Hunter syndromes: mutual correction of the defect in cultured fibroblasts. Science 162 (3853): 570–572.

Hers H‐G (1963) α‐Glucosidase deficiency in generalised glycogen‐storage disease (Pompe's disease). Biochemical Journal 86: 11–16.

Hers H‐G (1976) The control of glycogen metabolism in the liver. Annual Review of Biochemistry 45: 167–189.

Hochuli M, Christ E, Meienberg F, et al. (2015) Alternative nighttime nutrition regimens in glycogen storage disease type I: a controlled crossover study. Journal of Inherited Metabolic Disease 38: 1093–1098.

Kishnani PS, Corzo D, Nicolino M, et al. (2007) Recombinant human acid α-glucosidase: major clinical benefits in infantile-onset Pompe disease. Neurology 68: 99–109. [Erratum in: Neurology. 2008 Nov 18; 71(21): 1748].

Kreuder J, Borkhardt A, Repp R, et al. (1996) Inherited metabolic myopathy and hemolysis due to a mutation in aldolase A. New England Journal of Medicine 334: 1100–1110.

Laforêt P, Richard P, Said MA, et al. (2006) A new mutation in PRKAG2 gene causing hypertrophic cardiomyopathy with conduction system disease and muscular glycogenosis. Neuromuscular Disorders 16: 178–182.

Lafôret P, Weinstein DA and Smit GPA (2011) The Glycogen Storage diseases and related disorders. Chap 6. In: Saudbray JM, van den Berghe G and Walters J (eds) Inborn Metabolic Diseases. Berlin: Springer.

Leloir LF and Cardini CE (1957) Biosynthesis of glycogen from uridine diphosphate glucose. Journal of the American Chemical Society 79: 6340–6341.

Malfatti E, Birouk N, Romero NB, et al. (2012) Juvenile‐onset permanent weakness in muscle phosphofructokinase deficiency. Journal of the Neurological Sciences 316: 173–177.

Mamoune A, Bahuau M, Hamel Y, et al. (2014) Casanova JL, de Lonlay P (2014) A thermolabile aldolase A mutant causes fever‐induced recurrent rhabdomyolysis without hemolytic anemia. PLoS Genetics 10 (11): e1004711.

Morava E (2014) Galactose supplementation in phosphoglucomutase‐1 deficiency; review and outlook for a novel treatable CDG. Molecular Genetics and Metabolism 112: 275–279.

Moslemi A‐R, Lindberg C, Nilsson J, et al. (2010) Glycogenin‐1 deficiency and inactivated priming of glycogen synthesis. New England Journal of Medicine 362: 1203–1210.

Nilsson J, Schoser B, Laforet P, et al. (2013) Polyglucosan body myopathy caused by defective ubiquitin ligase RBCK1. Annals of Neurology 74: 914–919.

Nogales‐Gadea G, Santalla A, Brull A, et al. (2015) The pathogenomics of McArdle disease‐‐genes, enzymes, models, and therapeutic implications. Journal of Inherited Metabolic Disease 38: 221–230.

Pilkis SJ, Claus TH, Kurland IJ and Lange AJ (1995) 6‐Phosphofructo‐2‐kinase/fructose‐2,6‐bisphosphatase: a metabolic signaling enzyme. Annual Review of Biochemistry 64: 799–835.

Rodriguez IR and Whelan WJ (1985) A novel glycosyl–amino acid linkage: rabbit muscle glycogen is covalently linked to a protein via tyrosine. Biochemical and Biophysical Research Communications 132: 829–836.

Ryman BE and Whelan WJ (1971) New aspects of glycogen metabolism. Advances in Enzymology 34: 285–443.

Schoenheimer R (1929) Über eine eigenartige Störung des Kohlenhydratstoffwechsels. Hoppe‐Seyler's Zeitschrift für Physiologische Chemie 182: 149–151.

Seydewitz HH and Matern D (2000) Molecular genetic analysis of 40 patients with glycogen storage disease type Ia: 100% mutation detection rate and 5 novel mutations. Human Mutation 15: 115–116.

Smythe C, Caudwell FB, Ferguson M and Cohen P (1988) Isolation and structural analysis of a peptide containing the novel tyrosyl‐glucose linkage in glycogenin. EMBO Journal 7: 2681–2686.

Stojkovic T, Vissing J, Petit F, et al. (2009) Muscle glycogenosis due to phosphoglucomutase 1 deficiency. New England Journal of Medicine 361: 425–427.

Tegtmeyer LC, Rust S, van Scherpenzeel M, et al. (2014) Multiple phenotypes in phosphoglucomutase 1 deficiency. New England Journal of Medicine 370: 533–542.

Timal S, Hoischen A, Lehle L, et al. (2012) Gene identification in the congenital disorders of glycosylation type I by whole‐exome sequencing. Human Molecular Genetics 21: 4151–4161.

Turnbull J, Girard JM, Lohi H, et al. (2012) Early‐onset Lafora body disease. Brain 135: 2684–2698.

Further Reading

Alonso MD, Lomako J, Lomako WM and Whelan WJ (1995) A new look at the biogenesis of glycogen. FASEB Journal 9: 1126–1137.

Broomfield A, Fletcher J, Davison J, et al. (2015) Response of 33 UK patients with infantile‐onset Pompe disease to enzyme replacement therapy. Journal of Inherited Metabolic Disease 39 (2): 261–271.

Chen Y‐T, Cornblath M and Sidbury JB (1984) Cornstarch therapy in type 1 glycogen storage disease. New England Journal of Medicine 310: 171–175.

Chen Y‐T, Coleman RA, Scheinman JI, Kolbeck PC and Sidbury JB (1988) Renal disease in type I glycogen storage disease. New England Journal of Medicine 318: 7–11.

Chen Y‐T (2001) Glycogen storage diseases. In: Scriver CR, Beaudet A, Valle D and Sly WS (eds) The Metabolic and Molecular Bases of Inherited Metabolic Disease, vol. III, pp. 1521–1552. New York, NY: McGraw‐Hill.

Cornblath M and Schwartz R (1991) Disorders of Carbohydrate Metabolism in Infancy, 3rd edn. Cambridge, MA: Blackwell Scientific.

Kilimann MW and Oldfors A (2015) Glycogen pathways in disease: new developments in a classical field of medical genetics. Journal of Inherited Metabolic Disease 38: 483–487.

Kishnani PS, Corzo D, Nicolino M, et al. (2007) Recombinant human acid [alpha]‐glucosidase: major clinical benefits in infantile‐onset Pompe disease. Neurology 68: 99–109.

Kishnani PS, Corzo D, Leslie ND, et al. (2009) Early treatment with alglucosidase alfa prolongs long‐term survival of infants with Pompe disease. Pediatric Research 66: 329–335.

Marti GE, Rick ME, Sidbury JB and Gralnick HR (1986) DDAVP infusion in five patients with type Ia glycogen storage disease and associated correction of prolonged bleeding times. Blood 68: 180–184.

Moses SW (2002) Historical highlights and unsolved problems in glycogen storage disease type 1. European Journal of Pediatrics 161: S2–S9.

Hedburg‐Oldfors C and Oldfors A (2015) Polyglucosan storage myopathies. Molecular Aspects of Medicine 46: 85–100.

van der Ploeg AT, Clemens P, Corzo D, et al. (2010) A randomized study of alglucosidase alfa in late‐onset Pompe's disease. New England Journal of Medicine 362: 1396–1406.

Preisler N, Haller RG and Vissing J (2015) Exercise in muscle glycogen storage disorders. Journal of Inherited Metabolic Disease 38: 551–563.

Raben N, Danon MJ, Lu N, et al. (2001) Surprises of genetic engineering: a possible model of polyglucosan body disease. Neurology 56: 1739–1745.

Raben N, Takikita S, Pittis MG, et al. (2007) Deconstructing Pompe disease by analyzing single muscle fibers: to see a world in a grain of sand. Autophagy 3: 546–552.

Raben N, Hill V, Shea L, et al. (2008) Suppression of autophagy in skeletal muscle uncovers the accumulation of ubiquitinated proteins and their potential role in muscle damage in Pompe disease. Human Molecular Genetics 17: 3897–3908.

Salway JG (1999) Metabolism at a Glance, 2nd edn. Oxford, UK: Blackwell Science.

Shin YS (1990) Diagnosis of glycogen storage disease. Journal of Inherited Metabolic Disease 13: 419–434.

Spampanato C, Feeney E, Li L, et al. (2013) Transcription factor EB (TFEB) is a new therapeutic target for Pompe disease. EMBO Molecular Medicine 5: 691–706.

Wang J, Cui H, Lee NC, et al. (2013) Clinical application of massively parallel sequencing in the molecular diagnosis of glycogen storage diseases of genetically heterogeneous origin. Genetics in Medicine 15: 106–114.

Wolfsdorf JI, Rudlin CR and Crigler JF (1990) Physical growth and development of children with type 1 glycogen‐storage disease: comparison of the effects of long‐term use of dextrose and uncooked cornstarch. American Journal of Clinical Nutrition 52: 1051–1057.

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Cox, Timothy M(Apr 2017) Glycogen Storage Diseases. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0002270.pub2]