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Glycogen storage diseases

Nature Reviews Disease Primers volume 9, Article number: 46 (2023) Cite this article

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Abstract

Glycogen storage diseases (GSDs) are a group of rare, monogenic disorders that share a defect in the synthesis or breakdown of glycogen. This Primer describes the multi-organ clinical features of hepatic GSDs and muscle GSDs, in addition to their epidemiology, biochemistry and mechanisms of disease, diagnosis, management, quality of life and future research directions. Some GSDs have available guidelines for diagnosis and management. Diagnostic considerations include phenotypic characterization, biomarkers, imaging, genetic testing, enzyme activity analysis and histology. Management includes surveillance for development of characteristic disease sequelae, avoidance of fasting in several hepatic GSDs, medically prescribed diets, appropriate exercise regimens and emergency letters. Specific therapeutic interventions are available for some diseases, such as enzyme replacement therapy to correct enzyme deficiency in Pompe disease and SGLT2 inhibitors for neutropenia and neutrophil dysfunction in GSD Ib. Progress in diagnosis, management and definitive therapies affects the natural course and hence morbidity and mortality. The natural history of GSDs is still being described. The quality of life of patients with these conditions varies, and standard sets of patient-centred outcomes have not yet been developed. The landscape of novel therapeutics and GSD clinical trials is vast, and emerging research is discussed herein.

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Fig. 1: Cell biology and organs affected in GSDs.
Fig. 2: Biochemical defects in GSDs.
Fig. 3: Histological features of muscle and liver GSDs.
Fig. 4: Standard treatments and investigational therapeutics for GSDs.

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Acknowledgements

The authors thank T. Krag and M. Sheikh for their work preparing histological images for publication (Fig. 3), R. Koch for her review of the manuscript and for her contributions to preparing histological images and D. Bali for her thoughtful edits of Table 2.

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Authors and Affiliations

  1. Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA

    William B. Hannah & Mitchell L. Drumm

  2. Division of Metabolic Diseases, Beatrix Children’s Hospital, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

    Terry G. J. Derks

  3. Department of General Paediatrics, Adolescent Medicine and Neonatology, Medical Centre-University of Freiburg, Faculty of Medicine, Freiburg, Germany

    Sarah C. Grünert

  4. Division of Medical Genetics, Department of Paediatrics, Duke University Medical Center, Durham, NC, USA

    Priya S. Kishnani

  5. Copenhagen Neuromuscular Center, Copenhagen University Hospital, Copenhagen, Denmark

    John Vissing

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Contributions

Introduction (W.B.H.); Epidemiology (T.G.J.D.); Mechanisms/pathophysiology (M.L.D.); Diagnosis, screening and prevention (S.C.G.); Management (P.S.K.); Quality of life (J.V.); Outlook (W.B.H.); Overview of Primer (all authors). Authors contributed equally to this work and are listed alphabetically.

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Correspondence to William B. Hannah.

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Competing interests

W.B.H. has received consulting fees from PTC Therapeutics and ReCode Therapeutics. T.G.J.D. declares that he experiences no competing interests concerning the content of this manuscript. However, there are confidentiality agreements with third parties. In the past 36 months, there have been consultation agreements (with Danone, Ultragenyx Pharmaceutical, Inc., ModernaTX, Inc. and Beam Therapeutics), contracts for financial research support for investigator-initiated research (NCT04311307) and sponsor-initiated research (NCT03517085, NCT03970278, NCT05139316 and NCT05196165), honoraria for lectures or presentations (by MEDTalks, Prelum and Danone) and participation in a Data Safety Monitoring Board (NCT05095727) and advisory boards (Ultragenyx Pharmaceutical, Inc., ModernaTX, Inc. and Beam Therapeutics). For all private–public relationships, all contracts are via UMCG Contract Research Desk and all payments are to UMCG. S.C.G.: the Centre for Paediatrics and Adolescent Medicine Freiburg received funding for the following sponsor-initiated study, for which S.C.G. is a local subinvestigator: NCT05139316 – ‘a study of adeno-associated virus serotype 8-mediated gene transfer of glucose-6-phosphatase in patients with glycogen storage disease type Ia (GSDIa)’, sponsored by Ultragenyx Pharmaceutical, Inc. S.C.G. has received honoraria for educational lectures from Vitaflo GmbH and Ultragenyx Pharmaceutical Inc. and support for attending metabolic expert meetings from Nutricia Metabolics GmbH. S.C.G. participated in an advisory board for Ultragenyx Pharmaceutical, Inc. P.S.K. has received research/grant support from Sanofi Genzyme, Amicus Therapeutics and Kriya Therapeutics. P.S.K. has received consulting fees and honoraria from Sanofi Genzyme, Amicus Therapeutics, Maze Therapeutics, JCR Pharmaceutical, Asklepios Biopharmaceutical, Inc. (AskBio), Ultragenyx Pharmaceutical, Moderna, Inc. and Kriya Therapeutics. P.S.K. is a member of the Pompe and Gaucher Disease Registry Advisory Board for Sanofi Genzyme, Amicus Therapeutics and Baebies. P.S.K. has equity in Asklepios Biopharmaceutical, Inc. (AskBio), Maze Therapeutics, and equity options with Kriya Therapeutics. J.V. has received honoraria for acting as speaker or consulting for Sanofi Genzyme and Amicus Therapeutics and has participated in a clinical trial sponsored by Sanofi Genzyme without getting honorarium. M.L.D. has no competing interests to declare relevant to this article.

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Hannah, W.B., Derks, T.G.J., Drumm, M.L. et al. Glycogen storage diseases. Nat Rev Dis Primers 9, 46 (2023). https://doi.org/10.1038/s41572-023-00456-z

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