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

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.