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Glycogen storage diseases (GSDs)refer to a group of metabolic disorders caused by congenital enzyme deficiencies. This group of diseases are characterized by abnormal glycogen metabolism. Most subtypes can lead to increased glycogen accumulation in tissues of the liver, muscles, kidneys etc. GSD type Ⅰ (GSDⅠ) is the most common type of the liver glycogen storage diseases that are caused by a deficiency in glucose-6-phosphatase in the liver, kidneys, and intestines. This typle has two subtypes: type Ⅰa and type Ⅰb(GSDⅠb). Recently, research into the molecular mechanisms of GSD Ⅰb made further progress, leading to significant improvements in clinical diagnosis and the new treatment methods based on the pathogenesis. This article summarizes the current research status of diagnosis and screening, molecular genetic mechanisms, and treatment of GSD Ⅰb. The article also points out the opportunities, the challenges and future possibilities.

Glycogen storage disease type Ib (GSD Ib) is a rare and extremely severe disease included in the group of hereditary carbohydrate metabolism disorders. The condition is caused by pathogenic variants in the SLC37A4 gene leading to glucose metabolic disorder in the liver and kidneys, and as a result to severe organomegaly, hypoglycemia, and metabolic decompensation. Moreover, neutropenia and neutrophil dysfunction are noted in patients with GSD Ib. The use of granulocyte colony stimulating factor only increases the number of dysfunctional neutrophils without affecting their functional activity, what determines the inefficacy of such treatment. In recent years, the mechanism of neutropenia in GSD Ib has been clarified, so new therapeutic agents for its relief have been created. This article presents the overview of data on the successful results of renal sodium-glucose cotransporter type 2 inhibitors (gliflozins) usage in patients with GSD Ib.

Abstract Background Glycogen storage disease type Ib (GSD Ib) is a rare disorder characterized by impaired glucose homeostasis caused by mutations in the SLC37A4 gene. It is a severe inherited metabolic disease associated with hypoglycemia, hyperlipidemia, lactic acidosis, hepatomegaly, and neutropenia. Traditional treatment consists of feeding raw cornstarch which can help to adjust energy metabolism but has no positive effect on neutropenia, which is fatal for these patients. Recently, the pathophysiologic mechanism of the neutrophil dysfunction and neutropenia in GSD Ib has been found, and the treatment with the SGLT2 inhibitor empaglifozin is now well established. In 2020, SGLT2 inhibitor empagliflozin started to be used as a promising efficient remover of 1,5AG6P in neutrophil of GSD Ib patients worldwide. However, it is necessary to consider long-term utility and safety of a novel treatment. Results In this study, we retrospectively examined the clinical manifestations, biochemical examination results, genotypes, long-term outcomes and follow-up of thirty-five GSD Ib children who visited our department since 2009. Fourteen patients among them underwent empagliflozin treatment since 2020. This study is the largest cohort of pediatric GSD Ib patients in China as well as the largest cohort of pediatric GSD Ib patients treated with empagliflozin in a single center to date. The study also discussed the experience of long-term management on pediatric GSD Ib patients. Conclusion Empagliflozin treatment for pediatric GSD Ib patients is efficient and safe. Increase of urine glucose is a signal for pharmaceutical effect, however attention to urinary infection and hypoglycemia is suggested.

Background: Glycogen storage disease type Ib (GSD Ib) is a rare disorder characterized by impaired glucose homeostasis caused by mutations in the SLC37A4 gene. It is a severe inherited metabolic disease associated with hypoglycemia, hyperlipidemia, lactic acidosis, hepatomegaly, and neutropenia. Traditional treatment consists of feeding raw cornstarch which can help to adjust energy metabolism but has no positive effect on neutropenia, which is fatal for these patients. Recently, the pathophysiologic mechanism of the neutrophil dysfunction and neutropenia in GSD Ib has been found, and the treatment with the SGLT2 inhibitor empaglifozin is now well established. In 2020, SGLT2 inhibitor empagliflozin started to be used as a promising efficient remover of 1,5AG6P in neutrophil of GSD Ib patients worldwide. However, it is necessary to consider long-term utility and safety of a novel treatment. Results: In this study, we retrospectively examined the clinical manifestations, biochemical examination results, genotypes, long-term outcomes and follow-up of thirty-five GSD Ib children who visited our department since 2009. Fourteen patients among them underwent empagliflozin treatment since 2020. This study is the largest cohort of pediatric GSD Ib patients in China as well as the largest cohort of pediatric GSD Ib patients treated with empagliflozin in a single center to date. The study also discussed the experience of long-term management on pediatric GSD Ib patients. Conclusion: Empagliflozin treatment for pediatric GSD Ib patients is efficient and safe. Increase of urine glucose is a signal for pharmaceutical effect, however attention to urinary infection and hypoglycemia is suggested. [ABSTRACT FROM AUTHOR]

Off‐label repurposing of empagliflozin allows pathomechanism‐based treatment of neutropenia/neutrophil‐dysfunction in glycogen storage disease type Ib (GSDIb). From a value‐based healthcare (VBHC) perspective, we here retrospectively studied patient‐reported, clinical and pharmacoeconomic outcomes in 11 GSDIb individuals before and under empagliflozin at two centers (the Netherlands [NL], Austria [AT]), including a budget impact analysis, sensitivity‐analysis, and systematic benefit–risk assessment. Under empagliflozin, all GSDIb individuals reported improved quality‐of‐life‐scores. Neutrophil dysfunction related symptoms allowed either granulocyte colony‐stimulating factor cessation or tapering. Calculated cost savings per patient per year ranged between € 6482–14 190 (NL) and € 1281–41 231 (AT). The budget impact analysis estimated annual total cost savings ranging between € 75 062–225 716 (NL) and € 37 697–231 790 (AT), based on conservative assumptions. The systematic benefit‐risk assessment was favorable. From a VBHC perspective, empagliflozin treatment in GSDIb improved personal and clinical outcomes while saving costs, thereby creating value at multiple pillars. We emphasize the importance to reimburse empagliflozin for GSDIb individuals, further supported by the favorable systematic benefit‐risk assessment. These observations in similar directions in two countries/health care systems strongly suggest that our findings can be extrapolated to other geographical areas and health care systems. [ABSTRACT FROM AUTHOR]

Glycogen storage disease type Ib (GSD Ib) — is a disease from the group of hereditary metabolic diseases caused by insufficiency of the glucose-6-phosphate transporter (G6PT, SLC37A4), which leads to a violation of both glycogenolysis and gluconeogenesis and, as a consequence, to excessive accumulation of glycogen and fat in the liver, kidneys and intestinal mucosa. The main clinical manifestations and laboratory data include growth retardation, hepatomegaly, hypoglycemia, lactic acidosis, hyperuricemia and hyperlipidemia. Complications of this disease are hepatocellular adenoma with a possible risk of malignancy, nephropathy and osteoporosis. A specific sign of GSD Ib is neutropenia with impaired neutrophil function, which creates prerequisites for recurrent infections and the development of inflammatory bowel disease. Until the present, enzyme replacement therapy of GSD Ib has not been developed, therefore, the main methods of treatment are a specialized diet with the addition of raw corn starch (for relief of hypoglycemia) and the use of granulocyte colony stimulating factor (for relief of neutropenia). However, the recent establishment of the role of 1,5-anhydroglucitol in the pathogenesis of neutrophil dysfunction in GSD Ib has led to a reprofiling of indications for the use of empagliflozin, a type 2 renal sodium—glucose cotransporter inhibitor (SGLT2). In the modern literature, it is reported about a minor, but very successful experience of its use in patients with GSD Ib (outside the framework of official indications for use) and a beneficial effect on neutrophil dysfunction and its clinical consequences. Oddly enough, this hypoglycemic drug improved not only metabolic, but also glycemic control in patients with GSD Ib, despite the fact that the pathology is based on chronic hypoglycemia. More and more evidence points to the role of empagliflozin in the regulation of cellular homeostasis (for example, fatty acid metabolism, glucose, cholesterol, apoptosis and cell proliferation, in particular in the liver) by influencing the activity of sirtuin 1 (SIRT1), AMP-activated protein kinase (AMPK) and signal molecules such as -serine/threonine protein kinase (Akt) and a mechanical target of rapamycin (mTOR), which leads to an improvement in the structure and function of mitochondria, stimulation of autophagy, reducing oxidative stress and suppressing inflammation. Modulation of these pathways shifts oxidative metabolism from carbohydrates to lipids and leads to a key decrease in insulin levels, resistance to it, glucose and lipotoxicity. This review presents current data on the pathogenesis of neutropenia and the possibility of using empagliflozin for its relief in patients with GSD Ib.

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.

Glycogen storage disease type Ib (GSD Ib) is a rare hereditary glycogen disorder that results in inadequate maintenance of glucose homeostasis, accumulation of glycogen in different organs, loss and dysfunction of neutrophils. Crohn's-like disease is observed in up to 24–77% of GDS Ib cases. Recently, empagliflozin has been recommended as a treatment for neutrophil dysfunction in GDS Ib patients with or without Crohn's-like disease. There are no guidelines for the treatment of inflammatory bowel disease (IBD) manifestation in GSD Ib patients, although some cases have been treated with granulocyte colony-stimulating factor and others with IBD conventional therapy, resulting in partial IBD remission. Herein, we describe a child with GDS Ib and Crohn's-like disease who was treated with empagliflozin and achieved complete remission after 2 years of treatment. This case is the first one with such a long follow-up evaluation including endoscopic and magnetic resonance enterography assessment. Our clinical evidence of remission of IBD manifestation in our GSD Ib patient and the role of neutrophils in GDS Ib described in the literature suggest a strong association with IBD pathophysiology and neutrophil function. The use of empagliflozin resulted in significant improvements in gastrointestinal symptoms, reduced drug usage, and enhanced quality of life in the patient, with a favorable safety profile, offering a promising new therapeutic option for this population. [ABSTRACT FROM AUTHOR]

Neutropenia and neutrophil dysfunction in glycogen storage disease type 1b (GSD1b) and severe congenital neutropenia type 4 (SCN4), associated with deficiencies of the glucose-6-phosphate transporter (G6PT/SLC37A4) and the phosphatase G6PC3, respectively, are the result of the accumulation of 1,5-anhydroglucitol-6-phosphate in neutrophils. This is an inhibitor of hexokinase made from 1,5-anhydroglucitol (1,5-AG), an abundant polyol in blood. 1,5-AG is presumed to be reabsorbed in the kidney by a sodium-dependent-transporter of uncertain identity, possibly SGLT4/SLC5A9 or SGLT5/SLC5A10. Lowering blood 1,5-AG with an SGLT2-inhibitor greatly improved neutrophil counts and function in G6PC3-deficient and GSD1b patients. Yet, this effect is most likely mediated indirectly, through the inhibition of the renal 1,5-AG transporter by glucose, when its concentration rises in the renal tubule following inhibition of SGLT2. To identify the 1,5-AG transporter, both human and mouse SGLT4 and SGLT5 were expressed in HEK293T cells and transport measurements were performed with radiolabelled compounds. We found that SGLT5 is a better carrier for 1,5-AG than for mannose, while the opposite is true for human SGLT4. Heterozygous variants in SGLT5, associated with a low level of blood 1,5-AG in humans cause a 50–100% reduction in 1,5-AG transport activity tested in model cell lines, indicating that SGLT5 is the predominant kidney 1,5-AG transporter. These and other findings led to the conclusion that (1) SGLT5 is the main renal transporter of 1,5-AG; (2) frequent heterozygous mutations (allelic frequency > 1%) in SGLT5 lower blood 1,5-AG, favourably influencing neutropenia in G6PC3 or G6PT deficiency; (3) the effect of SGLT2-inhibitors on blood 1,5-AG level is largely indirect; (4) specific SGLT5-inhibitors would be more efficient to treat these neutropenias than SGLT2-inhibitors. [ABSTRACT FROM AUTHOR]

Abstract In patients with glycogen storage disease type Ib (GSD Ib), quality of life is severely hampered by neutropenia and neutropenia‐associated symptoms. SGLT2 inhibitors are a new treatment option and have shown improved medical outcomes in more than 120 patients so far. The aim of this international questionnaire study was to assess patient‐reported outcomes of this new treatment in GSD Ib patients. Patients and caregivers of pediatric patients were invited to complete a web‐based questionnaire. This was designed to evaluate treatment effects of the SGLT2 inhibitor empagliflozin on clinical symptoms and important aspects of daily life including physical performance, sleep, social and work life, traveling, socioeconomic aspects, and quality of life. The questionnaire was completed by 73 respondents from 17 different countries. The mean duration of treatment was 15 months, the cumulative treatment time was 94.8 years. More than 80% of patients reported an improved quality of life. The number of hospitalizations was reduced (66% of patients), as well as the number of days absent from school or work. Granulocyte colony‐stimulating factor (G‐CSF) treatment could be stopped in 49% of patients and reduced in another 42%. Clear improvement of neutropenia and all neutropenia‐associated symptoms was reported by the majority of patients. Additionally, patients or caregivers reported positive effects on appetite (63%), level of activity (75%), overall well‐being (96%), and sleep (63%). Empagliflozin positively impacts many aspects of daily life including work and social life and thereby significantly improves quality of life of patients and caregivers.

Abstract Glycogen storage disease type Ib (GSD Ib) is caused by biallelic variants in SLC37A4. GSD Ib is characterized by hepatomegaly, recurrent hypoglycemia, neutropenia, and neutrophil dysfunction. Only seven pregnancies in four women with GSD Ib have been reported so far. We report on two further successful pregnancies in two patients with GSD Ib. One of these pregnancies was managed with empagliflozin, an SGLT2 inhibitor, repurposed for the treatment of neutropenia in GSD Ib. Both pregnancies were unremarkable and resulted in healthy offspring. Gestational care and pre‐ and perinatal management in GSD Ib are challenging and require close interdisciplinary metabolic and obstetric monitoring. In our patient, the use of empagliflozin during pregnancy was successful in the prevention of neutropenic symptoms and infections and enabled good wound healing after Cesarean section, while no adverse effects were observed.

Introduction Recently published case reports suggest the benefit of empagliflozin use in subjects with glycogen storage disease Ib (GSD Ib). Material and methods We present the clinical and laboratory data of 2 adult brothers with GSD Ib treated with empagliflozin for 12 months. Results There was no severe infection during administration of empagliflozin. The improvement of clinical symptoms of inflammatory bowel disease and arthritis along with reduction in serum CRP levels and urinary albumin excretion were noted. Neutrophil count increased allowing for reduction or temporary withdrawal of G-CSF treatment. Conclusions Empagliflozin may be new safe treatment in GSD Ib patients with advanced stage of the disease.

Abstract Background Glycogen storage disease type Ib (GSD Ib) is a severe disorder of carbohydrate metabolism due to bi-allelic variants in SLC37A4. It is associated with neutropaenia and neutrophil dysfunction, which has recently been attributed to the accumulation of 1,5-anhydroglucitol-6-phosphate (1,5AG6P) within neutrophils. Treatment with sodium-glucose co-transporter-2 (SGLT2) inhibitors, such as empagliflozin, is a novel therapy that reduces 1,5-anhydroglucitol (1,5AG) in plasma. Results We report our experience in treating 8 paediatric GSD Ib patients with empagliflozin with a cumulative treatment time greater than 12 years. Treatment with a median dose of 5 mg (0.22 mg/kg height weight) of empagliflozin resulted in improvement in bowel health, growth, and laboratory parameters. Plasma 1,5AG levels reduced by a median of 78%. Baseline 1,5AG levels in our cohort were higher than in adult patients with GSD Ib. Hypoglycaemia on empagliflozin treatment occurred in 50% of our cohort. Conclusion We report the largest single centre cohort of GSD Ib patients treated with empagliflozin to date. Treatment with SGLT2 inhibitors is a novel and favourable treatment option for neutropaenia and neutrophil dysfunction in GSD Ib. We suggest a low starting dose of empagliflozin with careful titration due to the risk of hypoglycaemia. The interpretation of 1,5AG levels and their role in treatment monitoring is yet to be established, and requires ongoing research.

Background: Glycogen storage disease type Ib (GSD Ib) is an autosomal recessively inherited deficiency of the glucose-6-phosphate translocase (G6PT). Clinical features include a combination of a metabolic phenotype (fasting hypoglycemia, lactic acidosis, hepatomegaly) and a hematologic phenotype with neutropenia and neutrophil dysfunction. Dietary treatment involves provision of starches such as uncooked cornstarch (UCCS) and Glycosade® to provide prolonged enteral supply of glucose. Granulocyte colony-stimulating factor (G-CSF) is the treatment of choice for neutropenia. Because long-term stimulation of hematopoiesis with G-CSF causes serious complications such as splenomegaly, hypersplenism, and osteopenia; hematopoietic stem cell transplantation (HSCT) has been considered in some patients with GSD Ib to correct neutropenia and avoid G-CSF related adverse effects. Whether HSCT also has an effect on the metabolic phenotype and utilization of carbohydrate sources has not been determined. Objective: Our objective was to measure the utilization of starch in a patient with GSD Ib before and after HSCT using the minimally invasive 13C-glucose breath test (13C-GBT). Design: A case of GSD Ib (18y; female) underwent 13C-GBT four times: UCCS (pre-HSCT), UCCS (3, 5 months post-HSCT) and Glycosade® (6 months post-HSCT) with a dose of 80 g administered via nasogastric tube after a 4 h fast according to our patient's fasting tolerance. Breath samples were collected at baseline and every 30 min for 240 min. Rate of CO2 production was measured at 120 min using indirect calorimetry. Finger-prick blood glucose was measured using a glucometer hourly to test hypoglycemia (glucose

Abstract Background Besides major clinical/biochemical features, neutropenia and inflammatory bowel disease (IBD) constitute common complications of Glycogen storage disease type Ib (GSD Ib). However, their management is still challenging. Although previous reports have shown benefit of empagliflozin administration on neutropenia, no follow-up data on bowel (macro/microscopic) morphology are available. We herein present for the first time longitudinal assessment of bowel morphology in a GSD Ib child suffering from Crohn disease-like enterocolitis treated with empagliflozin. Case presentation A 14-year-old boy with GSD Ib and severe IBD was (off-label) treated with empagliflozin (20 mg/day) after informed oral and written consent was obtained from the patient’s parents. No adverse events were noted. Clinical symptoms and stool frequency improved within the first week of treatment. Pediatric Crohn disease activity index (PCDAI) normalised within the first month of treatment. Abdomen magnetic resonance imaging (MRI) performed 3 months after treatment initiation showed dramatic decrease in disease activity and length. Similar findings were reported on histology at 5.5 months. At 7.5 months hemoglobin levels normalised and fecal calprotectin almost normalised. Improved neutrophil count, metabolic control and quality of life were also noted. G-CSF dose was decreased by 33% and the patient was partly weaned from tube feeding. Conclusions This is the first report presenting extensive gastrointestinal morphology follow-up in a GSD Ib patient receiving empagliflozin. The present case suggests that empagliflozin can be safe and effective in inducing IBD remission in GSD Ib patients and can even postpone surgery. Future studies are required to confirm its effect over time and assess its benefit in various disease stages. The development of an international collaborating networks for systematic data collection is worthy.

Introduction: Recently published case reports suggest the benefit of empagliflozin use in subjects with glycogen storage disease Ib (GSD Ib).Methods: We present the clinical and laboratory data of 2 adult brothers with GSD Ib treated with empagliflozin for 12 months.Results: There was no severe infection during administration of empagliflozin. The improvement of clinical symptoms of inflammatory bowel disease and arthritis along with reduction in serum CRP levels and urinary albumin excretion was noted. Neutrophil count increased, allowing for reduction or temporary withdrawal of G-CSF treatment.Conclusions: Empagliflozin may be a new safe treatment in GSD Ib patients with an advanced stage of the disease. [ABSTRACT FROM AUTHOR]

Abstract Glycogen storage disease type Ib (GSDIb) is characterized by hepatomegaly and fasting hypoglycaemia as well as neutropaenia and recurrent infections. We conducted a retrospective observational study on a cohort of patients with GSDIb across England. A total of 35 patients, with a median age of 9.1 years (range 1‐39 years), were included in the study. We examined the genotype and phenotype of all patients and reported 14 novel alleles. The phenotype of GSDIb in England involves a short fasting tolerance that extends into adulthood and a high prevalence of gastrointestinal symptoms. Growth is difficult to manage and neutropaenia and recurrent infections persist throughout life. Liver transplantation was performed in nine patients, which normalized fasting tolerance but did not correct neutropaenia. This is the first natural history study on the cohort of GSDIb patients in England.

Abstract Background To investigate the clinical and genetic characteristics of patients with glycogen storage disease type Ib (GSD Ib). Case presentation This report retrospectively analyzed the clinical data of 3 patients with GSD Ib admitted into our hospital, and summarized their onset characteristics, clinical manifestations, related examinations and treatment as well as mutational spectrum. After gene sequencing, the diagnosis of GSD Ib was confirmed in all 3 patients. Five variants of SLC37A4 gene were detected, of which c. 572C > T was the common variant and c. 680G > A was a novel variant. The 3 cases of GSD Ib were mainly affected by liver enlargement, growth retardation, etc., and all had a history of repeated infections. At the onset, patients mainly manifested as mildly elevated alanine-aminotransferase (ALT), accompanied by decreased absolute neutrophil count (ANC), hypertriglyceridemia, and metabolic disorders (hypoglycemia, hyperlactic acidemia, metabolic acidosis, etc.). After long-term treatment by oral uncooked cornstarch, the abnormal liver enzymes gradually returned to normal, and metabolic abnormalities were basically controlled most of the time. With increasing age, ANC of 2 patients decreased progressively, whereas the times of infections was reduced. Conclusions We reported 3 cases with GSD Ib and a novel SLC37A4 variant. The possibility of GSD type Ib should be kept on alert when a patient suffers recurrent infections, accompanied by hepatomegaly, elevated liver enzymes, hypoglycemia, dyslipidemia, and metabolic disorders.

Objective To investigate the clinical characteristics of glycogen storage disease typeⅠb(GSDⅠb) with Crohn's Disease(CD) and to improve the recognition of the disease. Methods Retrospectively analyze the clinical characteristics of 2 cases diagnosed with the GSDⅠb and CD in the pediatric department of Peking Union Medical College Hospital. Results A boy and a girl were included in the study. They were genetically diagnosed as GSDⅠb at 2 years age. Gastrointestinal symptoms including abdominal pain and diarrhea were observed at 4, 5 years old respectively. They were diagnosed as CD with endoscopic characteristics and pathology results. Besides corn starch, granulocyte colony-stimulating factor(G-CSF) was used to elevate the neutrophil to above 1.0×109/L. The gastrointestinal symptoms got alleviated. 5-aminosalicylic acid agents were used as supportive treatment. Conclusions Evaluation of the gastrointestinal system is necessary as the abdominal pain or diarrhea were observed in GSDⅠb patients. G-CSF with a relatively low dose is the mainstay to elevate neutrophil with few side effects. Splenomegaly is the most common side effect. Monitor renal function is necessary in the use of 5-ASA.

Background: Glycogen storage disease type Ib (GSD Ib) is a severe disorder of carbohydrate metabolism due to bi-allelic variants in SLC37A4. It is associated with neutropaenia and neutrophil dysfunction, which has recently been attributed to the accumulation of 1,5-anhydroglucitol-6-phosphate (1,5AG6P) within neutrophils. Treatment with sodium-glucose co-transporter-2 (SGLT2) inhibitors, such as empagliflozin, is a novel therapy that reduces 1,5-anhydroglucitol (1,5AG) in plasma.Results: We report our experience in treating 8 paediatric GSD Ib patients with empagliflozin with a cumulative treatment time greater than 12 years. Treatment with a median dose of 5 mg (0.22 mg/kg height weight) of empagliflozin resulted in improvement in bowel health, growth, and laboratory parameters. Plasma 1,5AG levels reduced by a median of 78%. Baseline 1,5AG levels in our cohort were higher than in adult patients with GSD Ib. Hypoglycaemia on empagliflozin treatment occurred in 50% of our cohort.Conclusion: We report the largest single centre cohort of GSD Ib patients treated with empagliflozin to date. Treatment with SGLT2 inhibitors is a novel and favourable treatment option for neutropaenia and neutrophil dysfunction in GSD Ib. We suggest a low starting dose of empagliflozin with careful titration due to the risk of hypoglycaemia. The interpretation of 1,5AG levels and their role in treatment monitoring is yet to be established, and requires ongoing research. [ABSTRACT FROM AUTHOR]

Abstract Background Glycogen storage disease type Ib (GSD Ib) is a rare inborn error of glycogen metabolism due to mutations in SLC37A4. Besides a severe form of fasting intolerance, the disorder is usually associated with neutropenia and neutrophil dysfunction causing serious infections, inflammatory bowel disease, oral, urogenital and perianal lesions as well as impaired wound healing. Recently, SGLT2 inhibitors such as empagliflozin that reduce the plasma levels of 1,5-anhydroglucitol have been described as a new treatment option for the neutropenia and neutrophil dysfunction in patients with GSD Ib. Results We report on a 35-year-old female patient with GSD Ib who had been treated with G-CSF for neutropenia since the age of 9. She had a large chronic abdominal wound as a consequence of recurrent operations due to complications of her inflammatory bowel disease. Treatment with 20 mg empagliflozin per day resulted in normalisation of the neutrophil count and neutrophil function even after termination of G-CSF. The chronic abdominal wound that had been unchanged for 2 years before the start of empagliflozin nearly closed within 12 weeks. No side effects of empagliflozin were observed. Conclusion SGLT2 inhibitors are a new and probably safe treatment option for GSD Ib-associated neutropenia and neutrophil dysfunction. We hypothesize that restoration of neutrophil function and normalisation of neutrophil apoptosis leads to improvement of wound healing and ameliorates symptoms of inflammatory bowel disease.

Background: Besides major clinical/biochemical features, neutropenia and inflammatory bowel disease (IBD) constitute common complications of Glycogen storage disease type Ib (GSD Ib). However, their management is still challenging. Although previous reports have shown benefit of empagliflozin administration on neutropenia, no follow-up data on bowel (macro/microscopic) morphology are available. We herein present for the first time longitudinal assessment of bowel morphology in a GSD Ib child suffering from Crohn disease-like enterocolitis treated with empagliflozin. Case presentation: A 14-year-old boy with GSD Ib and severe IBD was (off-label) treated with empagliflozin (20 mg/day) after informed oral and written consent was obtained from the patient's parents. No adverse events were noted. Clinical symptoms and stool frequency improved within the first week of treatment. Pediatric Crohn disease activity index (PCDAI) normalised within the first month of treatment. Abdomen magnetic resonance imaging (MRI) performed 3 months after treatment initiation showed dramatic decrease in disease activity and length. Similar findings were reported on histology at 5.5 months. At 7.5 months hemoglobin levels normalised and fecal calprotectin almost normalised. Improved neutrophil count, metabolic control and quality of life were also noted. G-CSF dose was decreased by 33% and the patient was partly weaned from tube feeding. Conclusions: This is the first report presenting extensive gastrointestinal morphology follow-up in a GSD Ib patient receiving empagliflozin. The present case suggests that empagliflozin can be safe and effective in inducing IBD remission in GSD Ib patients and can even postpone surgery. Future studies are required to confirm its effect over time and assess its benefit in various disease stages. The development of an international collaborating networks for systematic data collection is worthy. [ABSTRACT FROM AUTHOR]

Background: To investigate the clinical and genetic characteristics of patients with glycogen storage disease type Ib (GSD Ib). Case presentation: This report retrospectively analyzed the clinical data of 3 patients with GSD Ib admitted into our hospital, and summarized their onset characteristics, clinical manifestations, related examinations and treatment as well as mutational spectrum. After gene sequencing, the diagnosis of GSD Ib was confirmed in all 3 patients. Five variants of SLC37A4 gene were detected, of which c. 572C > T was the common variant and c. 680G > A was a novel variant. The 3 cases of GSD Ib were mainly affected by liver enlargement, growth retardation, etc., and all had a history of repeated infections. At the onset, patients mainly manifested as mildly elevated alanine-aminotransferase (ALT), accompanied by decreased absolute neutrophil count (ANC), hypertriglyceridemia, and metabolic disorders (hypoglycemia, hyperlactic acidemia, metabolic acidosis, etc.). After long-term treatment by oral uncooked cornstarch, the abnormal liver enzymes gradually returned to normal, and metabolic abnormalities were basically controlled most of the time. With increasing age, ANC of 2 patients decreased progressively, whereas the times of infections was reduced. Conclusions: We reported 3 cases with GSD Ib and a novel SLC37A4 variant. The possibility of GSD type Ib should be kept on alert when a patient suffers recurrent infections, accompanied by hepatomegaly, elevated liver enzymes, hypoglycemia, dyslipidemia, and metabolic disorders. [ABSTRACT FROM AUTHOR]

Abstract Background Glycogen storage disease (GSD) type Ib is an autosomal recessive disease caused by defects of glucose‐6‐phosphate transporter (G6PT), encoded by the SLC37A4 gene. To date, over 100 mutations have been revealed in the SLC37A4 gene. GSD‐Ib patients manifest a metabolic phenotype of impaired blood glucose homeostasis and also carry the additional complications of neutropenia and myeloid dysfunction. Methods Here, we present two daughters with an initial diagnosis of gout in a Chinese consanguineous family. Whole‐exome sequencing was performed to identify the mutations. The mechanism of leukocytopenia was investigated. Results Whole‐exome sequencing analysis of the proband identified a novel homozygous p.P119L mutation in SLC37A4, leading to a diagnosis of GSD‐Ib. We found that the potential pathogenic p.P119L mutation leads to an unusual phenotype characterized by gout at onset, and GSD‐Ib arising from this variant also manifests multiple metabolic abnormalities, leukocytopenia, and anemia, but no hepatomegaly. The leukocytes from the proband showed increased mRNA levels of sXBP‐1, BIP, and CHOP genes in the unfolded protein response pathway, and enhanced Bax mRNA and caspase‐3 activity, which might contribute to leukocytopenia. Conclusion Our findings broaden the variation spectrum of SLC37A4 and suggest no strict genotype–phenotype correlations in GSD‐Ib patients.

Background: Glycogen storage disease (GSD) type Ib is an autosomal recessive disease caused by defects of glucose‐6‐phosphate transporter (G6PT), encoded by the SLC37A4 gene. To date, over 100 mutations have been revealed in the SLC37A4 gene. GSD‐Ib patients manifest a metabolic phenotype of impaired blood glucose homeostasis and also carry the additional complications of neutropenia and myeloid dysfunction. Methods: Here, we present two daughters with an initial diagnosis of gout in a Chinese consanguineous family. Whole‐exome sequencing was performed to identify the mutations. The mechanism of leukocytopenia was investigated. Results: Whole‐exome sequencing analysis of the proband identified a novel homozygous p.P119L mutation in SLC37A4, leading to a diagnosis of GSD‐Ib. We found that the potential pathogenic p.P119L mutation leads to an unusual phenotype characterized by gout at onset, and GSD‐Ib arising from this variant also manifests multiple metabolic abnormalities, leukocytopenia, and anemia, but no hepatomegaly. The leukocytes from the proband showed increased mRNA levels of sXBP‐1, BIP, and CHOP genes in the unfolded protein response pathway, and enhanced Bax mRNA and caspase‐3 activity, which might contribute to leukocytopenia. Conclusion: Our findings broaden the variation spectrum of SLC37A4 and suggest no strict genotype–phenotype correlations in GSD‐Ib patients. [ABSTRACT FROM AUTHOR]

Background & Objectives: Glycogen storage disease type Ib is a metabolic disease of carbohydrate metabolism. Patients suffer from metabolic disorders as a result of insufficient production of glucose from glycogen, and recurrent infections due to neutropenia. For the first time in Iran and in the world, we introduce a patient who was improved with herbal medicine. Case: A 5-year-old girl with glycogen storage disease type Ib, with a history of infantile hypoglycemic seizures, hepatomegaly, neutropenia, hyperlipidemia and metabolic acidosis participated in this study. She was under monthly treatment with G-CSF due to neutropenia induced recurrent oral ulcers and severe infection. After using Jujube fruit, her oral lesions improved and the patient’s infection attacks and neutropenia disappeared and there was no need for the administration of G-CSF after six months. Conclusion: The use of jujube can lead to the improvement of neutropenia, infection and oral lesions in glycogen storage disease type Ib.

The article presents case study of patient who was admitted to hospital because of incidental hypoglycemia soon after birth and showed persistent hypoglycemia and hyperlactatemia after 3–4 h fasting, and she gradually developed hepatomegaly. It mentions diagnosis of glycogen storage disease type Ib (GSDIb); and also mentions SGLT2i can ameliorate neutropenia and IBD symptoms in GSD1b patients.

Cellular metabolism generally refers to biochemical processes that produce or consume energy within the cell. Recent studies have established that aberrant metabolic states caused by internal or external stresses and genetic mutations are intertwined with several human pathologies. Gaining insight into these metabolic alterations is, therefore, essential for understanding the pathophysiology of various diseases. Glycogen storage disease type Ib (GSD‐Ib) is an autosomal recessive disorder characterized by hypoglycemia, excessive glycogen accumulation in the liver and kidney, neutropenia, neutrophil dysfunction, and inflammatory bowel disease. GSD‐Ib is caused by a deficiency of glucose‐6‐phosphate transporter (G6PT). Recently, it was reported that deficiency of G6PT also leads to the aberrant proliferation and differentiation of mesenchymal stem cells and impaired regulatory T‐cell function. This review describes the broad impact of altered cellular metabolism resulting from a lack of G6PT activity on cellular function and considers the prospects of developing novel approaches for GSD‐Ib treatment. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. • Hepatic ChREBP knockdown increases GCK levels and-flux. • Hepatic ChREBP knockdown enhances hepatic glycogen synthesis and-phosphorylation in acute GSD Ib. • Hepatic ChREBP knockdown reduces hepatic STBD1 levels and GAA activity. • Hepatic ChREBP knockdown slightly reduces blood glucose levels in acute GSD Ib. [ABSTRACT FROM AUTHOR]

The human SLC37 gene family includes four proteins SLC37A1-4, localized in the endoplasmic reticulum (ER) membrane. They have been grouped into the SLC37 family due to their sequence homology to the bacterial organophosphate/phosphate (Pi) antiporter. SLC37A1-3 are the less characterized isoforms. SLC37A1 and SLC37A2 are Pi-linked glucose-6-phosphate (G6P) antiporters, catalyzing both homologous (Pi/Pi) and heterologous (G6P/Pi) exchanges, whereas SLC37A3 transport properties remain to be clarified. Furthermore, SLC37A1 is highly homologous to the bacterial glycerol 3-phosphate permeases, so it is supposed to transport also glycerol-3-phosphate. The physiological role of SLC37A1-3 is yet to be further investigated. SLC37A1 seems to be required for lipid biosynthesis in cancer cell lines, SLC37A2 has been proposed as a vitamin D and a phospho-progesterone receptor target gene, while mutations in the SLC37A3 gene appear to be associated with congenital hyperinsulinism of infancy. SLC37A4, also known as glucose-6-phosphate translocase (G6PT), transports G6P from the cytoplasm into the ER lumen, working in complex with either glucose-6-phosphatase-α (G6Pase-α) or G6Pase-β to hydrolyze intraluminal G6P to Pi and glucose. G6PT and G6Pase-β are ubiquitously expressed, whereas G6Pase-α is specifically expressed in the liver, kidney and intestine. G6PT/G6Pase-α complex activity regulates fasting blood glucose levels, whereas G6PT/G6Pase-β is required for neutrophil functions. G6PT deficiency is responsible for glycogen storage disease type Ib (GSD-Ib), an autosomal recessive disorder associated with both defective metabolic and myeloid phenotypes. Several kinds of mutations have been identified in the SLC37A4 gene, affecting G6PT function. An increased autoimmunity risk for GSD-Ib patients has also been reported, moreover, SLC37A4 seems to be involved in autophagy.

Background & Objectives: Glycogen storage disease type Ib is a metabolic disease of carbohydrate metabolism. Patients suffer from metabolic disorders as a result of insufficient production of glucose from glycogen, and recurrent infections due to neutropenia. For the first time in Iran and in the world, we introduce a patient who was improved with herbal medicine. Case: A 5-year-old girl with glycogen storage disease type Ib, with a history of infantile hypoglycemic seizures, hepatomegaly, neutropenia, hyperlipidemia and metabolic acidosis participated in this study. She was under monthly treatment with G-CSF due to neutropenia induced recurrent oral ulcers and severe infection. After using Jujube fruit, her oral lesions improved and the patient's infection attacks and neutropenia disappeared and there was no need for the administration of G-CSF after six months. Conclusion: The use of jujube can lead to the improvement of neutropenia, infection and oral lesions in glycogen storage disease type Ib. [ABSTRACT FROM AUTHOR]

Glycogen storage disease (GSD) type Ib is caused by the deficiency of glucose-6-phosphate translocase activity. The elder brother of the proband died at age 20 months, and GSD Ia, a disease caused by the deficiency of glucose-6-phosphatase, was the diagnosis. The proband developed hypoglycemia shortly after birth. Dietary therapy was instituted immediately, but his growth was poor and there were repeated episodes of pyogenic infection. Neutropenia had been observed since 6 months of age, but the diagnosis of GSD Ib was established only at 18 months of age after two mutations (c.354_355insC (p. W118fsX12) and c.736T >C (p.W246R)) were detected on his SLC37A4 gene. Regular administration of G-CSF rapidly improved his health and decreased his hospital stay. Although GSD Ib is very rare in Taiwan, correct diagnosis is essential to save the lives of such patients.