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  • Review Article
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Glycogen storage disease type I and G6Pase-β deficiency: etiology and therapy

Nature Reviews Endocrinology volume 6, pages 676–688 (2010)Cite this article

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Abstract

Glycogen storage disease type I (GSD-I) consists of two subtypes: GSD-Ia, a deficiency in glucose-6-phosphatase-α (G6Pase-α) and GSD-Ib, which is characterized by an absence of a glucose-6-phosphate (G6P) transporter (G6PT). A third disorder, G6Pase-β deficiency, shares similarities with this group of diseases. G6Pase-α and G6Pase-β are G6P hydrolases in the membrane of the endoplasmic reticulum, which depend on G6PT to transport G6P from the cytoplasm into the lumen. A functional complex of G6PT and G6Pase-α maintains interprandial glucose homeostasis, whereas G6PT and G6Pase-β act in conjunction to maintain neutrophil function and homeostasis. Patients with GSD-Ia and those with GSD-Ib exhibit a common metabolic phenotype of disturbed glucose homeostasis that is not evident in patients with G6Pase-β deficiency. Patients with a deficiency in G6PT and those lacking G6Pase-β display a common myeloid phenotype that is not shared by patients with GSD-Ia. Previous studies have shown that neutrophils express the complex of G6PT and G6Pase-β to produce endogenous glucose. Inactivation of either G6PT or G6Pase-β increases neutrophil apoptosis, which underlies, at least in part, neutrophil loss (neutropenia) and dysfunction in GSD-Ib and G6Pase-β deficiency. Dietary and/or granulocyte colony-stimulating factor therapies are available; however, many aspects of the diseases are still poorly understood. This Review will address the etiology of GSD-Ia, GSD-Ib and G6Pase-β deficiency and highlight advances in diagnosis and new treatment approaches, including gene therapy.

Key Points

  • Glycogen storage disease type I (GSD-I) comprises GSD-Ia, a deficiency in glucose-6-phosphatase-α (G6Pase-α) and GSD-Ib, a deficiency in a glucose-6-phosphate transporter (G6PT)

  • G6Pase-α is expressed primarily in gluconeogenic tissues, whereas G6PT is ubiquitously expressed; G6Pase-α couples functionally to G6PT to form a complex that maintains interprandial blood glucose homeostasis

  • Patients with GSD-I display a metabolic phenotype characterized by hypoglycemia, hepatomegaly, nephromegaly, hyperlipidemia, hyperuricemia, lactic acidemia, growth retardation and long-term renal and liver disease

  • G6Pase-β is ubiquitously expressed and couples functionally to G6PT to form a complex that maintains neutrophil homeostasis and function

  • Patients with GSD-Ib and those with G6Pase-β-deficiency exhibit a common myeloid phenotype characterized by neutropenia and neutrophil dysfunction

  • Patients with GSD-Ia or GSD-Ib are treated by dietary therapies to correct metabolic abnormalities; to correct myeloid dysfunction, individuals with GSD-Ib or G6Pase-β deficiency require therapy with granulocyte colony-stimulating factor

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Figure 1: The primary anabolic and catabolic pathways of glucose-6-phosphate in gluconeogenic organs.
Figure 2: Glucose homeostasis in gluconeogenic organs and neutrophils.
Figure 3: Proposed roles of the active-site residues in G6Pase-α and G6Pase-β during catalysis.
Figure 4: Proposed pathways for glucose-6-phosphate metabolism in neutrophils.

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Acknowledgements

The authors were supported by the Intramural Research Program of the National Institute of Child Health & Human Development (NICHD), NIH.

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  1. Section on Cellular Differentiation, Program on Developmental Endocrinology and Genetics, Building 10, Room 9D42, 10 Center Drive, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, 20892-1830, MD, USA

    Janice Y. Chou, Hyun Sik Jun & Brian C. Mansfield

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J. Y. Chou and H. S. Jun researched the data for the article. J. Y. Chou and B. C. Mansfield provided a substantial contribution to discussions of the content and contributed equally to writing the article. All authors reviewed and/or edited the manuscript before submission.

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Correspondence to Janice Y. Chou.

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Chou, J., Jun, H. & Mansfield, B. Glycogen storage disease type I and G6Pase-β deficiency: etiology and therapy. Nat Rev Endocrinol 6, 676–688 (2010). https://doi.org/10.1038/nrendo.2010.189

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