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Glycogen storage disease type I (GSDI), an inborn error of carbohydrate metabolism, is caused by defects in the glucose-6-transporter/glucose-6-phosphatase complex, which is essential in glucose homeostasis. Two types exist, GSDIa and GSDIb, each caused by different defects in the complex. GSDIa is characterized by fasting intolerance and subsequen...
Contexts in source publication
Context 1
... living- related transplantation was performed in 16 cases. 6 Patients underwent a combined liver-kidney trans- plantation (Table 2). The immunosuppressive regime consisted of steroids, combined with cyclosporine in 12 patients, with cyclosporine and azathioprine in 17 patients and with tacrolimus in 9 patients. ...
Context 2
... transplantation was performed in 22 patients with GSDIb between 1991 and 2012, at an average age of 10 years (range 1-44 years) ( Table 1, Additional file 1: Table S2). One patient had a kidney transplantation 2 years prior to the liver transplantation, with good func- tion of both grafts reported 8 months after liver trans- plantation (Table 2). Indications for liver transplantation in GSDIb patients included poor metabolic control (21 pa- tients) and/or recurrent infections (10 patients), growth retardation (3 patients), and oral and anal ulcera (1 pa- tient). ...
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Glycogen storage disease type Ia (GSD1A) is caused by mutations in the G6PC gene. The G6PC gene was first cloned in 1993. Since then, many different mutations have been identified leading to this disease. Hepatomegaly is one of the important clinical manifestations of the disease. A 23-day-old girl was admitted to the hospital due to respiratory di...
Glycogen storage disease type Ia (GSD Ia) is caused by mutations in the glucose-6-phosphatase (G6Pase) catalytic subunit gene (G6PC). GSD Ia complications include hepatocellular adenomas (HCA) with a risk for hepatocellular carcinoma (HCC) formation. Genome editing with adeno-associated virus (AAV) vectors containing a zinc-finger nuclease (ZFN) an...
Objective
Glycogen storage disease type 1a (GSD Ia) is a rare inherited metabolic disorder caused by mutations in the glucose-6-phosphatase (G6PC1) gene. When untreated, GSD Ia leads to severe fasting-induced hypoglycemia. Although current intensive dietary management aims to prevent hypoglycemia, patients still experience hypoglycemic events. Poor...
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Von Gierke disease, also known as glycogen storage disease type I, co-existent with an abdominal aortic aneurysm (AAA), is an extremely rare combination of diseases that requires challenging therapeutic measures. We present, for the first time in literature, the case of a 62-year-old female with von Gierke disease who required open surgical repair...
Citations
... In the absence of effective drug treatments, uncooked cornstarch (UCCS) and symptomatic therapies including injections of granulocyte colonystimulating factor (GCSF) and allopurinol, have been the principal treatment options. Liver transplantation is effective for GSD Ia but does not ameliorate myeloid dysfunction in GSD Ib patients [9][10][11]. Recently, the mechanism of neutropenia and dysfunction of neutrophils in GSD Ib patients was revealed. ...
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.
... Indications for LT in GSD type Ib are similar, but also includes recurrent infections due to neutropenia. 34 Important perioperative concerns in GSD type I are lactic acidosis and hypoglycemia. Stress-induced lactic acidosis may be life-threatening. ...
... Results from a cohort of 80 patients with GSD type I who received LT showed that metabolic control and tolerance to fasting improved after the transplant procedure. 34 LT reverses the liver dysfunction, growth retardation, and neutropenia. LT was also shown to cure the inflammatory bowel disease in patients with GSD type Ib. ...
Monogenic diseases are the results of a single gene mutation leading to alterations or defects in a single enzyme causing severe metabolic derangements causing multi-systemic systemic disease and even death Current management strategies include diet to reduce the accumulation of metabolic waste products and treatment to increase the excretion of the toxic metabolites and to induce the activity of the mutant enzyme. However, liver transplantation is the only therapeutic strategy that offers a chance of cure to children with certain genetic diseases.
... Of note, none of the explanted liver histology showed malignant changes. In other reports, indications for LT included multiple hepatic adenomas or hepatocellular carcinoma [11]. Therefore, indications are different in GSD patients for LT which are particularly acceptable in cases where optimal metabolic management has not been achieved [12,13]. ...
Background
Glycogen storage diseases (GSDs) are inherited glycogen metabolic disorders which have various subtypes. GSDs of type I, III, IV, VI, and IX show liver involvement and are considered as hepatic types of GSDs. Thus, liver transplantation (LT) has been proposed as a final therapy for these types of GSD. LT corrects the primary hepatic enzyme defect; however, the long-term outcomes of LT in these patients have not been extensively evaluated so far. There are few reports in the English literature about the outcome of GSD patients after LT. There has been no report from Iran. The present retrospective study aimed to evaluate the long-term outcomes of eight patients with GSD types I, III, and IV who underwent LT in the affiliated hospitals of Shiraz University of Medical Sciences, from March 2013 to June 2021. During this period, there were no patients with GSD VI and IX identified in this center.
Results
The median time of diagnosis of the GSDs and at transplant was 1 year and 11 years, respectively. All eight transplanted patients were alive at the time of follow-up in this study. None of them required a re-transplant. All of the patients showed normalized liver enzymes after LT with no sign of hypoglycemia.
Conclusions
LT is an achievable treatment for end-stage hepatic involvement of GSDs with a cure for metabolic deficiency. Our experience in these eight patients shows a favorable outcome with no mortality and no major complication.
... GSD Ib patients have neutropaenia and neutrophil dysfunction causing recurrent infections, periodontal inflammation and inflammatory bowel disease (IBD) [5]. The neutropaenia and neutrophil dysfunction in GSD Ib persists throughout life, and is not ameliorated by liver transplantation [6][7][8][9]. This is likely to impact on quality of life (QoL) with studies finding Open Access *Correspondence: r.halligan@nhs.net ...
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.
... 5 The neutropaenia and neutrophil dysfunction in GSD Ib persists throughout life, and is not ameliorated by liver transplantation. [6][7][8][9] This is likely to impact on quality of life (QoL) with studies nding that patients with GSD Ib typically reported a lower QoL than patients with GSD Ia. [10][11] An international priority setting partnership with the James Lind Alliance has listed the treatment of neutropaenia and infections, and management of IBD in GSD Ib as a top research priority. 12 Recently, the neutropaenia and neutrophil dysfunction seen in GSD Ib has been attributed to a build-up of 1,5-anhydroglucitol-6-phosphate (1,5AG6P) within neutrophils. ...
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 total treatment time greater than 12 years. Treatment with a median dose of 5mg (0.22mg/kg height weight) of empagliflozin resulted in improvement in bowel health, growth, and laboratory parameters. Plasma 1,5AG levels reduced by a median 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.
... HCA with the potential for transformation into HCC remains one of the most concerning long-term complications of GSDIa [24]. Boers et al. published a retrospective, observational study of 80 patients with GSD type I, in whom liver transplantation was indicated because of HCA/liver abnormalities/focal nodular hyperplasia (29 patients), poor metabolic control (27 patients), growth retardation (13 patients, some with delayed puberty and sexual maturation), renal failure (five patients, three of whom received a combined liver and kidney transplant), bleeding complications leading to anaemia (one patient) and acute pancreatitis due to severe hypertriglyceridaemia (one patient) [82]. Patients with GSDIa who undergo liver transplantation are at risk of severe lactic acidosis in the perioperative period if managed by healthcare providers with limited experience in GSDIa [83]. ...
... Patients with GSDIa who undergo liver transplantation are at risk of severe lactic acidosis in the perioperative period if managed by healthcare providers with limited experience in GSDIa [83]. While patients with GSD type I who receive a functional liver transplant achieve normal metabolic control and normal fasting tolerance, they are at risk of complications associated with the transplant itself and require subsequent immune suppression [82]. Normalisation of metabolic control has also been achieved with human hepatocyte transplantations; however, the beneficial effect was not sustained long term [82,84,85]. ...
... While patients with GSD type I who receive a functional liver transplant achieve normal metabolic control and normal fasting tolerance, they are at risk of complications associated with the transplant itself and require subsequent immune suppression [82]. Normalisation of metabolic control has also been achieved with human hepatocyte transplantations; however, the beneficial effect was not sustained long term [82,84,85]. Liver transplantation does not protect against renal complications; therefore, a combined liver and kidney transplant may be considered. ...
Glycogen storage disease type Ia (GSDIa) is caused by defective glucose-6-phosphatase, a key enzyme in carbohydrate metabolism. Affected individuals cannot release glucose during fasting and accumulate excess glycogen and fat in the liver and kidney, putting them at risk of severe hypoglycaemia and secondary metabolic perturbations. Good glycaemic/metabolic control through strict dietary treatment and regular doses of uncooked cornstarch (UCCS) is essential for preventing hypoglycaemia and long-term complications. Dietary treatment has improved the prognosis for patients with GSDIa; however, the disease itself, its management and monitoring have significant physical, psychological and psychosocial burden on individuals and parents/caregivers. Hypoglycaemia risk persists if a single dose of UCCS is delayed/missed or in cases of gastrointestinal intolerance. UCCS therapy is imprecise, does not treat the cause of disease, may trigger secondary metabolic manifestations and may not prevent long-term complications. We review the importance of and challenges associated with achieving good glycaemic/metabolic control in individuals with GSDIa and how this should be balanced with age-specific psychosocial development towards independence, management of anxiety and preservation of quality of life (QoL). The unmet need for treatment strategies that address the cause of disease, restore glucose homeostasis, reduce the risk of hypoglycaemia/secondary metabolic perturbations and improve QoL is also discussed.
... In contrast to glucose therapy, LT provides a healthy liver graft that not only corrects the genetically acquired error of metabolism but also mitigates the risk of developing adenoma growth or liver cirrhosis [12,14]. Although LT corrects glucose homeostasis and metabolic derangement, some GSD patients receiving LT progress to renal insufficiency or end-stage renal disease (ESRD) [7,15]. Whether the development of CKD in GSD-I patients after LT is attributable to the nature of GSD progression in the kidneys itself or secondary to LT surgery or immunosuppression therapy remains unclear. ...
... Even after LT, some patients may progress to CKD. In the literature review by Boers et al., among 80 GSD-I patients undergoing LT, approximately 20% of patients experienced subsequent renal failure [15]. In our cohort of GSD-I, the eGFR remained stabilized or improved after LT among 7 out of 9 patients (78%) over a median follow-up of 15 years. ...
Background and aims:
Glycogen storage disease type I (GSD-I) is an autosomal recessive disorder of carbohydrate metabolism, resulting in limited production of glucose and excessive glycogen storage in the liver and kidneys. These patients are characterized by life-threatening hypoglycemia, metabolic derangements, hepatomegaly, chronic kidney disease, and failure to thrive. Liver transplantation (LT) has been performed for poor metabolic control and delayed growth. However, renal outcome was diverse in pediatric GSD patients after LT. The aim of this study was to investigate the long-term outcome of renal function in pediatric GSD-I patients after living donor LT (LDLT), and to identify modifiable variables that potentially permits LT to confer native renal preservation.
Methods:
The study included eight GSD-Ia and one GSD-Ib children with a median age of 9.0 (range 4.2-15.7) years at the time of LT. Using propensity score matching, 20 children with biliary atresia (BA) receiving LT were selected as the control group by matching for age, sex, pre-operative serum creatinine (SCr) and pediatric end-stage liver disease (PELD) score. Renal function was evaluated based on the SCr, estimated glomerular filtration rate (eGFR), microalbuminuria, and morphological changes in the kidneys. Comparability in long-term renal outcome in terms of anatomic and functional parameters will help to identify pre-LT factors of GSD-I that affect renal prognosis.
Results:
The clinical and biochemical characteristics of the GSD and BA groups were similar, including immunosuppressive regimens and duration of follow-up (median 15 years) after LT. Overall, renal function, including eGFR and microalbuminuria was comparable in the GSD-I and BA groups (median eGFR: 111 vs. 123 ml/min/1.73m2, P = 0.268; median urine microalbuminuria to creatinine ratio: 16.0 vs. 7.2 mg/g, P = 0.099, respectively) after LT. However, in the subgroups of the GSD cohort, patients starting cornstarch therapy at an older age (≥ 6-year-old) before transplantation demonstrated a worse renal outcome in terms of eGFR change over years (P < 0.001). In addition, the enlarged kidney in GSD-I returned to within normal range after LT.
Conclusions:
Post-LT renal function was well-preserved in most GSD-I patients. Early initiation of cornstarch therapy before preschool age, followed by LT, achieved a good renal prognosis.
... In contrast to glucose therapy, LT provides a healthy liver graft that not only corrects the genetically acquired error of metabolism but also mitigates the risk of developing adenoma growth or liver cirrhosis [11,13]. Although LT corrects glucose homeostasis and metabolic derangement, some GSD patients receiving LT progress to renal insu ciency or end-stage renal disease (ESRD) [6,14]. Whether the development of CKD in GSD-I patients after LT is attributable to the nature of GSD progression in the kidneys itself or secondary to LT surgery or immunosuppression therapy remains unclear. ...
... Even after LT, some patients may progress to CKD. In the literature review by Boers et al., among 80 GSD-I patients undergoing LT, approximately 20% of patients experienced subsequent renal failure [14]. In our cohort, two GSD-I patients (22%) demonstrated deteriorated renal perfusion (eGFR < 60 ml/min/1.73 ...
Background and aims
Glycogen storage disease type I (GSD-I) is an autosomal recessive disorder of carbohydrate metabolism, resulting in limited production of glucose and excessive glycogen storage in the liver and kidneys. These patients are characterized by life-threatening hypoglycemia, metabolic derangements, hepatomegaly, chronic kidney disease, and failure to thrive. Liver transplantation (LT) has been performed for poor metabolic control, delayed growth, and complications including liver cirrhosis or failure. However, renal outcome was diverse in pediatric GSD patients after LT. The aim of this study was to investigate the long-term outcome of renal function in pediatric GSD-I patients after living donor LT (LDLT), and to identify modifiable variables that potentially permits LT to confer native renal preservation.
Methods
The study included eight GSD-Ia and one GSD-Ib children with a median age of 9.0 (range 4.2-15.7) years at the time of LT. Using propensity score matching, 20 children with biliary atresia (BA) receiving LT were selected as the control group by matching for age, sex, pre-operative creatinine (Cr) and pediatric end-stage liver disease (PELD) score. Renal function was evaluated based on the serum Cr, estimated glomerular filtration rate (eGFR), microalbuminuria, and morphological changes in the kidneys. Comparability in long-term renal outcome in terms of anatomic and functional parameters will help to identify pre-LT factors of GSD-I that affect renal prognosis.
Results
The clinical and biochemical characteristics of the GSD and BA groups were similar, including immunosuppressive regimens and duration of follow-up (median 15 years) after LT. Overall, renal function, including eGFR and microalbuminuria was comparable in the GSD-I and BA groups (median eGFR: 111 vs. 123 ml/min/1.73m², P=0.268; median urine microalbuminuria to creatinine ratio: 16.0 vs 7.2 mg/g, P=0.099, respectively) after LT. However, in the subgroups of the GSD cohort, patients starting cornstarch therapy at an older age (≥ 6-year-old) before transplantation demonstrated a worse renal outcome in terms of eGFR change over years (P<0.001). In addition, the enlarged kidney in GSD-I returned to within normal range after LT.
Conclusions
Post-LT renal function was well-preserved in most GSD-I patients. Early initiation of cornstarch therapy before preschool age, followed by LT, achieved a good renal prognosis.
... Type I GSD is an AR disorder caused by deficiency of glucose-6phosphatase enzyme in 1 in 100000 live births, and there are two subtypes, 1a and 1b, with the latter having neutropenia or neutrophil dysfunction [62]. The liver function remains normal in these patients, but they are prone to develop hepatic adenomas and HCC (on a non-cirrhotic background). ...
Metabolic liver diseases (MLD) are the second most common indication for liver transplantation (LT) in children. This is based on the fact that the majority of enzymes involved in various metabolic pathways are present within the liver and LT can cure or at least control the disease manifestation. LT is also performed in metabolic disorders for end-stage liver disease, its sequelae including hepatocellular cancer. It is also performed for preventing metabolic crisis’, arresting progression of neurological dysfunction with a potential to reverse symptoms in some cases and for preventing damage to end organs like kidneys as in the case of primary hyperoxalosis and methyl malonic acidemia. Pathological findings in explant liver with patients with metabolic disease include unremarkable liver to steatosis, cholestasis, inflammation, variable amount of fibrosis, and cirrhosis. The outcome of LT in metabolic disorders is excellent except for patients with mitochondrial disorders where significant extrahepatic involvement leads to poor outcomes and hence considered a contraindication for LT. A major advantage of LT is that in the post-operative period most patients can discontinue the special formula which they were having prior to the transplant and this increases their well-being and improves growth parameters. Auxiliary partial orthotopic LT has been described for patients with noncirrhotic MLD where a segmental graft is implanted in an orthotopic position after partial resection of the native liver. The retained native liver can be the potential target for future gene therapy when it becomes a clinical reality.
... 2,5 Catch-up growth was seen in the pediatric patients post liver transplant, which is consistent with previous reports. 12,13,14 Guidelines on the dietary management of GSDIb are published together with GSDIa, and fasting tolerance is expected to increase with age as glucose requirements decrease. 5 However, our findings do not completely align with this, with some patients on overnight enteral feeds and 90-minute daytime feeds in adulthood. ...
... 16 None of our pediatric liver transplant cohort has had renal complications to date, and it is unclear whether liver transplant conveys a protective factor for renal function in patients with GSDIb. 13,14 Gastrointestinal complaints were common in our cohort, with several having either a diagnosis or clinical signs and symptoms suggestive of IBD. This directly correlates with neutropaenia and neutrophil dysfunction and indeed GCSF seems to help ameliorate symptoms. ...
... Liver transplantation did not cause resolution of neutropaenia or recurrent infections in our cohort, which is consistent with previous studies. 12,13,14 There is no doubt that GSDI has a severe impact on QoL, particularly regarding social functioning and more so in patients with GSDIb. 26,27 It would be beneficial to extend this study to formally explore the QoL of our cohort and to examine differences between patients who have had liver transplant and those who have not. ...
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.
