RARE DISEASE
Glycogen storage disease due to glucose-6-phosphatase deficiency type Ia
Glycogen storage disease due to glucose-6-phosphatase deficiency type Ia
Glycogen storage disease due to glucose-6-phosphatase deficiency type Ia
Synonyms: G6P deficiency type 1a, GSD due to G6P deficiency type 1a, GSD due to G6P deficiency type Ia, GSD type 1a, GSDIa, Glycogen storage disease due to G6P deficiency type Ia, Glycogen storage disease type 1a, Glycogenosis due to glucose-6-phosphatase deficiency type 1a, Glycogenosis due to glucose-6-phosphatase deficiency type Ia, Glycogenosis type Ia
Synonyms: G6P deficiency type 1a, GSD due to G6P deficiency type 1a, GSD due to G6P deficiency type Ia, GSD type 1a, GSDIa, Glycogen storage disease due to G6P deficiency type Ia, Glycogen storage disease type 1a, Glycogenosis due to glucose-6-phosphatase deficiency type 1a, Glycogenosis due to glucose-6-phosphatase deficiency type Ia, Glycogenosis type Ia
Synonyms: G6P deficiency type 1a, GSD due to G6P deficiency type 1a, GSD due to G6P deficiency type Ia, GSD type 1a, GSDIa, Glycogen storage disease due to G6P deficiency type Ia, Glycogen storage disease type 1a, Glycogenosis due to glucose-6-phosphatase deficiency type 1a, Glycogenosis due to glucose-6-phosphatase deficiency type Ia, Glycogenosis type Ia
Drug discovery
5
drugs
With orphan designations
Overview
Glycogen Storage Disease Type Ia (GSD Ia) is a rare autosomal recessive disorder caused by G6PC gene mutations, leading to glucose-6-phosphatase deficiency. This impairs glycogenolysis and gluconeogenesis, resulting in fasting hypoglycemia, hepatomegaly, lactic acidosis, hyperuricemia, and hyperlipidemia. Chronic complications include hepatic adenomas, renal dysfunction, and osteoporosis. Diagnosis typically occurs in infancy (3–4 months) with hypoglycemic seizures and hepatomegaly. Management focuses on dietary glucose stabilization, though complications persist despite treatment [1][4][12][15].
Burden
Physical: Progressive liver/kidney damage, adenoma risk (25–75% of adults), anemia, and osteoporosis [2][8][12].
Metabolic: Lifelong hypoglycemia risk, requiring strict dietary adherence [7][15].
Psychosocial: High caregiver burden, anxiety, and reduced quality of life due to dietary rigidity and monitoring demands [7][16].
Therapies
Dietary: Frequent carbohydrate intake, nocturnal enteral feeds, and uncooked cornstarch (UCCS) to prevent hypoglycemia [3][8][20].
Pharmacologic: Allopurinol (hyperuricemia), statins (dyslipidemia), ACE inhibitors (renal protection) [8][12].
Emerging Therapies: Phase III trials for AAV8-mediated gene therapy (NCT05139316) and mRNA therapy (NCT05095727) [10][13][16].
Categories: rare genetic diseases, rare hepatic diseases, rare inborn errors of metabolism, rare renal diseases, rare transplant-related disorders
Research Papers
217 drug discovery papers about Glycogen storage disease due to glucose-6-phosphatase deficiency type Ia, with 4 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
217 drug discovery papers about Glycogen storage disease due to glucose-6-phosphatase deficiency type Ia, with 4 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
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.
2026-06-11 | 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.
2026-03-20 | Infantile extreme hypertriglyceridemia diagnosed as glycogen storage disease type Ia: A case report.
Glycogen storage disease type Ia (GSD Ia) typically presents with fasting hypoglycemia and hyperlipidemia. Atypical infantile presentations can delay diagnosis. We report an infant with extreme hypertriglyceridemia ultimately diagnosed as GSD Ia. A 5-month-old girl presented with poor appetite, growth retardation, hepatomegaly, and extreme hypertriglyceridemia (72 mmol/L), hypercholesterolemia, elevated transaminases, hyperuricemia, and hyperlactatemia, but initial normal blood glucose. Initial differentials included familial hypertriglyceridemia, but metabolic screening was normal. Whole-exome sequencing confirmed GSD Ia with compound heterozygous G6PC mutations (c.648G>T and c.814G>T). Initial lipid-lowering (low-fat diet, fenofibrate, omega-3, plasma exchange) reduced triglyceride. Post-diagnosis, she received lactose-free formula with frequent feeds and nocturnal nutrition; uncooked cornstarch was introduced at 6 months, though adherence was initially poor. Metabolic control was unstable until age 2 due to poor adherence. After 24 months of structured cornstarch therapy, fasting glucose normalized (4.2-6.6 mmol/L), triglycerides decreased (1.8-6.7 mmol/L), and catch-up growth occurred (height Z-score from -3.9 to -2.2 by 36 months). GSD Ia should be considered in infantile extreme hypertriglyceridemia with growth retardation, even without classic hypoglycemia. Sustained metabolic control requires multidisciplinary strategies addressing both biochemical and adherence barriers.
2026-02-12 | Trial Interviews to Explore Glycogen Storage Disease Type Ia Patient Experiences Following Gene Therapy
Background: Glycogen storage disease type Ia (GSDIa) is a rare, inherited, autosomal recessive deficiency of glucose-6-phosphatase (G6Pase), an enzyme necessary in glycogenolysis and gluconeogenesis. To maintain normal blood glucose levels and ensure survival, individuals living with GSDIa must frequently consume complex carbohydrates (eg, uncooked cornstarch). Dietary management can result in chronic complications and significant patient burden. DTX401 (pariglasgene brecaparvovec) is an investigational adeno-associated virus serotype 8 vector (AAV8)–based gene therapy designed to restore endogenous glucose production. Objectives: Patient experience interviews were conducted as part of an open-label, phase 1/2 dose-escalation trial (NCT03517085) evaluating the safety and efficacy of DTX401 in adults ≥18 years with GSDIa. Methods: Telephone interviews were conducted at Weeks 24, 52, and 104, using a semistructured interview guide. Qualitative interview data were audio recorded, transcribed, coded, and analyzed. Results: Most (86%; n = 6/7) reported overall symptom improvement and reduced burden following DTX401 treatment. Three (43%) reported no negative outcomes following gene therapy; 4 (57%) mentioned at least one negative change attributed to instances of blood sugar instability, lifestyle, or diet adjustments. Satisfaction fluctuated across timepoints; however, most were somewhat satisfied/very satisfied with gene therapy at Weeks 24 (80%), 52 (86%), and 104 (86%). No participants reported being very dissatisfied. Discussion: Following DTX401 treatment, most participants reported substantial reduction in cornstarch intake and corresponding improvements in symptoms, physical function, diet management, emotional function, self-perception, social function, sleep quality, work performance, and overall health. Few negative changes were reported. While some results regarding met expectations were mixed, most indicated they would still want gene therapy even if they had to continue cornstarch and if they had continued diet restrictions, and most reported satisfaction with treatment. While the study had limitations, interview results suggest that DTX401 helps to address aspects of the condition and treatment that patients have identified as burdensome. Conclusions: Most interviewees in this open-label trial of investigational DTX401 described positive experiences, including substantial reduction in burden and improved health-related quality of life following treatment throughout the trial. To optimize patient outcomes and experience with gene therapy, guidance on and close monitoring of dietary changes during implementation should be provided.
2026-01-07 | Congenital nephrotic syndrome in a newborn with glycogen storage disease and Wilms tumor 1 (WT1) mutation.
Genetic disorders in neonates often present with overlapping clinical features, posing significant diagnostic challenges. Glycogen storage diseases (GSD) disrupt glycogen metabolism, leading to energy deficits. Pathogenic variants in the Wilms tumor 1 (WT1) gene represent a rare but significant cause of early-onset steroid-resistant nephrotic syndrome (SRNS), associated with a broad range of both kidney and extrakidney phenotypic manifestations. The coexistence of these genetic diseases in a single patient has not been previously reported. Herein, we present a case of a newborn with symptomatic hypoglycemia and metabolic acidosis that was transferred to the Neonatal Intensive Care Unit. During hospitalization, he developed hyponatremia and nephrotic-range proteinuria, a genetic test was performed, and he was transferred to the nephrology unit. Genetic analysis identified a compound homozygous mutation (c.247 C > T) in the G6PC gene, confirming glycogen storage disease type 1a (GSD-1a) and a pathogenic WT1 mutation (c.1400G > A) associated with Denys-Drash syndrome. This case highlights the importance of a multidisciplinary approach in the evaluation and management of neonates with a complex combination of genetically-determined conditions.
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.
2026-06-11 | 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.
2026-03-20 | Infantile extreme hypertriglyceridemia diagnosed as glycogen storage disease type Ia: A case report.
Glycogen storage disease type Ia (GSD Ia) typically presents with fasting hypoglycemia and hyperlipidemia. Atypical infantile presentations can delay diagnosis. We report an infant with extreme hypertriglyceridemia ultimately diagnosed as GSD Ia. A 5-month-old girl presented with poor appetite, growth retardation, hepatomegaly, and extreme hypertriglyceridemia (72 mmol/L), hypercholesterolemia, elevated transaminases, hyperuricemia, and hyperlactatemia, but initial normal blood glucose. Initial differentials included familial hypertriglyceridemia, but metabolic screening was normal. Whole-exome sequencing confirmed GSD Ia with compound heterozygous G6PC mutations (c.648G>T and c.814G>T). Initial lipid-lowering (low-fat diet, fenofibrate, omega-3, plasma exchange) reduced triglyceride. Post-diagnosis, she received lactose-free formula with frequent feeds and nocturnal nutrition; uncooked cornstarch was introduced at 6 months, though adherence was initially poor. Metabolic control was unstable until age 2 due to poor adherence. After 24 months of structured cornstarch therapy, fasting glucose normalized (4.2-6.6 mmol/L), triglycerides decreased (1.8-6.7 mmol/L), and catch-up growth occurred (height Z-score from -3.9 to -2.2 by 36 months). GSD Ia should be considered in infantile extreme hypertriglyceridemia with growth retardation, even without classic hypoglycemia. Sustained metabolic control requires multidisciplinary strategies addressing both biochemical and adherence barriers.
2026-02-12 | Trial Interviews to Explore Glycogen Storage Disease Type Ia Patient Experiences Following Gene Therapy
Background: Glycogen storage disease type Ia (GSDIa) is a rare, inherited, autosomal recessive deficiency of glucose-6-phosphatase (G6Pase), an enzyme necessary in glycogenolysis and gluconeogenesis. To maintain normal blood glucose levels and ensure survival, individuals living with GSDIa must frequently consume complex carbohydrates (eg, uncooked cornstarch). Dietary management can result in chronic complications and significant patient burden. DTX401 (pariglasgene brecaparvovec) is an investigational adeno-associated virus serotype 8 vector (AAV8)–based gene therapy designed to restore endogenous glucose production. Objectives: Patient experience interviews were conducted as part of an open-label, phase 1/2 dose-escalation trial (NCT03517085) evaluating the safety and efficacy of DTX401 in adults ≥18 years with GSDIa. Methods: Telephone interviews were conducted at Weeks 24, 52, and 104, using a semistructured interview guide. Qualitative interview data were audio recorded, transcribed, coded, and analyzed. Results: Most (86%; n = 6/7) reported overall symptom improvement and reduced burden following DTX401 treatment. Three (43%) reported no negative outcomes following gene therapy; 4 (57%) mentioned at least one negative change attributed to instances of blood sugar instability, lifestyle, or diet adjustments. Satisfaction fluctuated across timepoints; however, most were somewhat satisfied/very satisfied with gene therapy at Weeks 24 (80%), 52 (86%), and 104 (86%). No participants reported being very dissatisfied. Discussion: Following DTX401 treatment, most participants reported substantial reduction in cornstarch intake and corresponding improvements in symptoms, physical function, diet management, emotional function, self-perception, social function, sleep quality, work performance, and overall health. Few negative changes were reported. While some results regarding met expectations were mixed, most indicated they would still want gene therapy even if they had to continue cornstarch and if they had continued diet restrictions, and most reported satisfaction with treatment. While the study had limitations, interview results suggest that DTX401 helps to address aspects of the condition and treatment that patients have identified as burdensome. Conclusions: Most interviewees in this open-label trial of investigational DTX401 described positive experiences, including substantial reduction in burden and improved health-related quality of life following treatment throughout the trial. To optimize patient outcomes and experience with gene therapy, guidance on and close monitoring of dietary changes during implementation should be provided.
2026-01-07 | Congenital nephrotic syndrome in a newborn with glycogen storage disease and Wilms tumor 1 (WT1) mutation.
Genetic disorders in neonates often present with overlapping clinical features, posing significant diagnostic challenges. Glycogen storage diseases (GSD) disrupt glycogen metabolism, leading to energy deficits. Pathogenic variants in the Wilms tumor 1 (WT1) gene represent a rare but significant cause of early-onset steroid-resistant nephrotic syndrome (SRNS), associated with a broad range of both kidney and extrakidney phenotypic manifestations. The coexistence of these genetic diseases in a single patient has not been previously reported. Herein, we present a case of a newborn with symptomatic hypoglycemia and metabolic acidosis that was transferred to the Neonatal Intensive Care Unit. During hospitalization, he developed hyponatremia and nephrotic-range proteinuria, a genetic test was performed, and he was transferred to the nephrology unit. Genetic analysis identified a compound homozygous mutation (c.247 C > T) in the G6PC gene, confirming glycogen storage disease type 1a (GSD-1a) and a pathogenic WT1 mutation (c.1400G > A) associated with Denys-Drash syndrome. This case highlights the importance of a multidisciplinary approach in the evaluation and management of neonates with a complex combination of genetically-determined conditions.
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Drug Discovery Landscape
5 orphan drug designations for Glycogen storage disease due to glucose-6-phosphatase deficiency type Ia.
5 orphan drug designations for Glycogen storage disease due to glucose-6-phosphatase deficiency type Ia.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
mRNA encoding human glucose-6-phosphatase variant S298C | RNAs | EMA | 2022-01-14 | — | Moderna Biotech Spain S.L. |
Modified mRNA that encodes human glucose-6-phosphatase-alpha | RNAs | FDA | 2021-08-27 | — | ModernaTX, Inc. |
Adeno-associated viral vector serotype 8 containing the human glucose-6-phosphatase gene | gene therapies | EMA | 2016-11-18 | — | Ultragenyx Germany GmbH |
amylopectin | gene therapies | FDA | 2015-03-24 | — | Voltera Pharmaceuticals, LLC |
AAV-G6Pase vector | gene therapies | FDA | 2013-03-11 | — | GlyGenix Therapeutics, Inc. |
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