Researchers reveal a basic mechanism that has never been suggested in the literature and that explains neutropenia in G6PC3 and G6PT deficiencies: the lack of dephosphorylation of a non-canonical metabolite, (1,5-anhydroglucitol-6-phosphate; 1,5AG6P) which can easily be made from a major polyol present in blood (1,5-anhydroglucitol), strongly impairs glucose metabolism in neutrophils. In patients or mice with G6PC3 or G6PT deficiency, 1,5AG6P accumulates and inhibits the first step of glycolysis. This is particularly detrimental in neutrophils, since their energy metabolism depends almost entirely on glycolysis. Consistent with the findings, Prof. Van Schaftingen’s team observed that treatment with a 1,5-anhydroglucitol-lowering drug treats neutropenia in G6PC3-deficient mice. These mouse experiments now provide the ground for a proof of concept human study in G6PC3 deficient and GSD 1b patients using an SGLT2 inhibitor to lower blood 1,5-anhydroglucitol.
Article references: Veiga-da-Cunha M, et al. (2019), Failure to eliminate a phosphorylated glucose analog leads to neutropenia in patients with G6PT and G6PC3 deficiency. PNAS. doi: 10.1073/pnas.1816143116
Dr Maria Veiga da Cunha has received for this work a Late Breaking News Award during the “Annual Conference of the Society for the Study of Inborn Errors of Metabolism (SSIEM) » which was held in Athens last year.
In a study led by Prof. Emile Van Schaftingen (WELBIO investigator at Université Catholique de Louvain), scientists showed that 2 rare genetic diseases leading to an abnormally low concentration of neutrophils in the blood (neutropenia) are due to a lack of metabolic repair which causes the accumulation of a toxic product. The results of this study have been published in PNAS.