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.

Due to the high molecular weight and polarity, glycans suffer low ionization efficiency in electrospray ionization mass spectrometry (ESI-MS). Chemical derivatization is necessary to improve the MS response. In this work, rhodamine B hydrazine (RBH) derivatives with different end groups were synthesized, among which RBH with tetraethyl end groups performed best. After optimization, the signals were 8-30 times higher than those of the commercial reagent, 2-aminobenzamide, when analyzing maltopentaose, maltohexaose, and maltaheptaose, demonstrating the advantages of fast, mild labeling, simple post-treatment, better separation, and significant improvement in ionization. This method was first applied to the detection of carbohydrates in the plasma of mice with glycogen storage disease Ib (GSDIb). The free glycogen content in the plasma of diseased mice was confirmed and determined by the standard addition method to be approximately 7.1 ng mL-1. Given the lack of standards and structural complexity of N-glycan complexes, a stable isotope-labeled RBH with 20 deuterons was designed and synthesized at very low cost to reduce the difficulty of N-glycan determination and enable relative quantification. With Python for spectral analysis, 19 N-glycans were successfully identified with only 1 μL of mouse plasma. Subsequently, the method was used to quantify plasma N-glycans from GSDIb and normal mice. The fucosylated contents of diseased mice were abnormally increased, while the non-fucosylated contents were reduced, indicating the fucosylation level of plasma N-glycan was expected to be an indicator for the detection of GSDIb.

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 Ia is a rare inherited metabolic disorder characterized by glucose-6-phosphatase deficiency. Hepatocellular adenoma development is a frequent complication in patients with this condition, with prevalence rates reaching up to 75%. The management of hepatic adenomas in these patients remains challenging due to risks of hemorrhage, malignant transformation, and surgical complications. Case Presentation We report a 22-year-old Chinese female with glycogen storage disease type Ia who presented with acute metabolic decompensation, including hypoglycemia (2.8 mmol/L), severe hyperlactatemia (20.0 mmol/L), and marked hypertriglyceridemia (31.78 mmol/L). The patient had been diagnosed with glycogen storage disease type Ia at age 5 and maintained on dietary therapy. At age 18, multiple hepatic adenomas were detected. Following intensive preoperative metabolic optimization and a comprehensive perioperative management protocol, she underwent successful indocyanine green fluorescence-guided left hepatectomy at age 22 with excellent postoperative recovery and no evidence of malignant transformation. This case demonstrates that hepatic adenomas in patients with glycogen storage disease type Ia can be successfully managed surgically with appropriate perioperative metabolic management. Early diagnosis, regular surveillance, and timely surgical intervention are crucial for preventing life-threatening complications in this patient population.

Glycogen storage disorders are a group of inherited metabolic disorders marked by dysfunctional glycogen metabolism and atypical glycogen buildup in different tissues. Timely diagnosis and sustained therapy are crucial to avoid metabolic complications and progressive organ impairment. We present the case of a 7-year-old male diagnosed with hepatic glycogen storage disease (GSD) type III at the age of two, following evaluation for progressive abdominal distension and hepatomegaly. Imaging and liver biopsy revealed characteristic features. Molecular genetic testing revealed a homozygous pathogenic nonsense mutation in the AGL gene (c. 967C > T), hence validating the diagnosis of GSD III. The patient was treated with dietary adjustments and close monitoring. Despite appropriate management, he presented with recurrent abdominal pain and persistent hepatomegaly on follow-up imaging. This case highlights the importance of early diagnosis, definitive molecular confirmation and continued long-term surveillance, as hepatic manifestations may persist despite standard therapy.

Glycogen storage disease type Ib (GSD-Ib) is commonly associated with refractory inflammatory bowel disease (GSD-IBD). Although the SGLT2 inhibitor empagliflozin has demonstrated remarkable clinical efficacy, its direct effects on the intestinal epithelium remain poorly understood. This study aimed to determine whether empagliflozin directly restores the impaired colonic mucus barrier and to identify the underlying molecular pathway. In terms of efficacy, we integrated clinical evaluations of GSD-IBD patients with a novel murine model of epithelial injury induced by a defined bacterial consortium (EVS: Enterococcus, Veillonella, Streptococcus) and dextran sulfate sodium (DSS). Invitro, we employed Caco-2 cells and intestinal organoids, combined with pharmacological inhibition of AMPK and siRNA-mediated gene knockdown to elucidate the underlying molecular mechanisms. Clinical data indicated that empagliflozin promoted ulcer healing and enhanced mucin production in patients. In the EVS + DSS mouse model, empagliflozin treatment reduced disease severity and attenuated goblet cell depletion. We demonstrated that empagliflozin upregulates the transcription factor SOX4 in intestinal epithelial cells both invivo and invitro, an effect dependent on AMPK activation. Notably, siRNA knockdown of SOX4 abolished empagliflozin-induced MUC2 upregulation. Furthermore, pharmacological inhibition of AMPK suppressed the induction of MUC2, which could be rescued by SOX4 overexpression. Our findings uncover a novel, epithelium-intrinsic mechanism of action for empagliflozin: the activation of the AMPK/SOX4/MUC2 signaling axis to restore the colonic mucus barrier. These results provide a mechanistic foundation for the repurposing of SGLT2 inhibitors in conditions characterized by epithelial barrier dysfunction.

Continuous glucose monitoring shows limited impact of daytime cornstarch on glycemia in glycogen storage disease type I.

Glycogen storage diseases are inherited disorders of glycogen metabolism and are commonly associated with hypoglycaemia, hepatic dysfunction, or skeletal and cardiac myopathy, depending on the affected enzyme. Glycogen storage disease type 15 (GSD15) is caused by pathogenic variants in GYG1, which encodes glycogenin-1, the auto-glucosylating primer required for glycogen synthesis. GSD15 is characterized by cardiomyopathy and storage of abnormal glycogen and polyglucosan in cardiomyocytes. To understand the pathobiology of GSD15, we investigated the storage material in heart explants from two previously reported patients and describe a new case of GSD15. The characteristic storage material was investigated using laser capture microdissection followed by quantitative mass spectrometry (MS) and immunohistochemistry comparing differentially abundant proteins in the storage material with normal-appearing cytoplasmic regions from the same patient. Global protein dysregulation in GSD15 was assessed by quantitative MS of whole-myocardial tissue samples from patients and normal controls. The storage material was enriched in proteins involved in glycogen metabolism, including glycogen synthase, UDP-glucose pyrophosphorylase 2, glycogenin-1, glycogen phosphorylase, and glycogen debranching enzyme. Sequestosome 1 (p62) and desmin were also enriched, without evidence of increased autophagocytosis. Whole-tissue analyses revealed upregulation of cardiomyopathy-associated biomarkers and downregulation of mitochondrial proteins, suggesting impaired energy metabolism contributing. to congestive heart failure. In GSD15, storage of abnormal glycogen in cardiomyocytes is associated with enrichment of specific proteins involved in glycogen metabolism, contributing to dysregulation of glycogen turnover. This dysregulation results in polyglucosan accumulation, disruption of sarcomeric and mitochondrial architecture, and progressive fibrosis. No disease-modifying therapy currently exists for GSD15; future strategies based on substrate reduction, enhancement of autophagy, or gene therapy require further investigation.

Genetic dyslipidemias.

ABSTRACTNeutrophil 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.

Ubiquitin signalling covers a wide range of protein modifications, but its scope may still be underestimated, owing to theubiquitination of non-proteinaceous substrates, such as sugars, lipids and nucleotides1. The breadth of ubiquitinated non-protein substrates, their abundance and theircellular roles are currently unclear, as current ubiquitinomic and proteomic techniques do not detect non-proteinaceous modifications. Here we report non-protein ubiquitinclipping (NoPro-clipping) as a mass spectrometry-based technique that combines ubiquitin clippases with sortase labelling. Targeted and untargeted workflows unveil a wide range of ubiquitinated substrates in mammalian cells and in mouse and human tissues. We find ubiquitinated glycogen in glycogen-containing tissues in mice, with the highest abundance in liver and skeletal muscle. Ubiquitination can deliver glycogen to lysosomes and leads to decreased glycogen levels. Glycogen ubiquitination is modulated in glycogen storage diseases and isregulated by the Met1-polyubiquitin machinery. Notably, glycogen depletion in the liver during fasting coincides with increased glycogen ubiquitination, suggesting that ubiquitin is a previously unknown component of physiological glycogen catabolism. We also reveal ubiquitination of endogenous glycerol and spermine in cells and tissues. NoPro-clipping thus reveals unexpected endogenous non-proteinaceous targets of ubiquitination, broadening the role of ubiquitin from a protein modifier to a general modifier of biomolecules.

Decoding genetic complexity in glycogen storage diseases: three novel variants in SLC37A4, GAA, and PHKG2 identified in an Iranian cohort.

Glycogen storage disease type Ia (GSDIa) is a rare, inherited, autosomal recessive condition with deficiency of glucose-6-phosphatase (G6Pase) characterized by fasting hypoglycemia due to an inability to release glucose from hepatic glycogen stores and other metabolic pathways, requiring frequent consumption of exogenous glucose for survival. Patient-reported outcome (PRO) measures are important to assess GSDIa burden, though no disease-specific PRO for GSDIa exists. This research describes the Glycogen Storage Disease Functional Assessment Diary (GSD FAD), a 31-item PRO developed to assess the signs/symptoms and impacts of GSDIa in individuals ages 8 and older. Mixed methods research including a literature review, online survey, and concept elicitation (CE) interviews informed the construction of the GSD FAD. Cognitive debriefing (CD) interviews evaluated concept relevance and understanding of the questionnaire. Psychometric properties were evaluated using Phase 3 trial screening/baseline data to assess item variability, structure/scaling potential, scoring, reliability, validity, and minimum detectable change. The literature review, online survey (N=26), and CE interviews (N=7) identified hypoglycemia and cornstarch regimen impacts as most burdensome and most important to treat from the patient perspective. The initial draft GSD FAD included 36 items. Most items were interpreted as intended in CD interviews (N=16); revisions to the GSD FAD addressed interpretation issues. Three domain scores (Symptoms Total Score, Sleep Impacts Total Score, and Daily Impacts Total Score) showed acceptable reliability and validity but had notable ceiling effects that may limit responsiveness in some settings. The GSD FAD is a novel, content-valid PRO that measures the humanistic burden of GSDIa and cornstarch treatment regimen, including the signs/symptoms of hypoglycemia and their impact on health-related quality of life (HRQoL) in individuals ≥ 8 years with GSDIa, that yields reliable and valid scores. While developed in a trial setting, the GSD FAD has potential for use in nutritional, behavioral, and/or educational applications.

This study explored the lived experiences of Jordanian mothers caring for children with Glycogen Storage Disease (GSD), with a particular focus on the spiritual and cultural frameworks that shaped their caregiving. Using a descriptive phenomenological approach, semi-structured interviews were conducted with 13 mothers. The findings revealed significant emotional, financial, and social burdens, including stigma, exhaustion, and strained family dynamics. Mothers consistently drew on their Islamic faith to interpret and endure these challenges, viewing caregiving as a spiritual duty and relying on practices such as prayer, patience, and Qur'ānic recitation. Many also expressed unmet spiritual care needs and called for greater integration of faith-sensitive support within healthcare and community settings. These findings underscore the need for holistic care models that acknowledge the central role of spirituality in shaping caregiver resilience and meaning-making in rare disease contexts.

Amylose:amylopectin ratio and digestibility of two cornstarch brands as predictors of glucose release of patients with glycogen storage diseases

Use of a ketogenic diet in an infant with glycogen storage disease type IIIa and severe hypertrophic cardiomyopathy

Sodium taurocholate cotransporter polypeptide deficiency combined with novel PYGL mutations in glycogen storage disease type VI: a rare case report.

26-CCC-14667-ACC A RARE CLINICAL PRESENTATION: CARDIOMYOPATHY IN A FEMALE WITH AUTOSOMAL RECESSIVE GLYCOGEN STORAGE DISEASE TYPE III

WCN26-4808 Treatment of Glycogen Storage Disease Type Ib with Empagliflozin and Angiotensin II Receptor Blockers: A Case Series

Successful maintenance of normal blood glucose levels in glycogen storage disease 1a during a prolonged open water swim