Oral SGLT2 Inhibitors in Glycogen Storage Disease Type Ib and G6PC3-Deficiency. Preliminary Results from an Off-Label Study of 21 Patients

Donadieu, Jean; Alimi, Aurélia; Brassier, Anaïs; Beaupain, Blandine; Wicker, Camille; Alili, Jean-Meidi; Bellanné‐Chantelot, Christine; Chaussade, Amelie; Castelle, Martin; Lamarque, Mathlide; Plo, Isabelle; Durix, Lea; Pion, Aude; Souquère, Sylvie; Marty, Caroline; Röhrlich, Pierre; Mention, Karine; Abou-Chahla, Wadih; Szymanowski, Marie; Dao, Myriam; Suarez, Félipe; Parronchi, Paola; Palterer, Boaz; Urvoy, Noemie; Lapillonne, Hélène; Andréelli, Fabrizio; Schaftingen, Emile Van; Labrune, Philippe; Lonlay, Pascale de; Cunha, Maria Veiga Da

doi:10.1182/blood-2022-169243

Cited by 4 publications

(2 citation statements)

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“…Treatment with sodium-glucose cotransporter 2 inhibitors, which inhibit renal glucose reabsorption, improved neutrophil counts and function and reduced the severity of infection episodes in G6PC3-CDG patients ( 112 , 113 ). On the other hand, GCSF is typically used in neutropenia management but failed to show therapeutic efficacy, despite increasing neutrophil production ( 112 ).…”

Section: Immunological Burden In Congenital Disorders Of Glycosylationmentioning

confidence: 99%

Revisiting the immunopathology of congenital disorders of glycosylation: an updated review

Pascoal,

Francisco,

Mexia

et al. 2024

Front. Immunol.

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Glycosylation is a critical post-translational modification that plays a pivotal role in several biological processes, such as the immune response. Alterations in glycosylation can modulate the course of various pathologies, such as the case of congenital disorders of glycosylation (CDG), a group of more than 160 rare and complex genetic diseases. Although the link between glycosylation and immune dysfunction has already been recognized, the immune involvement in most CDG remains largely unexplored and poorly understood. In this study, we provide an update on the immune dysfunction and clinical manifestations of the 12 CDG with major immune involvement, organized into 6 categories of inborn errors of immunity according to the International Union of Immunological Societies (IUIS). The immune involvement in phosphomannomutase 2 (PMM2)-CDG - the most frequent CDG - was comprehensively reviewed, highlighting a higher prevalence of immune issues during infancy and childhood and in R141H-bearing genotypes. Finally, using PMM2-CDG as a model, we point to links between abnormal glycosylation patterns in host cells and possibly favored interactions with microorganisms that may explain the higher susceptibility to infection. Further characterizing immunopathology and unusual host-pathogen adhesion in CDG can not only improve immunological standards of care but also pave the way for innovative preventive measures and targeted glycan-based therapies that may improve quality of life for people living with CDG.

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Section: Immunological Burden In Congenital Disorders Of Glycosylationmentioning

confidence: 99%

Revisiting the immunopathology of congenital disorders of glycosylation: an updated review

Pascoal,

Francisco,

Mexia

et al. 2024

Front. Immunol.

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“…Yet, in most of the reports available, empagliflozin was the one chosen, as was already extensively referenced above. However, the authors are aware of a large study presently being conducted in France [108], where dapagliflozin is being tested in GSD1b and G6PC3-deficient patients, and the results indicate similar therapeutical success once the dose has been adapted. Because of the limited number of patients (ultra-rare disease), it might be better to choose gliflozins that have already been tested (if available) to gain better knowledge of their efficacy and secondary effects.…”

Section: Choice Of the Gliflozinmentioning

confidence: 99%

Treatment of the Neutropenia Associated with GSD1b and G6PC3 Deficiency with SGLT2 Inhibitors

et al. 2023

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Glycogen storage disease type Ib (GSD1b) is due to a defect in the glucose-6-phosphate transporter (G6PT) of the endoplasmic reticulum, which is encoded by the SLC37A4 gene. This transporter allows the glucose-6-phosphate that is made in the cytosol to cross the endoplasmic reticulum (ER) membrane and be hydrolyzed by glucose-6-phosphatase (G6PC1), a membrane enzyme whose catalytic site faces the lumen of the ER. Logically, G6PT deficiency causes the same metabolic symptoms (hepatorenal glycogenosis, lactic acidosis, hypoglycemia) as deficiency in G6PC1 (GSD1a). Unlike GSD1a, GSD1b is accompanied by low neutrophil counts and impaired neutrophil function, which is also observed, independently of any metabolic problem, in G6PC3 deficiency. Neutrophil dysfunction is, in both diseases, due to the accumulation of 1,5-anhydroglucitol-6-phosphate (1,5-AG6P), a potent inhibitor of hexokinases, which is slowly formed in the cells from 1,5-anhydroglucitol (1,5-AG), a glucose analog that is normally present in blood. Healthy neutrophils prevent the accumulation of 1,5-AG6P due to its hydrolysis by G6PC3 following transport into the ER by G6PT. An understanding of this mechanism has led to a treatment aimed at lowering the concentration of 1,5-AG in blood by treating patients with inhibitors of SGLT2, which inhibits renal glucose reabsorption. The enhanced urinary excretion of glucose inhibits the 1,5-AG transporter, SGLT5, causing a substantial decrease in the concentration of this polyol in blood, an increase in neutrophil counts and function and a remarkable improvement in neutropenia-associated clinical signs and symptoms.

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DBS are suitable for 1,5-anhydroglucitol monitoring in GSD1b and G6PC3-deficient patients taking SGLT2 inhibitors to treat neutropenia

Dewulf,

Chevalier,

Marie

et al. 2023

Molecular Genetics and Metabolism

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Oral SGLT2 Inhibitors in Glycogen Storage Disease Type Ib and G6PC3-Deficiency. Preliminary Results from an Off-Label Study of 21 Patients

Cited by 4 publications

References 0 publications

Revisiting the immunopathology of congenital disorders of glycosylation: an updated review

Revisiting the immunopathology of congenital disorders of glycosylation: an updated review

Treatment of the Neutropenia Associated with GSD1b and G6PC3 Deficiency with SGLT2 Inhibitors

DBS are suitable for 1,5-anhydroglucitol monitoring in GSD1b and G6PC3-deficient patients taking SGLT2 inhibitors to treat neutropenia

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