small molecules

2026-06-16 | [A cross-sectional survey on uncooked corn starch application and gastrointestinal complications in children with hepatic glycogen storage disease].

Objective: To evaluate the clinical characteristics and current utilization of uncooked cornstarch (UCCS) in children with hepatic glycogen storage disease (GSD), so as to investigate the association between UCCS intake and gastrointestinal (GI) complications. Methods: A cross-sectional study was conducted using the GSD cohort at Guangdong Provincial People's Hospital. Standardized questionnaire surveys were administered in July 2024 and July 2025 among 343 genetically confirmed pediatric patients with hepatic GSD. Data included demographic information, genetic subtypes, clinical features, UCCS intake regimens, GI symptoms and laboratory findings were collected. Participants were stratified by genetic subtype, age group, and median daily UCCS intake. Growth and nutritional status were evaluated according to World Health Organization (WHO) growth standards, using height-for-age Z-scores (HAZ) and BMI-for-age Z-scores (BMIZ) across age groups and genetic subtypes. Clinical manifestations, laboratory parameters, UCCS intake regimens, and the prevalence of GI symptoms were compared across genetic subtypes. The burden of GI symptoms was quantified using a severity score (ranging from 0 to 3), assigned based on the presence and number of reported symptoms. Between-group comparisons were performed using the Mann-Whitney U test. Binary and ordinal Logistic regression models were employed to assess the association between UCCS intake and the risk or severity of GI symptoms. Results: Among the 343 enrolled patients, the distribution by genetic subtype was as follows: 138 with type Ⅰa, 75 with type Ⅰb, 55 with type Ⅲ, 3 with type Ⅳ, 24 with type Ⅵ, and 48 with type Ⅸ. Distinct inter-subtype differences in clinical presentation were observed. Metabolic disturbances were most pronounced in types Ⅰa and Ⅰb: hyperlactatemia was highly prevalent in type Ⅰa (124/138, 89.9%) and type Ⅰb (71/75, 94.7%), and hypertriglyceridemia was common in type Ⅰa (104/138, 75.4%) and type Ⅰb (47/75, 62.7%). A total of 166(48.4%) children reported at least one GI symptom during the preceding month. Daily UCCS intake was 5.8 (3.6, 8.0) g/kg, with the highest intakes observed in subtype Ⅰa (7.0 (4.6, 8.8) g/kg) and subtype Ⅰb (6.6 (4.3, 9.2) g/kg). The GI symptom score in the high-dose group (168 cases) was higher than that in the low-dose group (175 cases)(1 (0,1) vs.0 (0,1), P<0.001). After adjustment for age, sex, and body mass index (BMI), UCCS intake remained an independent risk factor for GI symptoms (OR=1.12, P=0.006). Daily UCCS intake was also independently associated with anorexia, diarrhea, and nausea/vomiting (all P<0.05). Growth assessment revealed an overall stunting prevalence (HAZ<-2 s) of 20.6% (66/320), with the highest rates observed in subtype Ⅰb (38.8%, 26/67) and 11-18 years group (37.9%, 22/58). The overall prevalence of overweight or obesity (BMIZ>+2 s) was 18.1%, most notably elevated among 0-3 years group (22.7%, 22/97) and in subtype Ⅰa (22.7%, 29/128). Conclusions: Children with hepatic GSD exhibit marked clinical heterogeneity across subtypes. A clear dose-response relationship demonstrate between UCCS intake and GI symptom burden. Moreover, these patients face a dual nutritional challenge of stunting and overweight or obesity. In clinical practice, careful attention should be paid to individual UCCS tolerance and subtype-specific management strategies, balancing glycemic control, intestinal health, optimal growth and development.

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2026-01-28 | Safety of SGLT-2 inhibitors in patients with glycogen storage disease type Ib and their efficacy in treating disease-associated digestive symptoms and disorders.

Employing rigorous epidemiological approaches, we performed a systematic evaluation of Sodium Glucose Cotransporter-2 (SGLT-2) inhibitors for managing digestive system disorders and symptoms associated with Glycogen Storage Disease Type Ib (GSD Ib). Electronic searches were conducted in three databases, with the latest update on 27 October 2025 (PROSPERO reference: CRD420251021881). Two reviewers independently screened records by title and abstract for full-text review. Eligible studies meeting the predefined criteria were assessed for quality using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for observational studies and the Methodological Index for Non-Randomized Studies (MINORS) for clinical trials, followed by data extraction. Meta-analysis or descriptive synthesis was performed for six common GSD Ib-related digestive symptoms. Multiple studies reported improvement in abnormal gastrointestinal patterns following SGLT-2 inhibitor therapy. Meta-analysis further demonstrated symptomatic relief in moderate-to-severe IBD, recurrent oral mucosal lesions, and anemia, with pooled remission rates (95% CI) under the two models being: 81.1% (68.4%-89.5%) and 85.3% (63.6%-99.2%) for IBD; 81.5% (73.6%-87.4%) and 83.5% (75.7%-90.3%) for oral lesions; and 60.5% (52.6%-68.0%) and 63.8% (48.0%-78.3%) for anemia. Regarding safety, hypoglycemia was the most frequently reported adverse event, followed by urinary tract and genital infections. The efficacy analysis demonstrated beneficial effects of SGLT-2 inhibitors on six GSD Ib-related digestive disorders and its extra-digestive manifestations, showing potential for improving abnormal gastrointestinal patterns, moderate-to-severe inflammatory bowel disease, recurrent oral mucosal lesions, and anemia.

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2026-01-01 | Continuous Glucose Monitoring–Driven Personalization of Cornstarch Therapy in Glycogen Storage Disease: A Retrospective Analysis

PURPOSE: Hepatic glycogen storage diseases (GSD), including types Ia, Ib, and IXa, are rare inherited disorders characterized by impaired hepatic glucose homeostasis. In GSD Ia, deficiency of glucose-6-phosphatase results in recurrent hypoglycemia and metabolic disturbances. Uncooked cornstarch (UCCS) is the standard therapy due to its slow digestion and sustained glucose release; however, dosing requirements vary according to age, digestion rate, metabolic demand, and lifestyle. Despite the central role of UCCS in long-term management, real-world data describing extended continuous glucose monitoring (CGM) patterns in hepatic GSD are extremely limited, and objective evidence guiding individualized dose adjustment remains scarce. This study examined CGM profiles in patients with hepatic GSD receiving long-term UCCS therapy and assessed the clinical utility of CGM in guiding individualized dosing adjustments. MATERIALS AND METHODS: We performed a retrospective, multi-year analysis of CGM data from 32 patients with hepatic GSD treated with UCCS. CGM traces were processed using 15-minute resampling, constrained interpolation, and physiologic clipping (40-400 mg/dL). Data were segmented into non-overlapping, calendar-anchored 7- and 14-day windows (anchor at 00:00) and retained when coverage was ≥70%. Per window, we calculated time in range (TIR, 70-150 mg/dL), time below range (TBR, <70 mg/dL), time above range (≥150 mg/dL), coefficient of variation, nocturnal TBR (00:00-06:00), and hypoglycemia burden [area under the curve (AUC) <70 mg/dL]. RESULTS: During routine clinic follow-up, CGM-informed, patient-specific UCCS and dietary adjustments maintained high TIR and low glycemic variability. Growth parameters and liver enzyme levels remained within normal limits. Episodes of recurrent nocturnal hypoglycemia identified on CGM prompted targeted modifications of UCCS dosing. CONCLUSION: A CGM-guided approach facilitates personalized UCCS management in hepatic GSD. Systematic review of TIR, nocturnal TBR, and AUC <70 mg/dL, alongside growth and liver assessments, provides a practical framework for optimizing long-term metabolic stability.

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2025-09-27 | Two Cases of Pulmonary Hypertension Associated with Glycogen Storage Disease

Abstract Background: Glycogen storage disease (GSD) is a group of diseases characterized by a defect of gene expression of the enzymes in the glycogen synthesis.Pulmonary arterial hypertension (PAH) is a rare complications of GSD, which could lead to right heart failure and even dead. Methods: We now report two patients with GSD and PH.We recorded and analyzed the course of the two cases, the blood test results including blood routine, biochemical function, blood gas analysis, common examinations including electrocardiogram, cardiac ultrasound, lung function, chest CT, and targeted drug treatment. Results: The first patient was 39-year-old women with a history of growth retardation and recurrent hypoglycemia and hyperlipidemia. In the past, she had been receiving regular corn starch supplementary food treatment. She was diagnosed with PH through right heart catheterization, mean pulmonary artery pressure(mPAP) was 61mmHg and she began to receive macitentan combined with sildenafil. Another patient was a 34-year-old woman hospitalized in 2018 because of shortness of breath. Echocardiography showed that PASP was 90 mmHg. Right cardiac catheterization showed that the mPAP was 45 mmHg. She was previously diagnosed with GSDI type by exon transcript sequencing, which suggest the presence of G6PC1 mutation. During follow-up, she was first given bosentan and sildenafil.The targeted therapy was changed to riociguat combined with macitentan in2023. Both patients were followed up routine, and after 6 months / 7 years, their systems were significantly improved. Conclusions: We have found that macitentan-based combined targeted drug therapy can significantly alleviate the symptoms of patients with GSD and PH.

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2025-04-11 | Nutritional management and geno-phenotyping of clinical nutrition in patients with glycogen storage diseases type VI and IX.

Glycogen storage diseases type VI (GSD-VI) and type IX (GSD-IX) are rare inherited metabolic disorders caused by enzyme deficiencies that disrupt glycogen metabolism. The aim of this study was to analyze the clinical features, nutritional management and geno-phenotyping of clinical nutrition in a cohort of patients with GSD-VI and GSD-IX. A retrospective cohort study was conducted with 16 patients with GSD-VI and GSD-IX. Demographic characteristics, clinical and laboratory findings, and nutritional treatment outcomes were collected and analyzed. The mean patient age was 10.57 years (±4.81). The distribution of the diagnoses was as follows: GSD-IXa (3), GSD-IXb (6), GSD-IXc (1), and GSD-VI (6). The average age at diagnosis was 36.5 months (±42.2) (13-114 months) in the GSD-VI group. Among the GSD-IX subgroups, the mean age at diagnosis varied: 23.3months (±4.16) for GSD-IXa, 35.7months (±17.5) for GSD-IXb, and 78months for GSD-IXc. Over the course of the study (4.5 ± 1.77 years), protein intake in GSD VI patients increased by 1.05 g/kg/day (91.3% increase), while in GSD IX patients, it rose by 1.09 g/kg/day (94% rise). Uncooked cornstarch (UCS) started at 1 g/kg/day for GSD-VI and 0.85 g/kg/day for GSD-IX, later reduced to 0.71 g/kg/day (29% decrease) and 0.52 g/kg/day (60% reduction), respectively. Overall, this paper provides valuable insights into managing GSDVI and GSDIX patients, emphasizing the role of a high-protein diet aligned with the disease's pathophysiology and the potential of genotyping to enhance nutritional treatment protocols.

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gene therapies

2023-07-08 | Gene therapy for glycogen storage diseases.

Glycogen storage disorders (GSDs) are inherited disorders of metabolism resulting from the deficiency of individual enzymes involved in the synthesis, transport, and degradation of glycogen. This literature review summarizes the development of gene therapy for the GSDs. The abnormal accumulation of glycogen and deficiency of glucose production in GSDs lead to unique symptoms based upon the enzyme step and tissues involved, such as liver and kidney involvement associated with severe hypoglycemia during fasting and the risk of long-term complications including hepatic adenoma/carcinoma and end stage kidney disease in GSD Ia from glucose-6-phosphatase deficiency, and cardiac/skeletal/smooth muscle involvement associated with myopathy +/- cardiomyopathy and the risk for cardiorespiratory failure in Pompe disease. These symptoms are present to a variable degree in animal models for the GSDs, which have been utilized to evaluate new therapies including gene therapy and genome editing. Gene therapy for Pompe disease and GSD Ia has progressed to Phase I and Phase III clinical trials, respectively, and are evaluating the safety and bioactivity of adeno-associated virus vectors. Clinical research to understand the natural history and progression of the GSDs provides invaluable outcome measures that serve as endpoints to evaluate benefits in clinical trials. While promising, gene therapy and genome editing face challenges with regard to clinical implementation, including immune responses and toxicities that have been revealed during clinical trials of gene therapy that are underway. Gene therapy for the glycogen storage diseases is under development, addressing an unmet need for specific, stable therapy for these conditions.

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2020-03-05 | Gene therapy for glycogen storage diseases.

The focus of this review is the development of gene therapy for glycogen storage diseases (GSDs). GSD results from the deficiency of specific enzymes involved in the storage and retrieval of glucose in the body. Broadly, GSDs can be divided into types that affect liver or muscle or both tissues. For example, glucose-6-phosphatase (G6Pase) deficiency in GSD type Ia (GSD Ia) affects primarily the liver and kidney, while acid α-glucosidase (GAA) deficiency in GSD II causes primarily muscle disease. The lack of specific therapy for the GSDs has driven efforts to develop new therapies for these conditions. Gene therapy needs to replace deficient enzymes in target tissues, which has guided the planning of gene therapy experiments. Gene therapy with adeno-associated virus (AAV) vectors has demonstrated appropriate tropism for target tissues, including the liver, heart and skeletal muscle in animal models for GSD. AAV vectors transduced liver and kidney in GSD Ia and striated muscle in GSD II mice to replace the deficient enzyme in each disease. Gene therapy has been advanced to early phase clinical trials for the replacement of G6Pase in GSD Ia and GAA in GSD II (Pompe disease). Other GSDs have been treated in proof-of-concept studies, including GSD III, IV and V. The future of gene therapy appears promising for the GSDs, promising to provide more efficacious therapy for these disorders in the foreseeable future.

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