Pathophysiology of the Neutropenia of GSDIb and G6PC3 Deficiency: Origin, Metabolism and Elimination of 1,5-Anhydroglucitol

J Inherit Metab Dis. 2025 Sep;48(5):e70085. doi: 10.1002/jimd.70085.

Abstract

Neutropenia in Glycogen Storage Disease Type Ib (GSDIb) and G6PC3 deficiency results from defects in metabolite repair, leading to the accumulation of 1,5-anhydroglucitol-6-phosphate (1,5-AG6P). Treatment currently relies on inhibitors of SGLT2, the renal sodium-glucose co-transporter, which indirectly enhances urinary excretion of 1,5-anhydroglucitol (1,5-AG), the precursor of the toxic 1,5-AG6P that accumulates in neutrophils and is at the origin of these patients' neutropenia. In this context, a detailed understanding of the formation, intestinal absorption, renal reabsorption, and metabolism of 1,5-AG is essential. Here, we review the current knowledge of these mechanisms, their role in the pathophysiology of 1,5-AG6P-related neutropenia, and explore potential strategies to improve treatment outcomes.

Publication types

  • Review

MeSH terms

  • Animals
  • Deoxyglucose* / metabolism
  • Deoxyglucose* / urine
  • Glucose-6-Phosphatase* / genetics
  • Glucose-6-Phosphatase* / metabolism
  • Glycogen Storage Disease Type I* / complications
  • Glycogen Storage Disease Type I* / metabolism
  • Glycogen Storage Disease Type I* / physiopathology
  • Humans
  • Intestinal Absorption
  • Neutropenia* / etiology
  • Neutropenia* / metabolism
  • Neutropenia* / physiopathology
  • Neutrophils / metabolism
  • Sodium-Glucose Transporter 2 / metabolism
  • Sodium-Glucose Transporter 2 Inhibitors / therapeutic use

Substances

  • 1,5-anhydroglucitol
  • Deoxyglucose
  • Glucose-6-Phosphatase
  • G6PC3 protein, human
  • Sodium-Glucose Transporter 2 Inhibitors
  • Sodium-Glucose Transporter 2

Supplementary concepts

  • Glycogen Storage Disease IB