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Neutropenia and elevated concentrations of hepatic transaminases often lead to referrals from emergency or outpatient departments to relevant specialists to diagnose underlying inborn errors of metabolism. Glycogen storage disease type (GSD) Ib, a rare congenital disorder of glucose metabolism caused by the SLC37A4 gene mutations, shows various manifestations, including persistent neutropenia and elevated hepatic transaminases. Empagliflozin has demonstrated its efficacy in treating GSD Ib-associated neutropenia by reducing the entry of 1,5-anhydroglucitol-6-phosphate into the neutrophils. This article reports successful empagliflozin therapy for GSD Ib-related neutropenia in 2 Korean adolescents. Diagnosing GSD Ib is complex and usually initiated by a referral from emergency or outpatient departments when there is a high index of suspicion. Once diagnosed, empagliflozin shows promising outcomes in restoring counts and function of the neutrophils without severe adverse effects in children with GSD Ib, supporting it as a safe and effective therapeutic option for GSD Ib-associated neutropenia.

Abstract No sensitive tumor marker for hepatocellular carcinoma (HCC) is available for patients with glycogen storage disease type Ia (GSDIa), in whom alpha‐fetoprotein and carcino‐embryonic antigen levels often remain normal. We describe increased levels of the HCC tumor marker des‐gamma‐carboxy prothrombin (DCP) in GSDIa patients with HCC. In one case DCP levels normalized after liver transplantation. We recommend including DCP as a screening HCC tumor marker in the surveillance of patients with GSDIa.

Background: Genetic metabolic illnesses called Glycogen Storage Disease type I (GSD I) are caused due to abnormalities in the glucose-6-phosphatase enzyme complex involved in the metabolism of glycogen. Objectives: The current study explores the induction and management of GSD I manifestations. Materials and Methods: Chlorogenic Acid (CGA), a hydroxycinnamic acid found in various fruits and abundant in green coffee, can inhibit the enzyme glucose-6-phosphatase complex and metformin can alter the lactic acid levels. Results: The in silico and in vivo approach unveiled, that ß-carotene showed the highest binding affinity with glucokinase, forming 7 hydrogen bonds. Riboflavin exhibited the highest binding affinity with protein phosphatase 1, forming 4 hydrogen bonds. Vitamin C interacted at the active site of the control ligand. Vitamin E also displayed significant binding affinity with glucokinase. Overall, these bioactive micro molecules show promising interactions with their respective target proteins. In vivo results revealed the significant impact of Macronutrients and Micronutrients, particularly when combining Cassava starch with the micronutrients. This combination showed notable improvements in various parameters, including liver glycogen levels, liver weight, fasting blood glucose levels, and liver histology. The findings suggest the potential of this synergistic approach in enhancing liver function and glucose regulation. To conclude this work, it was evident that the combination of Macro and Micronutrients revealed distinct advantages. UCCS and Cassava starch effectively maintained normoglycemia due to their sustained glucose release from complex carbohydrates. Remarkably, Cassava starch, both alone and combined with micronutrients, outperformed UCCS in promoting better outcomes. This highlights the potential for comprehensive research on Cassava starch's effects in GSD subjects, exploring its impact on other manifestations such as lactic acidosis, hypertriglyceridemia, and hyperuricemia. Conclusion: These findings offer promising avenues for further investigation and potential therapeutic applications. [ABSTRACT FROM AUTHOR]

Abstract Glycogen storage disease type I (GSDI) is an inherited metabolic disorder characterized by a deficiency of enzymes or proteins involved in glycogenolysis and gluconeogenesis, resulting in excessive intracellular glycogen accumulation. While GSDI is classified into four different subtypes based on molecular genetic variants, GSDIa accounts for approximately 80%. GSDIa and GSDIb are autosomal recessive disorders caused by deficiencies in glucose‐6‐phosphatase (G6Pase‐α) and glucose‐6‐phosphate‐transporter (G6PT), respectively. For the past 50 years, the care of patients with GSDI has been improved following elaborate dietary managements. GSDI patients currently receive dietary therapies that enable patients to improve hypoglycemia and alleviate early symptomatic signs of the disease. However, dietary therapies have many limitations with a risk of calcium, vitamin D, and iron deficiency and cannot prevent long‐term complications, such as progressive liver and renal failure. With the deepening understanding of the pathogenesis of GSDI and the development of gene therapy technology, there is great progress in the treatment of GSDI. Here, we review the underlying molecular genetics and the current clinical management strategies of GSDI patients with an emphasis on promising experimental gene therapies.

A 43-year-old woman with genetically confirmed glycogen storage disease type Ib was suspected to have left breast cancer. Fluorodeoxyglucose-positron emission tomography showed high fluorodeoxyglucose accumulation in the whole liver as well as left mammary gland. We consider that high fluorodeoxyglucose accumulation in the liver of patients with glycogen storage disease type I is caused by impaired glucose-6-phosphate metabolism due to the congenital deficiency of glucose-6-phosphatase activities in hepatocytes. This study describes fluorodeoxyglucose-positron emission tomography as a potential alternative tool to diagnose glycogen storage disease type I functionally.

Abstract Background Glycogen storage disease type I (GSD I) is a rare autosomal recessive disorder of carbohydate metabolism characterized by recurrent hypoglycaemia and hepatomegaly. Management of GSD I is demanding and comprises a diet with defined carbohydrate intake and the use of complex carbohydrates, nocturnal tube feeding or night-time uncooked cornstarch intake, regular blood glucose monitoring and the handling of emergency situations. With improved treatment, most patients nowadays survive into adulthood. Little research has been performed on the impact of GSD I on daily life, especially in adult patients. Results In this multi-centre study we assessed the impact of GSD I on adult daily life in 34 GSD I patients (27 GSD Ia, 7 GSD Ib) between 17 and 54 years (median 26 years) using a self-designed questionnaire that specifically focused on different aspects of daily life, such as job situation, social life, sports, travelling, composition of the household, night-time and day-time dietary management and disease monitoring as well as the patient’s attitude towards the disease. At the time of investigation, the majority of patients either attended school or university or were employed, while 3 patients (9%) were out of work. Most patients ranked GSD I as a disease with moderate severity and disease burden. Dietary treatment was considered challenging by many, but the vast majority of patients considered life with GSD I as well-manageable. Conclusions Although the management of GSD I poses a significant burden on daily life, most patients live an independent adult life, have a positive attitude towards their disease and seem to cope well with their situation.

ABSTRACT BACKGROUND Glycogen storage disease (GSD) type 1b is a multisystemic disease in which immune and infectious complications are present, in addition to the well-known metabolic manifestations of GSD. Treatment with granulocyte-colony stimulating factor (G-CSF) is often indicated in the management of neutropenia and inflammatory bowel disease. OBJECTIVE To report on the demographics, genotype, clinical presentation, management, and complications of pediatric patients with glycogen storage disease type 1b (GSD 1b), with special attention to immune-related complications. METHODS Retrospective case series of seven patients with GSD 1b diagnosed and followed at a tertiary university hospital in Brazil, from July/2000 until July/2016. RESULTS Mean age at referral was fourteen months. Diagnosis of GSD 1b was based on clinical and laboratory findings and supported by genetic studies in five cases. All patients presented suffered from neutropenia, managed with G-CSF - specifically Filgrastim. Hospitalizations for infections were frequent. Two patients developed inflammatory bowel disease. Six patients remained alive, one died at age 14 years and 9 months. The mean age at the end of the follow-up was 11.5 years. Compliance to treatment was suboptimal: poor compliance to medications, starch and dietetic management of GSD were documented, and outpatient appointments were frequently missed. CONCLUSION Managing GSD 1b is challenging not only for the chronic and multisystemic nature of this disease, but also for the additional demands related dietary restrictions, use of multiple medications and the need for frequent follow-up visits; furthermore in Brazil, the difficulties are increased in a scenario where we frequently care for patients with unfavorable socioeconomic status and with irregular supply of medications in the public health system.

Solute carrier family 37 member 4 (SLC37A4) is known to regulate glucose-6-phosphate transport from cytoplasm to the lumen of the endoplasmic reticulum, which serves to maintain glucose homeostasis. Glycogen storage disease type 1b (GSD1b) is caused by a mutation of SLC37A4, leading to a glycogenolysis defect. Although GSD1b cases are known to be complicated by periodontitis, the etiological molecular basis remains unclear. The present study investigated the effects of SLC37A4 on gingival barrier function. Examinations of immortalized human gingival epithelial (IHGE) cells showed SLC37A4 localized in the endoplasmic reticulum. SLC37A4 knockout decreased expression of JAM1, a tight junction-related protein, in IHGE cells. Using in silico analysis to investigate potential transcription factor binding sites, H6 family homeobox 3 (HMX3) was shown to be related to JAM1 expression. In HMX3-knockdown IHGE cells, JAM1 expression was markedly suppressed. Furthermore, HMX3 was scarcely detected in SLC37A4-knockout cells, while HMX3 overexpression restored JAM1 expression in those cells. Finally, using a three-dimensional multilayered gingival epithelial tissue model, knockout of SLC37A4 was also found to increase permeability to lipopolysaccharide and peptidoglycan, which was dependent on JAM1 expression. Specific downregulation of HMX3 by SLC37A4 and the consequent decrease in JAM1 expression provides findings indicating a molecular basis for the reduction in barrier function of gingival epithelial tissues in GSD1b cases., (© 2024. The Author(s).)

Rationale: Glycogen storage disease type 0a (GSD0a) is a rare autosomal recessive disorder caused by glycogen synthase deficiency. Short stature is a characteristic feature in 29% of GSD0a patients, but isolated short stature as the only presenting symptom is exceedingly rare, with only 2 cases reported worldwide., Patient Concerns: A 4-year-old girl presented with persistent growth retardation despite previous treatment for renal tubular acidosis., Diagnoses: Based on clinical presentation and whole exome sequencing results, the patient was diagnosed with GSD0a., Interventions: Uncooked cornstarch therapy was initiated at 2 g/kg every 6 hours., Outcomes: After 3 years of treatment, the patient's height SDS improved from -2.24 to -1.06, with enhanced glycemic control and no complications., Lessons: This case emphasizes considering GSD0a in unexplained short stature and the value of continuous glucose monitoring. Early diagnosis and treatment can optimize growth in GSD0a patients., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Glycogen storage disease type I (GSD I) is a rare autosomal recessive disorder of carbohydate metabolism characterized by recurrent hypoglycaemia and hepatomegaly. Management of GSD I is demanding and comprises a diet with defined carbohydrate intake and the use of complex carbohydrates, nocturnal tube feeding or night-time uncooked cornstarch intake, regular blood glucose monitoring and the handling of emergency situations. With improved treatment, most patients nowadays survive into adulthood. Little research has been performed on the impact of GSD I on daily life, especially in adult patients.Results: In this multi-centre study we assessed the impact of GSD I on adult daily life in 34 GSD I patients (27 GSD Ia, 7 GSD Ib) between 17 and 54 years (median 26 years) using a self-designed questionnaire that specifically focused on different aspects of daily life, such as job situation, social life, sports, travelling, composition of the household, night-time and day-time dietary management and disease monitoring as well as the patient's attitude towards the disease. At the time of investigation, the majority of patients either attended school or university or were employed, while 3 patients (9%) were out of work. Most patients ranked GSD I as a disease with moderate severity and disease burden. Dietary treatment was considered challenging by many, but the vast majority of patients considered life with GSD I as well-manageable.Conclusions: Although the management of GSD I poses a significant burden on daily life, most patients live an independent adult life, have a positive attitude towards their disease and seem to cope well with their situation. [ABSTRACT FROM AUTHOR]

ABSTRACT Objective: To perform anthropometric and dietary evaluation of patients with glycogenosis type Ia and Ib. Methods: This cross-sectional study is composed of a sample of 11 patients with glycogenosis divided into two subgroups according to the classification of glycogenosis (type Ia=5 and type Ib=6), aged between 4 and 20 years. The analyzed anthropometric variables were weight, height, body mass index, and measures of lean and fat body mass, which were compared with reference values. For dietary assessment, a food frequency questionnaire was used to calculate energy and macronutrients intake as well as the amount of raw cornstarch consumed. Mann-Whitney U test and Fisher’s exact test were performed, considering a significance level of 5%. Results: Patients ingested raw cornstarch in the amount of 0.49 to 1.34 g/kg/dose at a frequency of six times a day, which is lower than recommended (1.75-2.50 g/kg/dose, four times a day). The amount of energy intake was, on average, 50% higher than energy requirements; however, carbohydrate intake was below the adequacy percentage in 5/11 patients. Short stature was found in 4/10 patients; obesity, in 3/11; and muscle mass deficit, in 7/11. There were no statistical differences between the subgroups. Conclusions: In patients with glycogenosis type I, there was deficit in growth and muscle mass, but no differences were found between the subgroups (Ia and Ib). Although the diet did not exceed the adequacy of carbohydrates, about 1/3 of the patients presented obesity, probably due to higher energy intake.

Patients and Methods: A retrospective chart review of 32 GSD- I patients, followed at the American University of Beirut Medical Center, between 2007 and 2018 was conducted. Diagnosis was confirmed by enzymatic and/or genetic studies. Clinical presentation, growth, and kidney outcome were assessed. All patients were evaluated for body mass index, blood parameters of metabolic control including uric acid, alanine, lactic acid, and triglycerides in blood. Kidney evaluation included creatinine clearance, microalbuminuria, citraturia, and calciuria as well as urine microalbumin/creatinine ratio.Results: Almost one third of GSD-I patients developed microalbuminuria. This was detected below 7 months of age in 36% of patients who required early treatment with ACEI with significant reduction in albuminuria. Kidney stones were present in 6% and were associated with hypercalciuria and hypocitraturia. Poor metabolic control reflected by hyperuricemia, lactic acidosis, and hyperalaninemia were noted only in patients who developed microalbuminuria.Conclusion: Glomerular injury may appear in early infancy in poorly controlled patients. Adequate metabolic control and ACEI therapy may improve kidney outcome in GSD I patients. Plasma alanine appears to be a promising and reliable marker reflecting metabolic control in GSD-I patients.

The liver is an organ with many facets, including a role in energy production and metabolic balance, detoxification and extraordinary capacity of regeneration. Hepatic glucose production plays a crucial role in the maintenance of normal glucose levels in the organism i.e. between 0.7 to 1.1 g/l. The loss of this function leads to a rare genetic metabolic disease named glycogen storage disease type I (GSDI), characterized by severe hypoglycemia during short fasts. On the contrary, type 2 diabetes is characterized by chronic hyperglycemia, partly due to an overproduction of glucose by the liver. Indeed, diabetes is characterized by increased uptake/production of glucose by hepatocytes, leading to the activation of de novo lipogenesis and the development of a non-alcoholic fatty liver disease. In GSDI, the accumulation of glucose-6 phosphate, which cannot be hydrolyzed into glucose, leads to an increase of glycogen stores and the development of hepatic steatosis. Thus, in these pathologies, hepatocytes are subjected to cellular stress mainly induced by glucotoxicity and lipotoxicity. In this review, we have compared hepatic cellular stress induced in type 2 diabetes and GSDI, especially oxidative stress, autophagy deregulation, and ER-stress. In addition, both GSDI and diabetic patients are prone to the development of hepatocellular adenomas (HCA) that occur on a fatty liver in the absence of cirrhosis. These HCA can further acquire malignant traits and transform into hepatocellular carcinoma. This process of tumorigenesis highlights the importance of an optimal metabolic control in both GSDI and diabetic patients in order to prevent, or at least to restrain, tumorigenic activity during disturbed glucose metabolism pathologies.

Mucormycosis is an increasingly frequent, difficult to diagnose, difficult to treat, often fatal infection, especially in patients with hyperglycemia from uncontrolled diabetes. Type I (von Gierke) glycogen storage disease is due to inherited deficiency of enzymes in glycogen metabolism, which causes hypoglycemia. This report is the case of a patient with von Gierke disease and a missed diagnosis of pulmonary mucormycosis. This report illustrates the importance of having a high index of suspicion for mucormycosis in the appropriate clinical context.

Context: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is likely the most prevalent enzyme deficiency on the planet, with an estimated 4.9% of people, or approximately 330 million individuals, across the globe affected by the disease. In the United States, 4% to 7% of the population is likely affected, but each year our nation's major sport leagues become more international. It is important for medical professionals who treat athletes to understand how this genetic condition can affect the athletes we are working with, especially because exercise in itself results in oxidative stress.Evidence Acquisition: PubMed was searched for relevant articles published from 1980 to 2018. The search terms G6PD, athletes, military, and sports were used.Study Design: Clinical review.Level Of Evidence: Level 4.Results: Though some case reports suggest a potential impact on athlete safety and performance, controlled studies demonstrate limited impact of exercise on oxidative stress in G6PD-deficient individuals. The care of athletes with G6PD deficiency does not drastically differ from the care of athletes without this condition. Most of the medications and supplements that are regularly given to athletes should not negatively affect their health.Conclusion: Although the care of athletes with G6PD deficiency is for the most part no different from the care of other athletes, there are certain situations (visiting areas where malaria is endemic) and medications for which it is important to recognize how your management should change. G6PD deficiency is not regularly screened for but could be considered if an athlete has known sickle cell disease or when traveling to areas where malaria is prevalent. Expanding our knowledge of G6PD deficiency will allow for better care of athletes. [ABSTRACT FROM AUTHOR]

Abstract Background Glycogen storage disease type-1a is an inherited, autosomal recessive disorder caused by mutations in G6PC1 gene leading to deficiency of glucose-6-phosphatase-α specifically in the liver/kidney/intestine. Patients and methods DNA of six unrelated Indian GSD-1a patients were screened for mutations in the entire coding region of G6PC1 gene followed by direct DNA sequencing and functional was tested using glucose-6-phosphatase assay. Results Mutational screening of GSD-1a patients identified five novel mutations, viz., 1) p.V99Cfs*3, 2) p.G125R, 3) IVS1-2A > T, 4) IVS3 + 39G > A and 5) IVS3 + 42G > A along with three previously reported mutations p.G118D, p.R149Q and p.A331V. Interestingly, each of the p.V99Cfs*3, IVS1-2A > T and p.G118D mutations are identified in two unrelated GSD-1a cases. Further allelic distribution of p.V99Cfs*3 and p.A331V mutations were confirmed by RFLP analysis, consistent with autosomal recessive inheritance. Functional characterization revealed that glucose-6-phosphatase activity was completely abrogated with the mutant proteins p.G125R, p.R149Q, p.G118D, p.A331V and p.V99Cfs*3 than wild-type. However, no significant changes were observed in the expression of mutant constructs at transcription and translation level. Conclusion Five novel mutations, p.V99Cfs*3, p.G125R, IVS1-2A > T, IVS3 + 39G > A and IVS3 + 42G > A are reported first time to cause GSD-1a among Indian ethnicity and are not yet reported elsewhere, suggesting separate ethnic founder effects for some mutations among Indian ethnicity. Graphical abstract Unlabelled Image Highlights • We diagnosed the G6PC1 gene in a cohort of GSD-1a patient from Indian descent. • Overall, eight G6PC1 mutations were identified in G6PC1 gene. • G6Pase activity of variant G6PC1 was completely abrogated. • 5 novel G6PC1 mutations are reported first time that expanded mutational spectrum. [ABSTRACT FROM AUTHOR]

Objective: Carbohydrate Response Element Binding Protein (ChREBP) is a glucose 6-phosphate (G6P)-sensitive transcription factor that acts as a metabolic switch to maintain intracellular glucose and phosphate homeostasis. Hepatic ChREBP is well-known for its regulatory role in glycolysis, the pentose phosphate pathway, and de novo lipogenesis. The physiological role of ChREBP in hepatic glycogen metabolism and blood glucose regulation has not been assessed in detail, and ChREBP's contribution to carbohydrate flux adaptations in hepatic Glycogen Storage Disease type 1 (GSD I) requires further investigation., Methods: The current study aimed to investigate the role of ChREBP as a regulator of glycogen metabolism in response to hepatic G6P accumulation, using a model for acute hepatic GSD type Ib. The immediate biochemical and regulatory responses to hepatic G6P accumulation were evaluated upon G6P transporter inhibition by the chlorogenic acid S4048 in mice that were either treated with a short hairpin RNA (shRNA) directed against ChREBP (shChREBP) or a scrambled shRNA (shSCR). Complementary stable isotope experiments were performed to quantify hepatic carbohydrate fluxes in vivo., Results: ShChREBP treatment normalized the S4048-mediated induction of hepatic ChREBP target genes to levels observed in vehicle- and shSCR-treated controls. In parallel, hepatic shChREBP treatment in S4048-infused mice resulted in a more pronounced accumulation of hepatic glycogen and further reduction of blood glucose levels compared to shSCR treatment. Hepatic ChREBP knockdown modestly increased glucokinase (GCK) flux in S4048-treated mice while it enhanced UDP-glucose turnover as well as glycogen synthase and phosphorylase fluxes. Hepatic GCK mRNA and protein levels were induced by shChREBP treatment in both vehicle- and S4048-treated mice, while glycogen synthase 2 (GYS2) and glycogen phosphorylase (PYGL) mRNA and protein levels were reduced. Finally, knockdown of hepatic ChREBP expression reduced starch domain binding protein 1 (STBD1) mRNA and protein levels while it inhibited acid alpha-glucosidase (GAA) activity, suggesting reduced capacity for lysosomal glycogen breakdown., Conclusions: Our data show that ChREBP activation controls hepatic glycogen and blood glucose levels in acute hepatic GSD Ib through concomitant regulation of glucose phosphorylation, glycogenesis, and glycogenolysis. ChREBP-mediated control of GCK enzyme levels aligns with corresponding adaptations in GCK flux. In contrast, ChREBP activation in response to acute hepatic GSD Ib exerts opposite effects on GYS2/PYGL enzyme levels and their corresponding fluxes, indicating that GYS2/PYGL expression levels are not limiting to their respective fluxes under these conditions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

Glycogen storage disease type Ia (GSD-Ia) is caused by a deficiency in the enzyme glucose-6-phosphatase-α (G6Pase-α or G6PC) that is expressed primarily in the gluconeogenic organs, namely liver, kidney cortex, and intestine. Renal G6Pase-α deficiency in GSD-Ia is characterized by impaired gluconeogenesis, nephromegaly due to elevated glycogen accumulation, and nephropathy caused, in part, by renal fibrosis, mediated by activation of the renin-angiotensin system (RAS). The Wnt/β-catenin signaling regulates the expression of a variety of downstream mediators implicated in renal fibrosis, including multiple genes in the RAS. Sustained activation of Wnt/β-catenin signaling is associated with the development and progression of renal fibrotic lesions that can lead to chronic kidney disease. In this study, we examined the molecular mechanism underlying GSD-Ia nephropathy. Damage to the kidney proximal tubules is known to trigger acute kidney injury (AKI) that can, in turn, activate Wnt/β-catenin signaling. We show that GSD-Ia mice have AKI that leads to activation of the Wnt/β-catenin/RAS axis. Renal fibrosis was demonstrated by increased renal levels of Snail1, α-smooth muscle actin (α-SMA), and extracellular matrix proteins, including collagen-Iα1 and collagen-IV. Treating GSD-Ia mice with a CBP/β-catenin inhibitor, ICG-001, significantly decreased nuclear translocated active β-catenin and reduced renal levels of renin, Snail1, α-SMA, and collagen-IV. The results suggest that inhibition of Wnt/β-catenin signaling may be a promising therapeutic strategy for GSD-Ia nephropathy., Competing Interests: Declaration of competing interest CL, KP, LZ, HDC, SG, IA, MR, MFS, BCM, and JYC declare that they have no conflicts of interest. MK is a co-founder and has an equity position in 3 + 2 Pharma., (Published by Elsevier B.V.)

Genetic liver disease modeling is difficult because it is challenging to access patient tissue samples and to develop practical and relevant model systems. Previously, we developed novel proliferative and functional liver organoids from pluripotent stem cells; however, the protocol requires improvement for standardization and reproducible mass production. Here, we improved the method such that it is suitable for scalable expansion and relatively homogenous production, resulting in an efficient and reproducible process. Moreover, three medium components critical for long-term expansion were defined. Detailed transcriptome analysis revealed that fibroblast growth factor signaling, the essential pathway for hepatocyte proliferation during liver regeneration, was mainly enriched in proliferative liver organoids. Short hairpin RNA-mediated knockdown of FGFR4 impaired the generation and proliferation of organoids. Finally, glycogen storage disease type Ia (GSD1a) patient-specific liver organoids were efficiently and reproducibly generated using the new protocol. They well maintained disease-specific phenotypes such as higher lipid and glycogen accumulation in the liver organoids and lactate secretion into the medium consistent with the main pathologic characteristics of patients with GSD1a. Therefore, our newly established liver organoid platform can provide scalable and practical personalized disease models and help to find new therapies for incurable liver diseases including genetic liver diseases., (© 2023. The Author(s).)

Glycogen storage disease type I (GSD I) is a relatively rare metabolic disease with variable clinical intensity. It is caused by deficient activity of the glucose 6-phosphatase enzyme (GSD Ia) or a deficiency in the microsomal transport proteins for glucose 6-phosphate (GSD Ib). We searched the most recent English literature (1997-2017) regarding any article with the key word of "glycogen storage disease type I" in PubMed, Science Direct, Scopus, EMBASE, and Google Scholar. We will present all of the published articles about the molecular genetic characteristics and old-to-new diagnostic methods used to identify GSD I in regard of methodology, advantages and disadvantages. Diagnosis of GSD type I and its variants is challenging because it is a genetically heterogeneous disorder. Many molecular methods have been used to diagnose GSD I most of which have been based on mutation detection. Therefore, we discuss complete aspects of all of the molecular diagnostic tests, which have been used in GSD type I so far. With the advent of high throughput advanced molecular tests, molecular diagnosis is going to be an important platform for the diagnosis of storage and metabolic diseases such as GSD type I. Next-generation sequencing, in combination with the biochemical tests and clinical signs and symptoms create an accurate, reliable and feasible method. It can overcome the difficulties by the diagnosis of diseases with broad clinical and genetic heterogeneity. [ABSTRACT FROM AUTHOR]

Glycogen storage disease (GSD) type I is inborn metabolic disease characterized by accumulation of glycogen in multiple organs. We analyzed 38 patients with clinical suspicion of GSD I using Sanger and next‐generation sequencing (NGS). We identified 28 GSD Ib and 5 GSD Ia patients. In 5 patients, GSD III, VI, IX, cholesteryl‐ester storage disease and Shwachman‐Diamond syndrome diagnoses were set using NGS. Incidences for GSD Ia and GSD Ib were estimated at 1:172 746 and 1:60 461 live‐births, respectively. Two variants were identified in G6PC gene: c.247C>T (p.Arg83Cys) and c.518T>C (p.Leu173Pro). In SLC37A4 gene, 6 variants were detected. Three previously reported variants c.81T>A (p.Asn27Lys), c.162C>A (p.Ser54Arg) and c.1042_1043delCT (p.Leu348Valfs*53) accounted for 87% of all analyzed alleles. Computational, transcription studies and/or clinical presentation in patients confirmed pathogenic effect of 3 novel variants: c.248G>A (p.Gly83Glu), c.404G>A (p.Gly135Asp) and c.785G>A (p.Ser263Glyfs*33 or p.Gly262Asp). In the cohort, hepatomegaly, hypoglycemia and failure to thrive were the most frequent presenting signs of GSD Ia, while hepatomegaly and recurrent bacterial infections were clinical hallmarks of GSD Ib. All GSD Ib patients developed neutropenia while 20.6% developed inflammatory bowel disease. Our study revealed the highest worldwide incidence of GSD Ib. Furthermore, description of 3 novel variants will facilitate medical genetic practice. [ABSTRACT FROM AUTHOR]

Objectives: To characterize the clinical, laboratory, and anthropometric profile of a sample of Brazilian patients with glycogen storage disease type I managed at an outpatient referral clinic for inborn errors of metabolism. Methods: This was a cross‐sectional outpatient study based on a convenience sampling strategy. Data on diagnosis, management, anthropometric parameters, and follow‐up were assessed. Results: Twenty‐one patients were included (median age 10 years, range 1–25 years), all using uncooked cornstarch therapy. Median age at diagnosis was 7 months (range, 1–132 months), and 19 patients underwent liver biopsy for diagnostic confirmation. Overweight, short stature, hepatomegaly, and liver nodules were present in 16 of 21, four of 21, nine of 14, and three of 14 patients, respectively. A correlation was found between height‐for‐age and BMI‐for‐age Z‐scores (r = 0.561; p = 0.008). Conclusions: Diagnosis of glycogen storage disease type I is delayed in Brazil. Most patients undergo liver biopsy for diagnostic confirmation, even though the combination of a characteristic clinical presentation and molecular methods can provide a definitive diagnosis in a less invasive manner. Obesity is a side effect of cornstarch therapy, and appears to be associated with growth in these patients.

Cells efficiently adjust their metabolism according to the abundance of nutrients and energy. The ability to switch cellular metabolism between anabolic and catabolic processes is critical for cell growth. Glucose-6 phosphate is the first intermediate of glucose metabolism and plays a central role in the energy metabolism of the liver. It acts as a hub to metabolically connect glycolysis, the pentose phosphate pathway, glycogen synthesis, de novo lipogenesis, and the hexosamine pathway. In this review, we describe the metabolic fate of glucose-6 phosphate in a healthy liver and the metabolic reprogramming occurring in two pathologies characterized by a deregulation of glucose homeostasis, namely type 2 diabetes, which is characterized by fasting hyperglycemia; and glycogen storage disease type I, where patients develop severe hypoglycemia during short fasting periods. In these two conditions, dysfunction of glucose metabolism results in non-alcoholic fatty liver disease, which may possibly lead to the development of hepatic tumors. Moreover, we also emphasize the role of the transcription factor carbohydrate response element-binding protein (ChREBP), known to link glucose and lipid metabolisms. In this regard, comparing these two metabolic diseases is a fruitful approach to better understand the key role of glucose-6 phosphate in liver metabolism in health and disease.