Empagliflozin for treating neutropenia and neutrophil dysfunction in 21 infants with glycogen storage disease 1b.

Empagliflozin has been successfully repurposed for treating neutropenia and neutrophil dysfunction in patients with glycogen storage disease type 1b (GSD 1b), however, data in infants are missing. We report on efficacy and safety of empagliflozin in infants with GSD 1b. This is an international retrospective case series on 21 GSD 1b infants treated with empagliflozin (total treatment time 20.6 years). Before starting empagliflozin (at a median age of 8.1 months with a median dose of 0.3 mg/kg/day) 12 patients had clinical signs and symptoms of neutrophil dysfunction. Six of these previously symptomatic patients had no further neutropenia/neutrophil dysfunction-associated findings on empagliflozin. Eight patients had no signs and symptoms of neutropenia/neutrophil dysfunction before start and during empagliflozin treatment. One previously asymptomatic individual with a horseshoe kidney developed a central line infection with pyelonephritis and urosepsis during empagliflozin treatment. Of the 10 patients who were treated with G-CSF before starting empagliflozin, this was stopped in four and decreased in another four. Eleven individuals were never treated with G-CSF. While in 17 patients glucose homeostasis remained stable on empagliflozin, four showed glucose homeostasis instability in the introductory phase. In 17 patients, no other side effects were reported, while genital (n = 2) or oral (n = 1) candidiasis and skin infection (n = 1) were reported in the remaining four. Empagliflozin had a good effect on neutropenia/neutrophil dysfunction-related signs and symptoms and a favourable safety profile in infants with GSD 1b and therefore qualifies for further exploration as first line treatment.

Efficacy and safety of empagliflozin in glycogen storage disease type Ib: Data from an international questionnaire.

PURPOSE: This paper aims to report collective information on safety and efficacy of empagliflozin drug repurposing in individuals with glycogen storage disease type Ib (GSD Ib). METHODS: This is an international retrospective questionnaire study on the safety and efficacy of empagliflozin use for management of neutropenia/neutrophil dysfunction in patients with GSD Ib, conducted among the respective health care providers from 24 countries across the globe. RESULTS: Clinical data from 112 individuals with GSD Ib were evaluated, representing a total of 94 treatment years. The median age at start of empagliflozin treatment was 10.5 years (range = 0-38 years). Empagliflozin showed positive effects on all neutrophil dysfunction-related symptoms, including oral and urogenital mucosal lesions, recurrent infections, skin abscesses, inflammatory bowel disease, and anemia. Before initiating empagliflozin, most patients with GSD Ib were on G-CSF (94/112; 84%). At the time of the survey, 49 of 89 (55%) patients previously treated with G-CSF had completely stopped G-CSF, and another 15 (17%) were able to reduce the dose. The most common adverse event during empagliflozin treatment was hypoglycemia, occurring in 18% of individuals. CONCLUSION: Empagliflozin has a favorable effect on neutropenia/neutrophil dysfunction-related symptoms and safety profile in individuals with GSD Ib.

Genetic characterization of GSD I in Serbian population revealed unexpectedly high incidence of GSD Ib and 3 novel SLC37A4 variants.

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.

Clinical spectrum, over 12-year follow-up and experience of SGLT2 inhibitors treatment on patients with glycogen storage disease type Ib: a single-center retrospective study.

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.

Determining mutations in G6PC and SLC37A4 genes in a sample of Brazilian patients with glycogen storage disease types Ia and Ib.

Glycogen storage disease (GSD) comprises a group of autosomal recessive disorders characterized by deficiency of the enzymes that regulate the synthesis or degradation of glycogen. Types Ia and Ib are the most prevalent; while the former is caused by deficiency of glucose-6-phosphatase (G6Pase), the latter is associated with impaired glucose-6-phosphate transporter, where the catalytic unit of G6Pase is located. Over 85 mutations have been reported since the cloning of G6PC and SLC37A4 genes. In this study, twelve unrelated patients with clinical symptoms suggestive of GSDIa and Ib were investigated by using genetic sequencing of G6PC and SLC37A4 genes, being three confirmed as having GSD Ia, and two with GSD Ib. In seven of these patients no mutations were detected in any of the genes. Five changes were detected in G6PC, including three known point mutations (p.G68R, p.R83C and p.Q347X) and two neutral mutations (c.432G > A and c.1176T > C). Four changes were found in SLC37A4: a known point mutation (p.G149E), a novel frameshift insertion (c.1338_1339insT), and two neutral mutations (c.1287G > A and c.1076-28C > T). The frequency of mutations in our population was similar to that observed in the literature, in which the mutation p.R83C is also the most frequent one. Analysis of both genes should be considered in the investigation of this condition. An alternative explanation to the negative results in this molecular study is the possibility of a misdiagnosis. Even with a careful evaluation based on laboratory and clinical findings, overlap with other types of GSD is possible, and further molecular studies should be indicated.

Elucidation of intermolecular interactions between chlorogenic acid and glucose-6-phosphate translocase: A step towards chemically induced glycogen storage disease type 1b model.

Glucose-6-phosphate translocase enzyme, encoded by SLC37A4 gene, is a crucial enzyme involved in transporting glucose-6-phosphate into the endoplasmic reticulum. Inhibition of this enzyme can cause Von-Gierke's/glycogen storage disease sub-type 1b. The current study dealt to elucidate the intermolecular interactions to assess the inhibitory activity of Chlorogenic acid (CGA) against SLC37A4 was assessed by molecular docking and dynamic simulation. The alpha folded model of SLC37A4 and CGA 3D structure were optimized using CHARMM force field, using energy minimization protocol in the Discovery Studio software. Glucose-6-phosphate (G6P) and CGA molecular docking, Molecular dynamics (MD) simulation, analysis of binding free energy of G6P-SLC37A4 and CGA-SLC37A4 complexes was performed for 100 ns using GROMACS, followed by principal component analysis (PCA). The docking score of the CGA-SLC37A4 complex exhibited a higher docking score (- 8.2 kcal/mol) when compared to the G6P-SLC37A4 complex (- 6.5 kcal/mol), suggesting a stronger binding interaction between CGA and SLC37A4. Further, the MD simulation demonstrated a stable backbone and complex Root Mean Square Deviation (RMSD), the least RMS fluctuation, and stable active site residue interactions throughout the 100 ns production run. The CGA complex with SLC37A4 exhibits higher compactness and formed 8 hydrogen bonds to achieve stability. The binding free energy of the G6P-SLC37A4 and CGA-SLC37A4 complex was found to be - 12.73 and - 31.493 kcal/mol. Lys29 formed stable contact for both G6P (- 4.73 kJ/mol) and SLC37A4 (- 2.18 kJ/mol). This study imparts structural insights into the competitive inhibition of SLC37A4 by CGA. CGA shows potential as a candidate to induce manifestations of GSD1b by inhibiting glycogenolysis, and gluconeogenesis. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-023-03661-5.

Three novel SLC37A4 variants in glycogen storage disease type 1b and a literature review.

Glycogen storage disease type 1b (GSD1b) is a rare genetic disorder, resulting from mutations in the SLC37A4 gene located on chromosome 11q23.3. Although the SLC37A4 gene has been identified as the pathogenic gene for GSD1b, the complete variant spectrum of this gene remains to be fully elucidated. In this study, we present three patients diagnosed with GSD1b through genetic testing. We detected five variants of the SLC37A4 gene in these three patients, with three of these mutations (p. L382Pfs*15, p. G117fs*28, and p. T312Sfs*13) being novel variants not previously reported in the literature. We also present a literature review and general overview of the currently reported SLC37A4 gene variants. Our study expands the mutation spectrum of SLC37A4, which may help enable genetic testing to facilitate prompt diagnosis, appropriate intervention, and genetic counseling for affected families.

Identification of mutations that causes glucose-6-phosphate transporter defect in tunisian patients with glycogenosis type 1b.

BACKGROUND: Glycogen storage disease type 1b (GSD1b) is an autosomal recessive lysosomal storage disease caused by defective glucose-6-phosphate transporter encoded by SLC37A4 leading to the accumulation of glycogen in various tissues. The high rate of consanguineous marriages in Tunisian population provides an ideal environment to facilitate the identification of homozygous pathogenic mutations. We aimed to determine the clinical and genetic profiles of patients with GSD1b to evaluate SLC37A4 mutations spectrum in Tunisian patients. METHODS: All exons and flanking intron regions of SLC37A4 gene were screened by direct sequencing to identify mutations and polymorphisms in three unrelated families with GSD1b. Bioinformatics tools were then used to predict the impacts of identified mutations on the structure and function of protein in order to propose a function-structure relationship of the G6PT1 protein. RESULTS: Three patients (MT, MB and SI) in Families I, II and III who had the severe phenotype were homoallelic for the two identified mutations: p.R300H (famillies I, II) and p.W393X (Family III), respectively. One of the alterations was a missense mutation p.R300H of exon 6 in SLC37A4 gene. The analysis of the protein structure flexibility upon p.R300H mutation using DynaMut tool and CABS-flex 2.0 server showed that the reported mutation increase the molecule flexibility of in the cytosol region and would probably lead to significant conformational changes. CONCLUSION: This is the first Tunisian report of SLC37A4 mutations identified in Tunisia causing the glycogenosis type Ib disease. Bioinformatics analysis allowed us to establish an approximate structure-function relationship for the G6PT1 protein, thereby providing better genotype/phenotype correlation knowledge.

A molecular signature for the G6PC3/SLC37A2/SLC37A4 interactors in glioblastoma disease progression and in the acquisition of a brain cancer stem cell phenotype.

Background: Glycogen plays an important role in glucose homeostasis and contributes to key functions related to brain cancer cell survival in glioblastoma multiforme (GBM) disease progression. Such adaptive molecular mechanism is dependent on the glycogenolytic pathway and intracellular glucose-6-phosphate (G6P) sensing by brain cancer cells residing within those highly hypoxic tumors. The involvement of components of the glucose-6-phosphatase (G6Pase) system remains however elusive. Objective: We questioned the gene expression levels of components of the G6Pase system in GBM tissues and their functional impact in the control of the invasive and brain cancer stem cells (CSC) phenotypes. Methods: In silico analysis of transcript levels in GBM tumor tissues was done by GEPIA. Total RNA was extracted and gene expression of G6PC1-3 as well as of SLC37A1-4 members analyzed by qPCR in four human brain cancer cell lines and from clinically annotated brain tumor cDNA arrays. Transient siRNA-mediated gene silencing was used to assess the impact of TGF-ß-induced epithelial-to-mesenchymal transition (EMT) and cell chemotaxis. Three-dimensional (3D) neurosphere cultures were generated to recapitulate the brain CSC phenotype. Results: Higher expression in G6PC3, SLC37A2, and SLC37A4 was found in GBM tumor tissues in comparison to low-grade glioma and healthy tissue. The expression of these genes was also found elevated in established human U87, U251, U118, and U138 GBM cell models compared to human HepG2 hepatoma cells. SLC37A4/G6PC3, but not SLC37A2, levels were induced in 3D CD133/SOX2-positive U87 neurospheres when compared to 2D monolayers. Silencing of SLC37A4/G6PC3 altered TGF-ß-induced EMT biomarker SNAIL and cell chemotaxis. Conclusion: Two members of the G6Pase system, G6PC3 and SLC37A4, associate with GBM disease progression and regulate the metabolic reprogramming of an invasive and CSC phenotype. Such molecular signature may support their role in cancer cell survival and chemoresistance and become future therapeutic targets.

Clinical characteristics and long-term outcomes of patients with glycogen storage disease type 1b: a retrospective multi-center experience in Poland.

Glycogen storage disease type 1b (GSD 1b) is an inherited metabolic defect caused by a deficiency of microsomal glucose-6-phosphate (G6P) transport protein across the endoplasmic reticulum membrane. Patients with GSD 1b have hypoglycemia episodes, lactate acidosis, hypertriglyceridemia, hypercholesterolemia, hyperuricemia, neutropenia and in imaging studies hepatomegaly and/or nephromegaly. The primary goals of treatment are to maintain proper blood glucose levels and to increase the number of properly functioning neutrophils. The aim of the study was a retrospective analysis of the clinical picture and treatment results of pediatric patients with type 1b glycogen storage disease from Poland. The study included 13 patients from 3 clinical centers, with a median age at diagnosis as 5 months. In 11/13 patients, the diagnosis was confirmed by molecular test, by the presence of pathogenic variants on both alleles of the SLC37A4 gene. Ten out of 13 patients developed the first symptoms in the form of severe infection (sepsis and/or pneumonia) already in the neonatal-infant period. A hypoglycemia episode was observed before diagnosis in 8/13 patients, of which 4/8 patients presented symptoms in the form of generalized relaxation and/or seizures. Two patients developed hypertension, and 4/13 required long-term treatment of inflammatory bowel disease.

Two successful pregnancies and first use of empagliflozin during pregnancy in glycogen storage disease type Ib.

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.

SLC37A4-CDG: New biochemical insights for an emerging congenital disorder of glycosylation with major coagulopathy.

SLC37A4-CDG is an emerging congenital disorder of glycosylation which is characterized by a dominant inheritance and a major coagulopathy originating from the liver. Recent studies took interest in the biochemical alterations found in this CDG and showed that they consisted of multiple glycosylation abnormalities, which result from mislocalization of the endoplasmic reticulum glucose-6-phosphate transporter and associated Golgi homeostasis defects. In this work, we highlight in six affected individuals abnormal patterns for various serum N-glycoproteins and bikunin proteoglycan isoforms, together with specific alterations of the mass spectra of endoglycosidase H-released serum N-glycans. Collectively, these data complement previous findings, help to better delineate SLC37A4-CDG and could present interest in diagnosing this disease.

Sensorineural hearing loss in GSD type I patients. A newly recognized symptomatic association of potential clinical significance and unclear pathomechanism.

OBJECTIVE: Glycogen storage disease (GSD) type I is an inborn error of carbohydrates metabolism characterized by inability to convert glucose-6-phosphate to glucose. It presents with serious liver and metabolic complications, as well as in type Ib with severe infections due to neutropenia. So far, the sensorineural hearing impairment has not been reported in these patients. Bilateral, sensorineural hearing impairment was diagnosed in four unrelated GSDI patients. Congenital origin of hearing loss and descending audiometric curves warranted the need for future investigations. METHODS: Hearing status was assessed in entire group of 40 children with GSD type I. Then, molecular testing, massive parallel sequencing was performed in the four probands and their parents in order to find possible genetic background of auditory dysfunction in these patients. RESULTS: Pathogenic variants in G6PC and SLC37A4 related to the phenotypes of GSDI subtype Ia and subtype Ib were detected, each in two probands, respectively. No change in the genes involved in auditory pathway dysfunction was found. CONCLUSIONS: Sensorineural hearing loss appears to be associated with GSDI in approximately one out of ten cases. Careful assessment and monitoring of auditory functions of patients with GSDI is recommended.

SLC37A4-CDG: Second patient.

Recently, a disorder caused by the heterozygous de novo c.1267C>T (p.R423*) substitution in SLC37A4 has been described. This causes mislocalization of the glucose-6-phosphate transporter to the Golgi leading to a congenital disorder of glycosylation type II (SLC37A4-CDG). Only one patient has been reported showing liver disease that improved with age and mild dysmorphism. Here we report the second patient with a type II CDG caused by the same heterozygous de novo c.1267C>T (p.R423*) mutation thereby confirming the pathogenicity of this variant and expanding the clinical picture with type 1 diabetes, severe scoliosis, and membranoproliferative glomerulonephritis. Additional clinical and biochemical data provide further insight into the mechanism and prognosis of SLC37A4-CDG.

Clinical analysis and long-term treatment monitoring of 3 patients with glycogen storage disease type Ib.

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.

A novel SLC37A4 missense mutation in GSD-Ib without hepatomegaly causes enhanced leukocytes endoplasmic reticulum stress and apoptosis.

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.

SLC37A4-CDG: Mislocalization of the glucose-6-phosphate transporter to the Golgi causes a new congenital disorder of glycosylation.

Loss-of-function of the glucose-6-phosphate transporter is caused by biallelic mutations in SLC37A4 and leads to glycogen storage disease Ib. Here we describe a second disease caused by a single dominant mutation in the same gene. The mutation abolishes the ER retention signal of the transporter and generates a weak Golgi retention signal. Intracellular mislocalization of the transporter leads to a congenital disorder of glycosylation instead of glycogen storage disease.

CRISPR/Cas9 genome editing of SLC37A4 gene elucidates the role of molecular markers of endoplasmic reticulum stress and apoptosis in renal involvement in glycogen storage disease type Ib.

Glycogen storage disease type Ib (GSD Ib) is an autosomal recessive disorder, caused by a deficiency of ubiquitously expressed SLC37A4 protein. Deficiency of SLC37A4 leads to abnormal storage of glycogen in the liver and kidneys, resulting in long-term complications of renal disease and hepatocellular adenomas, whose mechanisms are poorly understood. Molecular markers of the adaptive responses to the metabolic stress caused by a deficiency of SLC37A4, such as markers related to the endoplasmic reticulum (ER) stress and unfolded protein response (UPR), have not been extensively studied. The aim of this study was to investigate the expression of molecular markers of the UPR response and apoptosis related to a deficiency of SLC37A4 in kidney cells. For that purpose, we intended to establish a human kidney cell model system for GSD Ib. The novel variant c.248G>A, found in GSD Ib patients, was introduced into the Flp-In™T-REx™-293 cell line using CRISPR/Cas9-mediated precise gene editing method, resulting in significant decrease of SLC37A4 gene expression. In this model system we used RT-qPCR analysis to investigate the expression of molecular markers of the UPR response (ATF4, DDIT3, HSPA5, and XBP1s) and apoptosis (BCL2, BAX). We demonstrated that under chronic metabolic stress conditions caused by SLC37A4 deficiency, the ER stress-induced UPR was triggered, resulting in suppression of the UPR molecular markers and cell survival promotion (decreased expression levels of ATF4, DDIT3, HSPA5, with the exception of XBP1s). However, persistent metabolic stress overrides an adaptation and induces apoptosis through increased expression of pro-apoptotic markers (decreased ratio of BCL2/BAX genes). We established a cellular model system characterized by a deficiency of SLC37A4, which presents pathological manifestations of GSD Ib in the kidney. Expression analysis in a novel model system supports the hypothesis that renal dysfunction in the GSD Ib is partly due to the ER stress and increased apoptosis.

A Third Case of Glycogen Storage Disease IB and Giant Cell Tumour of the Mandible: A Disease Association or Iatrogenic Complication of Therapy.

We report the third case of Glycogen Storage Disease type 1b (GSD 1b) with Giant Cell Tumour (GCT) of the mandible, associated with Granulocyte Colony Stimulating Factor (G-CSF) use. G-CSF in GSD 1b is indicated for persistent neutropaenia, sepsis, inflammatory bowel disease and severe diarrhoea. Our patient was 12 years old at GCT diagnosis and had been treated with G-CSF from 5 years of age. He underwent therapy with interferon followed by local resection which was successful in initial control of the disease. Histology demonstrated spindle shaped stromal cells together with numerous interspersed multinuclear osteoclastic giant cells. G-CSF has been hypothesized to induce osteoclastic differentiation and thus may be involved in the pathogenesis of GCT formation. At age 19 years he required a repeat operation for local recurrence. He currently continues on G-CSF and was commenced on denosumab for control of the GCT with no recurrence to date. A cause and effect relationship between G-CSF therapy and the development of GCT in GSD type 1b remains to be established.