RARE DISEASE
Glycogen storage disease due to glucose-6-phosphatase deficiency
Glycogen storage disease due to glucose-6-phosphatase deficiency
Glycogen storage disease due to glucose-6-phosphatase deficiency
Synonyms: G6P deficiency, GSD due to G6P deficiency, GSD type 1, GSD type I, Glycogen storage disease due to G6P deficiency, Glycogen storage disease type 1, Glycogen storage disease type I, Glycogenosis type 1, Glycogenosis type I, Hepatorenal glycogenosis, Von Gierke disease
Synonyms: G6P deficiency, GSD due to G6P deficiency, GSD type 1, GSD type I, Glycogen storage disease due to G6P deficiency, Glycogen storage disease type 1, Glycogen storage disease type I, Glycogenosis type 1, Glycogenosis type I, Hepatorenal glycogenosis, Von Gierke disease
Synonyms: G6P deficiency, GSD due to G6P deficiency, GSD type 1, GSD type I, Glycogen storage disease due to G6P deficiency, Glycogen storage disease type 1, Glycogen storage disease type I, Glycogenosis type 1, Glycogenosis type I, Hepatorenal glycogenosis, Von Gierke disease
Drug discovery
3
drugs
With orphan designations
Overview
Glycogen storage disease due to glucose-6-phosphatase deficiency (GSDI) is an autosomal recessive disorder caused by defects in the glucose-6-phosphatase system, impairing glucose homeostasis. It includes subtypes Ia (G6PC gene mutations, 80% of cases) and Ib (SLC37A4 gene mutations, 20%) [1][6][12]. Clinical features include fasting hypoglycemia, hepatomegaly, hyperlipidemia, hyperuricemia, and growth retardation [1][12]. Long-term complications involve hepatic adenomas, renal disease, and metabolic sequelae [4][20].
Burden
Chronic risks: Hepatic adenomas (15–75% of patients), progressive renal insufficiency, and osteoporosis [4][20].
Psychosocial impact: Lifelong dietary vigilance, invasive monitoring, and anxiety related to hypoglycemia [4][9].
Economic burden: High healthcare utilization for metabolic crises, organ surveillance, and transplant management [9].
Therapies
Dietary management: Frequent feedings, uncooked cornstarch, and nocturnal enteral feeding to maintain normoglycemia [3][4][13].
Pharmacotherapy: Allopurinol (hyperuricemia), lipid-lowering agents, ACE inhibitors (renal protection), and G-CSF (for GSDIb neutropenia) [6][13][20].
Transplantation: Liver and/or kidney transplantation for severe metabolic complications or malignancies [4][6].
Categories: rare genetic diseases, rare hepatic diseases, rare inborn errors of metabolism, rare renal diseases, rare transplant-related disorders
Research Papers
418 drug discovery papers about Glycogen storage disease due to glucose-6-phosphatase deficiency, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
418 drug discovery papers about Glycogen storage disease due to glucose-6-phosphatase deficiency, with 2 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-14 | Empagliflozin in GSD-Ib: Long-term safety and sustained recovery of neutrophil function including NET formation.
Glycogen storage disease type Ib (GSD-Ib) engenders neutropenia and severe neutrophil dysfunction, leading to recurrent infections and inflammatory complications. Recent studies have identified intracellular accumulation of 1,5-anhydroglucitol-6-phosphate (1,5-AG6P) as a key mechanism underlying neutrophil impairment and have suggested therapeutic benefits of sodium-glucose cotransporter 2 (SGLT2) inhibitors, which lower plasma levels of its precursor 1,5-AG. In this study, we performed a four-year longitudinal evaluation of empagliflozin therapy in a genetically confirmed GSD-Ib infant, contributing to the growing body of long-term data on empagliflozin treatment in GSD-Ib. Routine laboratory parameters and key neutrophil effector functions were assessed before and during treatment, as well as in two additional GSD-Ib patients with and without therapy. Empagliflozin therapy resulted in complete restoration of neutrophil function, including reactive oxygen species (ROS) production and bactericidal activity. Notably, neutrophil extracellular trap (NET) formation and neutrophil survival recovered to levels comparable to healthy donors. These functional improvements occurred in conjunction with reduced plasma 1,5-AG levels, supporting the concept that GSD-Ib neutrophils are sensitive to physiological 1,5-AG concentrations. Functional recovery and normalization of neutrophil survival observed in vitro, was paralleled by improvement of absolute neutrophil counts to low-normal levels in vivo. Clinically, treatment was associated with a substantial reduction of severe infections. Collectively, these findings further support that empagliflozin corrects neutrophil dysfunction in GSD-Ib and demonstrate its potential to improve long-term clinical outcome across the lifespan, from infancy through adulthood.
2026-08-08 | ApoC-III Antisense Oligonucleotide Therapy Used in Glycogen Storage Disease Type 1a.
Glycogen storage disease type 1a (GSD1a) is an autosomal recessive disorder characterized by impaired glycogenolysis and gluconeogenesis. Individuals with GSD1a manifest significant hypertriglyceridemia refractory to dietary and lipid-lowering medication therapies. Apolipoprotein C-III antisense oligonucleotide (apoCIII-ASO) therapy is approved to reduce severe hypertriglyceridemia in familial chylomicronemia syndrome but is also effective in moderate hypertriglyceridemia of varied genetic backgrounds. We describe a 22-year-old with GSD1a and hypertriglyceridemia with past pancreatitis despite fibric acid derivative, niacin, and bempedoic acid therapy in whom apoCIII-ASO was associated with triglyceride reduction from 4,951 to 1,643 mg/dL. As GSD1a-associated hypertriglyceridemia is often refractory to standard therapies, apoCIII-ASO therapy may offer promise as a treatment. This case describes the first use of apoCIII-ASO in GSD1a-related hypertriglyceridemia. GSD1a-driven hypertriglyceridemia may be treatable using apoCIII-ASO.
2026-07-28 | Sequence determinants of pathogenicity in glucose-6-phosphatase linked to glycogen storage disease type 1a
Glycogen storage disease type 1a (GSD1a) is an autosomal recessive Mendelian disorder that can be caused by missense variants in glucose-6-phosphatase catalytic subunit 1 (G6PC1). Although hundreds of missense variants have been identified, the vast majority are of unknown clinical significance, and the molecular mechanism(s) of bona fide pathogenic variants are ill-defined. We combine bioinformatic data and clinical associations with the protein language model AlphaMissense to guide mechanistic exploration of 78 missense variants at 55 residue positions using robust biochemical and biophysical assays to distill general principles of enzyme dysfunction. Correlation analysis established a strong linear relationship between folded G6PC1 abundance and catalytic capacity for most variants. Pathogenic variants within this paradigm were linked to compromised stability and activation of the unfolded protein response. However, outliers characterized by relatively high abundance, yet low activity clustered to a network of sidechains adjacent to the active site that allosterically modulate catalysis. Contextualized by recent high-resolution structures and AlphaFold modeling, our holistic analysis of G6PC1 in vitro metrics facilitates clinical (re)classification of variants according to explicit molecular phenotypes and identifies therapeutic design directions. Moreover, our approach illustrates a blueprint for variant characterization that integrates computational prediction with experimental validation to discover disease etiology.
2026-07-28 | Structural basis for substrate recognition and inhibition of human glucose-6-phosphate transporter SLC37A4.
Glucose 6 phosphate (G6P) homeostasis is essential for maintaining blood glucose levels and coordinating anabolic and catabolic pathways. A key step in this process is the delivery of G6P into the endoplasmic reticulum (ER), where it is hydrolyzed by glucose 6 phosphatase to glucose and inorganic phosphate (Pi). This transport step is carried out by the ER carrier SLC37A4 (also known as the G6P transporter, G6PT), which imports G6P into the ER lumen while exporting Pi to the cytosol, and loss-of-function mutations in SLC37A4 cause glycogen storage disease type Ib. Despite its central role in G6P homeostasis, how SLC37A4 recognizes G6P and couples its transport to Pi antiport has remained unclear. Here we report cryo-electron microscopy structures of human SLC37A4 in three states: the apo form at 2.8 Å resolution, a G6P-bound state at 3.2 Å resolution and a chlorogenic acid (CHA) bound state at 3.3 Å resolution. SLC37A4 adopts the canonical Major Facilitator Superfamily fold and harbors a central, positively charged cavity that accommodates anionic substrates. In the G6P-bound structure, SLC37A4 adopts an outward-open conformation facing the ER lumen, in which G6P binds to the electropositive pocket. In the CHA-bound structure, SLC37A4 adopts an inward-facing conformation, with CHA bound at a cytosolic site that locks the transporter in an arrested state and prevents the conformational transitions required for G6P/Pi exchange. Combined with thermostability and transport-based analyses of G6P binding and disease variants, these structures support a rocker switch mechanism in which electrostatic neutralization of the central positively charged cavity by anionic substrate drives the conformational changes underlying G6P/Pi exchange. Together, these findings define the structural basis of G6P/Pi exchange by SLC37A4, provide a molecular rationale for pathogenic mutations in glycogen storage disease type Ib, and provide a framework for targeting SLC37A4 to modulate G6P homeostasis.
2026-07-23 | Base editing for precision therapeutics.
Base editing (BE), the precise installation of single-nucleotide changes in DNA or RNA without inducing double-strand breaks, holds substantial therapeutic promise for correcting single-nucleotide variants, which constitute more than half of the known pathogenic genetic variants. Recent advances have improved base editor specificity, efficiency, and delivery, enabling clinically oriented procedures. Clinically, BE has shown early success or strong translational promise in sickle cell disease, β-thalassemia, leukemia (via CAR T and epitope engineering), hypercholesterolemia (PCSK9 and ANGPTL3), alpha-1-antitrypsin deficiency, and glycogen storage disease type Ia. Key remaining challenges include bystander editing within the activity window, residual off-target DNA and RNA editing, delivery constraints (payload size, tissue targeting, and redosing limits), immunogenicity, and the need for durable long-term safety evidence across relevant cell types and disease contexts. Continued technological refinements, careful preclinical validation, and rigorous clinical assessment will be essential to fully realize BE's transformative potential in precision medicine.
2026-08-14 | Empagliflozin in GSD-Ib: Long-term safety and sustained recovery of neutrophil function including NET formation.
Glycogen storage disease type Ib (GSD-Ib) engenders neutropenia and severe neutrophil dysfunction, leading to recurrent infections and inflammatory complications. Recent studies have identified intracellular accumulation of 1,5-anhydroglucitol-6-phosphate (1,5-AG6P) as a key mechanism underlying neutrophil impairment and have suggested therapeutic benefits of sodium-glucose cotransporter 2 (SGLT2) inhibitors, which lower plasma levels of its precursor 1,5-AG. In this study, we performed a four-year longitudinal evaluation of empagliflozin therapy in a genetically confirmed GSD-Ib infant, contributing to the growing body of long-term data on empagliflozin treatment in GSD-Ib. Routine laboratory parameters and key neutrophil effector functions were assessed before and during treatment, as well as in two additional GSD-Ib patients with and without therapy. Empagliflozin therapy resulted in complete restoration of neutrophil function, including reactive oxygen species (ROS) production and bactericidal activity. Notably, neutrophil extracellular trap (NET) formation and neutrophil survival recovered to levels comparable to healthy donors. These functional improvements occurred in conjunction with reduced plasma 1,5-AG levels, supporting the concept that GSD-Ib neutrophils are sensitive to physiological 1,5-AG concentrations. Functional recovery and normalization of neutrophil survival observed in vitro, was paralleled by improvement of absolute neutrophil counts to low-normal levels in vivo. Clinically, treatment was associated with a substantial reduction of severe infections. Collectively, these findings further support that empagliflozin corrects neutrophil dysfunction in GSD-Ib and demonstrate its potential to improve long-term clinical outcome across the lifespan, from infancy through adulthood.
2026-08-08 | ApoC-III Antisense Oligonucleotide Therapy Used in Glycogen Storage Disease Type 1a.
Glycogen storage disease type 1a (GSD1a) is an autosomal recessive disorder characterized by impaired glycogenolysis and gluconeogenesis. Individuals with GSD1a manifest significant hypertriglyceridemia refractory to dietary and lipid-lowering medication therapies. Apolipoprotein C-III antisense oligonucleotide (apoCIII-ASO) therapy is approved to reduce severe hypertriglyceridemia in familial chylomicronemia syndrome but is also effective in moderate hypertriglyceridemia of varied genetic backgrounds. We describe a 22-year-old with GSD1a and hypertriglyceridemia with past pancreatitis despite fibric acid derivative, niacin, and bempedoic acid therapy in whom apoCIII-ASO was associated with triglyceride reduction from 4,951 to 1,643 mg/dL. As GSD1a-associated hypertriglyceridemia is often refractory to standard therapies, apoCIII-ASO therapy may offer promise as a treatment. This case describes the first use of apoCIII-ASO in GSD1a-related hypertriglyceridemia. GSD1a-driven hypertriglyceridemia may be treatable using apoCIII-ASO.
2026-07-28 | Sequence determinants of pathogenicity in glucose-6-phosphatase linked to glycogen storage disease type 1a
Glycogen storage disease type 1a (GSD1a) is an autosomal recessive Mendelian disorder that can be caused by missense variants in glucose-6-phosphatase catalytic subunit 1 (G6PC1). Although hundreds of missense variants have been identified, the vast majority are of unknown clinical significance, and the molecular mechanism(s) of bona fide pathogenic variants are ill-defined. We combine bioinformatic data and clinical associations with the protein language model AlphaMissense to guide mechanistic exploration of 78 missense variants at 55 residue positions using robust biochemical and biophysical assays to distill general principles of enzyme dysfunction. Correlation analysis established a strong linear relationship between folded G6PC1 abundance and catalytic capacity for most variants. Pathogenic variants within this paradigm were linked to compromised stability and activation of the unfolded protein response. However, outliers characterized by relatively high abundance, yet low activity clustered to a network of sidechains adjacent to the active site that allosterically modulate catalysis. Contextualized by recent high-resolution structures and AlphaFold modeling, our holistic analysis of G6PC1 in vitro metrics facilitates clinical (re)classification of variants according to explicit molecular phenotypes and identifies therapeutic design directions. Moreover, our approach illustrates a blueprint for variant characterization that integrates computational prediction with experimental validation to discover disease etiology.
2026-07-28 | Structural basis for substrate recognition and inhibition of human glucose-6-phosphate transporter SLC37A4.
Glucose 6 phosphate (G6P) homeostasis is essential for maintaining blood glucose levels and coordinating anabolic and catabolic pathways. A key step in this process is the delivery of G6P into the endoplasmic reticulum (ER), where it is hydrolyzed by glucose 6 phosphatase to glucose and inorganic phosphate (Pi). This transport step is carried out by the ER carrier SLC37A4 (also known as the G6P transporter, G6PT), which imports G6P into the ER lumen while exporting Pi to the cytosol, and loss-of-function mutations in SLC37A4 cause glycogen storage disease type Ib. Despite its central role in G6P homeostasis, how SLC37A4 recognizes G6P and couples its transport to Pi antiport has remained unclear. Here we report cryo-electron microscopy structures of human SLC37A4 in three states: the apo form at 2.8 Å resolution, a G6P-bound state at 3.2 Å resolution and a chlorogenic acid (CHA) bound state at 3.3 Å resolution. SLC37A4 adopts the canonical Major Facilitator Superfamily fold and harbors a central, positively charged cavity that accommodates anionic substrates. In the G6P-bound structure, SLC37A4 adopts an outward-open conformation facing the ER lumen, in which G6P binds to the electropositive pocket. In the CHA-bound structure, SLC37A4 adopts an inward-facing conformation, with CHA bound at a cytosolic site that locks the transporter in an arrested state and prevents the conformational transitions required for G6P/Pi exchange. Combined with thermostability and transport-based analyses of G6P binding and disease variants, these structures support a rocker switch mechanism in which electrostatic neutralization of the central positively charged cavity by anionic substrate drives the conformational changes underlying G6P/Pi exchange. Together, these findings define the structural basis of G6P/Pi exchange by SLC37A4, provide a molecular rationale for pathogenic mutations in glycogen storage disease type Ib, and provide a framework for targeting SLC37A4 to modulate G6P homeostasis.
2026-07-23 | Base editing for precision therapeutics.
Base editing (BE), the precise installation of single-nucleotide changes in DNA or RNA without inducing double-strand breaks, holds substantial therapeutic promise for correcting single-nucleotide variants, which constitute more than half of the known pathogenic genetic variants. Recent advances have improved base editor specificity, efficiency, and delivery, enabling clinically oriented procedures. Clinically, BE has shown early success or strong translational promise in sickle cell disease, β-thalassemia, leukemia (via CAR T and epitope engineering), hypercholesterolemia (PCSK9 and ANGPTL3), alpha-1-antitrypsin deficiency, and glycogen storage disease type Ia. Key remaining challenges include bystander editing within the activity window, residual off-target DNA and RNA editing, delivery constraints (payload size, tissue targeting, and redosing limits), immunogenicity, and the need for durable long-term safety evidence across relevant cell types and disease contexts. Continued technological refinements, careful preclinical validation, and rigorous clinical assessment will be essential to fully realize BE's transformative potential in precision medicine.
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Drug Discovery Landscape
3 orphan drug designations for Glycogen storage disease due to glucose-6-phosphatase deficiency.
3 orphan drug designations for Glycogen storage disease due to glucose-6-phosphatase deficiency.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Diazoxide choline | small molecules | EMA | 2024-12-13 | — | Soleno Therapeutics Europe Limited |
Diazoxide Choline | small molecules | FDA | 2021-05-26 | — | Soleno Therapeutics, Inc. |
recombinant adeno-associated virus serotype 8 vector encoding human glucose-6-phosphatase-alpha (G6Pase or G6PC) | gene therapies | FDA | 2016-09-28 | — | Ultragenyx Pharmaceutical, Inc. |
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