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

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.