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
412 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:
412 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:
2026-06-11 | Hepatocyte-specific Cas9-mediated editing of G6pc and Slc37a4 elicits comparable biochemical and regulatory responses between glycogen storage disease (GSD) type Ia and Ib mice.
Glycogen storage disease type I (GSD I) is an autosomal recessive inborn error of carbohydrate metabolism. Patients with GSD type Ia and Ib exhibit overlapping and distinct symptoms and complications. Notably, GSD Ia patients show more severe hypertriglyceridemia and higher risk of hepatic tumors than GSD Ib patients. Given the liver's pivotal role in these processes, this study utilized hepatocyte-specific CRISPR/Cas9-mediated somatic gene editing to explore the pathophysiological and biochemical adaptations in hepatic GSD Ia and Ib side-by-side. Additionally, hepatic histology, transcriptomics, and proteomics analysis was performed. Compared to controls, hepatic GSD Ia and Ib mice showed hepatomegaly, fasting hypoglycemia, hyperlactatemia, and increased uric acid in plasma, which was somewhat more pronounced in GSD Ia than Ib. Both GSD I subtypes showed similar reductions in hepatic acetyl-CoA precursor pool enrichment and increases in de novo biosynthesis of hepatic stearate and oleate. Interestingly, only GSD Ia mice showed mildly elevated plasma triglyceride and hepatic phosphate sugars. Metabolic changes were reflected at the transcriptomic and proteomic levels, with largely similar responses between GSD Ia and Ib livers. Moreover, altered mRNAs and protein levels related to nucleotide-binding oligomerization domain (NOD) signaling pathways, infection and inflammation, liver disease, and chemical carcinogenesis were somewhat more pronounced in hepatic GSD Ia than in GSD Ib mice. Overall, the metabolic disturbance was more severe in hepatocyte-specific GSD Ia than in GSD Ib mice, consistent with the clinical phenotype in patients. The metabolic disorders and specific metabolites, genes, and proteins identified in this study provided new insights into the pathophysiological and biochemical phenotypes of GSD I subtypes in the liver.
2026-05-04 | Shifting Towards Empagliflozin First-Line Therapy in Glycogen Storage Disease Type Ib: A Nationwide Real-World Study.
Neutrophil dysfunction and neutropenia are burdensome findings in glycogen storage disease type Ib (GSDIb). Treatment with granulocyte-colony stimulating factor (G-CSF) often corrects neutropenia but fails to improve clinical symptoms like inflammatory bowel disease (IBD). Recently, empagliflozin (EMPA) was shown to correct the neutrophil dysfunction and its clinical consequences. It is increasingly used as first-line monotherapy, but long-term, real-world data are lacking. This nation-wide retrospective study investigated 42 GSD1b patients (36 children) treated with EMPA as first-line monotherapy and compared them with those receiving combination therapy with G-CSF and treatment-naïve patients (I:EMPA first-line monotherapy [n = 9]; II:G-CSF monotherapy [n = 7]; III:EMPA plus G-CSF [n = 16]; and IV: neither EMPA nor GCSF [n = 10]). Pediatric (P) patients were evaluated separately. In pediatric patients receiving EMPA as first-line monotherapy (P-I) and those with EMPA plus G-CSF (P-III), the frequency of infections, hospital admissions, and IBD was significantly lower than in patients receiving GCSF-monotherapy (P-II) or no treatment (P-IV). Additionally, significantly improved weight gain was observed in P-I. While clinical improvement related to correction of neutrophil dysfunction was seen with EMPA first-line monotherapy (P-I), significant improvement in absolute neutrophil count (ANC) and hemoglobin levels was only seen in P-III with additional G-CSF treatment. In three cases, EMPA was safely paused and subsequently resumed, for example, during pregnancy or liver transplantation. First-line EMPA monotherapy effectively corrects clinical symptoms of neutrophil dysfunction in GSD Ib patients, even in the absence of a statistically significant increase in ANC.
2026-04-14 | Effects of Extended-Release Cornstarch Supplementation on Glycemic Stability and Metabolic Parameters in Korean Patients with Glycogen Storage Disease.
Background/Objectives: Patients with hepatic glycogen storage disease (GSD) require frequent nighttime intake of uncooked corn starch (UCCS) to prevent fasting hypoglycemia, which imposes a substantial burden. Glycosade, an extended-release cornstarch, was developed to prolong overnight glucose availability. However, data regarding South Korean patients are limited. Therefore, we aimed to evaluate the efficacy and safety of Glycosade in South Korean patients with hepatic GSD. Methods: In this single-center prospective observational study, patients with hepatic GSD underwent laboratory evaluations before and 1 month after Glycosade administration. Continuous glucose monitoring (CGM) was performed during UCCS and Glycosade administration periods. The nocturnal mean glucose, coefficient of variation, time in range (70-180 mg/dL), and time below the range (<70 and <54 mg/dL) were compared between the periods using paired analyses. Results: No significant differences were observed in the nocturnal CGM metrics between the treatment periods. However, time-aligned CGM profiles revealed distinct temporal patterns, with a decline in glucose levels approximately 3-4 h after UCCS intake, whereas Glycosade showed a more sustained glucose profile over an extended period. Liver enzyme and lipid levels improved significantly after 1 month of Glycosade supplementation. Conclusions: In a cohort of South Korean patients with hepatic GSD, Glycosade maintained nocturnal glycemic stability comparable to that of conventional cornstarch without increasing the risk of hypoglycemia. Glycosade was also associated with improved biochemical parameters, supporting its role in nighttime dietary management.
2026-06-11 | Hepatocyte-specific Cas9-mediated editing of G6pc and Slc37a4 elicits comparable biochemical and regulatory responses between glycogen storage disease (GSD) type Ia and Ib mice.
Glycogen storage disease type I (GSD I) is an autosomal recessive inborn error of carbohydrate metabolism. Patients with GSD type Ia and Ib exhibit overlapping and distinct symptoms and complications. Notably, GSD Ia patients show more severe hypertriglyceridemia and higher risk of hepatic tumors than GSD Ib patients. Given the liver's pivotal role in these processes, this study utilized hepatocyte-specific CRISPR/Cas9-mediated somatic gene editing to explore the pathophysiological and biochemical adaptations in hepatic GSD Ia and Ib side-by-side. Additionally, hepatic histology, transcriptomics, and proteomics analysis was performed. Compared to controls, hepatic GSD Ia and Ib mice showed hepatomegaly, fasting hypoglycemia, hyperlactatemia, and increased uric acid in plasma, which was somewhat more pronounced in GSD Ia than Ib. Both GSD I subtypes showed similar reductions in hepatic acetyl-CoA precursor pool enrichment and increases in de novo biosynthesis of hepatic stearate and oleate. Interestingly, only GSD Ia mice showed mildly elevated plasma triglyceride and hepatic phosphate sugars. Metabolic changes were reflected at the transcriptomic and proteomic levels, with largely similar responses between GSD Ia and Ib livers. Moreover, altered mRNAs and protein levels related to nucleotide-binding oligomerization domain (NOD) signaling pathways, infection and inflammation, liver disease, and chemical carcinogenesis were somewhat more pronounced in hepatic GSD Ia than in GSD Ib mice. Overall, the metabolic disturbance was more severe in hepatocyte-specific GSD Ia than in GSD Ib mice, consistent with the clinical phenotype in patients. The metabolic disorders and specific metabolites, genes, and proteins identified in this study provided new insights into the pathophysiological and biochemical phenotypes of GSD I subtypes in the liver.
2026-05-04 | Shifting Towards Empagliflozin First-Line Therapy in Glycogen Storage Disease Type Ib: A Nationwide Real-World Study.
Neutrophil dysfunction and neutropenia are burdensome findings in glycogen storage disease type Ib (GSDIb). Treatment with granulocyte-colony stimulating factor (G-CSF) often corrects neutropenia but fails to improve clinical symptoms like inflammatory bowel disease (IBD). Recently, empagliflozin (EMPA) was shown to correct the neutrophil dysfunction and its clinical consequences. It is increasingly used as first-line monotherapy, but long-term, real-world data are lacking. This nation-wide retrospective study investigated 42 GSD1b patients (36 children) treated with EMPA as first-line monotherapy and compared them with those receiving combination therapy with G-CSF and treatment-naïve patients (I:EMPA first-line monotherapy [n = 9]; II:G-CSF monotherapy [n = 7]; III:EMPA plus G-CSF [n = 16]; and IV: neither EMPA nor GCSF [n = 10]). Pediatric (P) patients were evaluated separately. In pediatric patients receiving EMPA as first-line monotherapy (P-I) and those with EMPA plus G-CSF (P-III), the frequency of infections, hospital admissions, and IBD was significantly lower than in patients receiving GCSF-monotherapy (P-II) or no treatment (P-IV). Additionally, significantly improved weight gain was observed in P-I. While clinical improvement related to correction of neutrophil dysfunction was seen with EMPA first-line monotherapy (P-I), significant improvement in absolute neutrophil count (ANC) and hemoglobin levels was only seen in P-III with additional G-CSF treatment. In three cases, EMPA was safely paused and subsequently resumed, for example, during pregnancy or liver transplantation. First-line EMPA monotherapy effectively corrects clinical symptoms of neutrophil dysfunction in GSD Ib patients, even in the absence of a statistically significant increase in ANC.
2026-04-14 | Effects of Extended-Release Cornstarch Supplementation on Glycemic Stability and Metabolic Parameters in Korean Patients with Glycogen Storage Disease.
Background/Objectives: Patients with hepatic glycogen storage disease (GSD) require frequent nighttime intake of uncooked corn starch (UCCS) to prevent fasting hypoglycemia, which imposes a substantial burden. Glycosade, an extended-release cornstarch, was developed to prolong overnight glucose availability. However, data regarding South Korean patients are limited. Therefore, we aimed to evaluate the efficacy and safety of Glycosade in South Korean patients with hepatic GSD. Methods: In this single-center prospective observational study, patients with hepatic GSD underwent laboratory evaluations before and 1 month after Glycosade administration. Continuous glucose monitoring (CGM) was performed during UCCS and Glycosade administration periods. The nocturnal mean glucose, coefficient of variation, time in range (70-180 mg/dL), and time below the range (<70 and <54 mg/dL) were compared between the periods using paired analyses. Results: No significant differences were observed in the nocturnal CGM metrics between the treatment periods. However, time-aligned CGM profiles revealed distinct temporal patterns, with a decline in glucose levels approximately 3-4 h after UCCS intake, whereas Glycosade showed a more sustained glucose profile over an extended period. Liver enzyme and lipid levels improved significantly after 1 month of Glycosade supplementation. Conclusions: In a cohort of South Korean patients with hepatic GSD, Glycosade maintained nocturnal glycemic stability comparable to that of conventional cornstarch without increasing the risk of hypoglycemia. Glycosade was also associated with improved biochemical parameters, supporting its role in nighttime dietary management.
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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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