Bickel Syndrome Research Articles

Understanding the Role of GLUT2 in Dysglycemia Associated with Fanconi-Bickel Syndrome.

Fanconi–Bickel Syndrome (FBS) is a rare disorder of carbohydrate metabolism that is characterized by the accumulation of glycogen mainly in the liver. It is inherited in an autosomal recessive manner due to mutations in the SLC2A2 gene. SLC2A2 encodes for the glucose transporter GLUT2 and is expressed in tissues that are involved in glucose homeostasis. The molecular mechanisms of dysglycemia in FBS are still not clearly understood. In this study, we report two cases of FBS with classical phenotypes of FBS associated with dysglycemia. Genomic DNA was extracted and analyzed by whole-genome and Sanger sequencing, and patient PBMCs were used for molecular analysis. One patient had an exonic SLC2A2 mutation (c.1093C>T in exon 9, R365X), while the other patient had a novel intronic SLC2A2 mutation (c.613-7T>G). Surprisingly, the exonic mutation resulted in the overexpression of dysfunctional GLUT2, resulting in the dysregulated expression of other glucose transporters. The intronic mutation did not affect the coding sequence of GLUT2, its expression, or glucose transport activity. However, it was associated with the expression of miRNAs correlated with type 1 diabetes mellitus, with a particular significant overexpression of hsa-miR-29a-3p implicated in insulin production and secretion. Our findings suggest that SLC2A2 mutations cause dysglycemia in FBS either by a direct effect on GLUT2 expression and/or activity or, indirectly, by the dysregulated expression of miRNAs implicated in glucose homeostasis.

Understanding the Mechanism of Dysglycemia in a Fanconi-Bickel Syndrome Patient.

Fanconi–Bickel Syndrome (FBS) is a rare disorder of carbohydrate metabolism that is characterized mainly by the accumulation of glycogen in the liver and kidney. It is inherited as an autosomal recessive disorder caused by mutations in the SLC2A2 gene, which encodes for GLUT2. Patients with FBS have dysglycemia but the molecular mechanisms of dysglycemia are still not clearly understood. Therefore, we aimed to understand the underlying molecular mechanisms of dysglycemia in a patient with FBS. Genomic DNA was isolated from a peripheral blood sample and analyzed by whole genome and Sanger sequencing. CRISPR-Cas9 was used to introduce a mutation that mimics the patient’s mutation in a human kidney cell line expressing GLUT2 (HEK293T). Mutant cells were used for molecular analysis to investigate the effects of the mutation on the expression and function of GLUT2, as well as the expression of other genes implicated in dysglycemia. The patient was found to have a homozygous nonsense mutation (c.901C>T, R301X) in the SLC2A2 gene. CRISPR-Cas9 successfully mimicked the patient’s mutation in HEK293T cells. The mutant cells showed overexpression of a dysfunctional GLUT2 protein, resulting in reduced glucose release activity and enhanced intracellular glucose accumulation. In addition, other glucose transporters (SGLT1 and SGLT2 in the kidney) were found to be induced in the mutant cells. These findings suggest the last loops (loops 9-12) of GLUT2 are essential for glucose transport activity and indicate that GLUT2 dysfunction is associated with dysglycemia in FBS.

Pediatric metanephric adenoma with Fanconi-Bickel syndrome: a case report and review of literature.

BackgroundMetanephric adenoma (MA) is a rare benign renal tumor that resembles renal cell carcinoma and Wilms’ tumor in radiological as well as pathological appearance. It can present at any age or gender, and it is extremely rare in the pediatric age group with less than 50 reported cases. Fanconi–Bickel syndrome (FBS) is a rare autosomal recessive disorder of carbohydrate metabolism. Herein, we report a rare incidence of MA in a boy with a genetically confirmed FBS who underwent a nephron-sparing surgery.Case presentationA 21-month-old boy was referred to the pediatric urology clinic for further evaluation of an incidentally discovered left renal mass. His laboratory investigations showed normal renal function, hypophosphatemia, high blood glucose level, markedly elevated serum alkaline phosphatase, and low serum vitamin D. Blood picture showed signs of polycythemia and urinalysis showed glucosuria and aminoaciduria. Genetic testing was positive for Fanconi–Bickel syndrome. Radiological investigations were carried out with abdominal ultrasound and computerized tomography (CT) with intravenous contrast documented a sharply marginated peripheral hypoechoic hypovascular homogeneously enhancing mass at the upper pole of the left kidney measuring 2.0 × 1.8 × 2.0 cm. The child was admitted and started on supportive treatment until his medical condition was stabilized, then underwent elective open left partial nephrectomy via a left upper transverse abdominal transperitoneal incision. The excised renal mass was sent for histopathological assessment and was found to be a tumor composed of tightly packed tubules with no mitotic figures or necrosis and scanty cytoplasm consistent with MA. After good hydration and tumor resection, his polycythemia gradually improved. The patient was discharged home in a good condition with his proper replacement therapies. His follow-up abdominal ultrasound after 12 months showed no signs of recurrence.ConclusionsMetanephric adenoma is extremely rare in the pediatric age group, especially in those who have a FBS. The only way to diagnose and treat this tumor is by surgical resection as most patients are asymptomatic. A nephron-sparing surgery is better for this age group in which the future renal function is considered.

Potential Role of Glucose Transporters in Glucose Homeostasis: a Narrative Review

Background: The GLUT2 (glucose transporter 2) is a glucose sensitive receptor gene found in the liver, pancreas, and sometimes in the CNS. The experiments conducted on the genetically modified mice revealed their role in the different regulatory mechanisms.
 Objective: The current narrative review aims to elucidate the role of GLUT2 in glucose homeostasis.
 Methods: The recent related articles were reviewed with the help of different databases including PubMed, Google Scholar, Springer link, and Science direct. To ensure the credibility of data, articles published only in indexed journals were considered.
 Results: In the liver (hepatocytes), it’s reported that there is an unsuspected glucose pathway (output) that is dependent on the membrane mechanism is in progress. In humans, due to the mutation in the GLUT2 gene, there is a syndrome known as “Fanconi–Bickel syndrome” which dictates a glycogen storage disease type 11 disease characterized by kidney and liver disorders.
 Conclusion: It is concluded from the genome-wide association studies that the genetic mutations in GLUT2 result in an increased risk of high cholesterol, cardiovascular diseases (CVDs), and fasting hyperglycemia.

An induced pluripotent stem cell line derived from a patient with neonatal diabetes and Fanconi-Bickel syndrome caused by a homozygous mutation in the SLC2A2 gene

Recessive mutations in the glucose transporter gene SLC2A2 (GLUT2) lead to permanent neonatal diabetes (PNDM) and Fanconi Bickel Syndrome (FBS). Here, we generated an induced pluripotent stem cell (iPSC) line, QBRIi012-A, from a 24-month-old boy with FBS and PNDM due to homozygous nonsense mutation in the SLC2A2 gene (c.901C > T). The QBRIi012-A was fully characterized using different approaches. The cell line showed normal karyotype and was able to differentiate into the three germ layers in vitro. This iPSC line provides a novel human cell model to understand the pathophysiology of FBS and diabetes associated with SLC2A2 defects.

Next-generation sequencing in children of West India with suspected inherited tubulopathies

Background: The renal tubules maintain homeostasis through an array of proteins coded by multiple genes, which directly or indirectly transport water and solutes in the tubules. Malfunction of these transport proteins leads to inherited tubulopathies. Objective: The objective of the study was to analyze the clinical utility of next-generation sequencing (NGS) in the diagnosis and management of children with tubulopathies. Materials and Methods: This retrospective study was conducted in a tertiary care nephrology center in West India between September 2016 and September 2020. All children ?18 years with suspected inherited tubulopathy, where an NGS was sent, were included. Clinical exome sequencing (CES) covering 6670 genes was done in 14 children. CES included 73 tubulopathy genes. The test result was interpreted as per American College of Medical Genetics classification: No pathogenic variant, variant of unknown significance (VUS), and likely pathogenic and pathogenic variant. Results: The median age (IQR) of the cohort at the onset of disease was 18 months (4–65). History of consanguinity was present in 2 children (14.2%). Five children (35.7%) had Fanconi syndrome, two had distal renal tubular acidosis (d-RTA), two had Bartter/Gitelman syndrome, two had rickets, two had nephrocalcinosis, and one had low-molecular-weight proteinuria. Nine children (64%) had pathogenic variants detected in eight genes: ATP6V0A4, CTNS1, FAH1, PHEX, SLC12A1, SLC4A1, SLCA2, and CLDN 16. Five (35.7%) were novel variants. Two children had three VUS in FAT1, EYA1, and KCNJ1 gene. Three children (21.4%) had no genetic variant. Bartter syndrome type 1 and d-RTA were the most common genetic diagnoses with two patients each. Other diagnoses were tyrosinemia type 1, nephropathic cystinosis, Fanconi Bickel syndrome, X-linked hypophosphatemic rickets, and familial hypomagnesemia, hypercalciuria, and nephrocalcinosis in one each. Conclusion: The yield of NGS in children with tubulopathy was remarkably high. NGS was useful in the diagnosis and management in these children.

Fanconi Bickel syndrome: clinical phenotypes and genetics in a cohort of Sudanese children

BackgroundFanconi-Bickel syndrome (FBS) is a rare condition of carbohydrate metabolism, caused by a recessive defect in the facilitative glucose transporter GLUT2 encoded by the SLC2A2 gene and characterized by a wide spectrum of phenotypical features. There is a paucity of reported data on FBS from Sub-Saharan Africa. Here, we describe the clinical, biochemical and genetic characteristics of our patients with FBS from Sudan, a country with a high consanguinity rate.Patients & methodsEleven patients from ten unrelated Sudanese families were included. Clinical & biochemical data were documented and imaging studies done including bone survey and abdominal ultrasound. Liver biopsy was done to confirm the pathological diagnosis in 45% of cases and molecular genetics was performed through contribution with the Exeter genomics laboratory for ten patients.ResultsReported consanguinity was 70% among our patients. Growth was significantly impaired at presentation with mean weights of (-5.3 ± 1.8) SD and heights (-5.4 ± 2.5) SD. Severe chest deformity was present in (27%) and all patients showed features of rickets at presentation. Three patients had neonatal diabetes requiring insulin therapy of which one has been reported before. Six families lost undiagnosed siblings with similar clinical presentations. We identified a total of four homozygous pathogenic SLC2A2 variants in our patients, one of whom had a novel mutation.ConclusionsFBS is not uncommon in Sudan where there is a high rate of consanguinity. Many cases are likely missed because of variable presentation and lack of public and professionals’ awareness. This is the first series to describe this condition from Sub-Saharan Africa.

Ion Transporters, channelopathies, and glucose disorders

Ion channels and transporters play essential roles in excitable cells including cardiac, skeletal and smooth muscle cells, neurons, and endocrine cells. In pancreatic beta-cells, for example, potassium KATP channels link the metabolic signals generated inside the cell to changes in the beta-cell membrane potential, and ultimately regulate insulin secretion. Mutations in the genes encoding some ion transporter and channel proteins lead to disorders of glucose homeostasis (hyperinsulinaemic hypoglycaemia and different forms of diabetes mellitus). Pancreatic KATP, Non-KATP, and some calcium channelopathies and MCT1 transporter defects can lead to various forms of hyperinsulinaemic hypoglycaemia (HH). Mutations in the genes encoding the pancreatic KATP channels can also lead to different types of diabetes (including neonatal diabetes mellitus (NDM) and Maturity Onset Diabetes of the Young, MODY), and defects in the solute carrier family 2 member 2 (SLC2A2) leads to diabetes mellitus as part of the Fanconi–Bickel syndrome. Variants or polymorphisms in some ion channel genes and transporters have been reported in association with type 2 diabetes mellitus.

Fanconi-Bickel Syndrome: A Review of the Mechanisms That Lead to Dysglycaemia.

Accumulation of glycogen in the kidney and liver is the main feature of Fanconi–Bickel Syndrome (FBS), a rare disorder of carbohydrate metabolism inherited in an autosomal recessive manner due to SLC2A2 gene mutations. Missense, nonsense, frame-shift (fs), in-frame indels, splice site, and compound heterozygous variants have all been identified in SLC2A2 gene of FBS cases. Approximately 144 FBS cases with 70 different SLC2A2 gene variants have been reported so far. SLC2A2 encodes for glucose transporter 2 (GLUT2) a low affinity facilitative transporter of glucose mainly expressed in tissues playing important roles in glucose homeostasis, such as renal tubular cells, enterocytes, pancreatic β-cells, hepatocytes and discrete regions of the brain. Dysfunctional mutations and decreased GLUT2 expression leads to dysglycaemia (fasting hypoglycemia, postprandial hyperglycemia, glucose intolerance, and rarely diabetes mellitus), hepatomegaly, galactose intolerance, rickets, and poor growth. The molecular mechanisms of dysglycaemia in FBS are still not clearly understood. In this review, we discuss the physiological roles of GLUT2 and the pathophysiology of mutants, highlight all of the previously reported SLC2A2 mutations associated with dysglycaemia, and review the potential molecular mechanisms leading to dysglycaemia and diabetes mellitus in FBS patients.

Derivation of a human induced pluripotent stem cell line (QBRIi007-A) from a patient carrying a homozygous intronic mutation (c.613-7T>G) in the SLC2A2 gene.

Fanconi Bickel Syndrome (FBS) is an autosomal recessive disease resulting from mutations in the SLC2A2 gene, encoding the GLUT2. FBS patients develop diabetes mellitus. Using non-integrating Sendai virus, we generated an induced pluripotent stem cell (iPSC) line, QBRIi007-A, carrying the c.613-7 T>G homozygous mutation in intron 5 of the SLC2A2 gene from a 19-year-old female with FBS and diabetes. The iPSC line was characterized for pluripotency, differentiation potential, genomic integrity, and genetic identity. This iPSC line provides a useful cell model to understand the role of GLUT2 in the disease development and to discover new drug candidates.

A Novel Mutation in Fanconi Bickel Syndrome Diagnosed in the Neonatal Period

A Novel Mutation in Fanconi Bickel Syndrome Diagnosed in the Neonatal Period

Ion Transporters, Channelopathies, and Glucose Disorders.

Ion channels and transporters play essential roles in excitable cells including cardiac, skeletal and smooth muscle cells, neurons, and endocrine cells. In pancreatic beta-cells, for example, potassium KATP channels link the metabolic signals generated inside the cell to changes in the beta-cell membrane potential, and ultimately regulate insulin secretion. Mutations in the genes encoding some ion transporter and channel proteins lead to disorders of glucose homeostasis (hyperinsulinaemic hypoglycaemia and different forms of diabetes mellitus). Pancreatic KATP, Non-KATP, and some calcium channelopathies and MCT1 transporter defects can lead to various forms of hyperinsulinaemic hypoglycaemia (HH). Mutations in the genes encoding the pancreatic KATP channels can also lead to different types of diabetes (including neonatal diabetes mellitus (NDM) and Maturity Onset Diabetes of the Young, MODY), and defects in the solute carrier family 2 member 2 (SLC2A2) leads to diabetes mellitus as part of the Fanconi–Bickel syndrome. Variants or polymorphisms in some ion channel genes and transporters have been reported in association with type 2 diabetes mellitus.

Dental findings in Fanconi Bickel Syndrome: Case Report

Dental findings in Fanconi Bickel Syndrome: Case Report

Transient Neonatal Diabetes with Fanconi Bickel Syndrome

Fanconi- Bickel Syndrome (FBS) is a rare glycogen storage disease (GSD) . Transient diabetes is rarely reported with FBS. We describe a patient with FBS diagnosed by diabetes findings and identification of a mutation in the GLUT2. A male infant, from a consanguineous marriage, presented with hyperglycemia and urinary system infections at 59 days and was given insulin therapy. At age 3 months, insulin was discontinued. Neonatal diabetes may be a first presentation of infants with FBS.

Segregation of a novel homozygous 6 nucleotide deletion in GLUT2 gene in a Fanconi–Bickel syndrome family

Fanconi–Bickel syndrome (FBS) is a rare autosomal recessive disorder characterized by hepatorenal glycogen accumulation, proximal renal tubular dysfunction, impaired utilization of glucose and galactose, rickets, and severe short stature. It has been shown to be caused by mutations in GLUT2 gene, a member of the facilitative glucose transporter family. Here, we report an Iranian family with 2 affected siblings. The clinical findings in the patients include developmental delay, failure to thrive, hepatomegaly, enlarged kidneys and rickets. A novel 6 nucleotide deletion (c.1061_1066del6, p.V355_S356del2) is shown to be segregated with the disease in this family.

Orofacial and Skeletal Manifestations of Hypophosphatemic Rickets in Fanconi Bickel Syndrome

Wide array of systemic disorders have their manifestations in oral cavity. These disorders can be mainly syndromic, metabolic or congenital diseases. The dental features in these disorders can be expressed on a wider latitude from mild to extensive forms. Here is an incidence of a case of hypophosphatemic rickets in Fanconi Bickel syndrome with multiple oral and general phenotypic features.

Abordagem da glicosúria renal na criança: a propósito de um caso clínico

Introduction : The accidental finding of glycosuria should lead to the exclusion of diabetes mellitus. In the absence of hyperglycemia, glycosuria is probably of renal origin. It can be isolated, as in familiar renal glycosuria, or it can be part of a hereditary tubular disorder such as Fanconi -Bickel syndrome or associated with an acquired tubular dysfunction. The renal and tubular function should be investigated. Case report : The authors describe the case of a previously healthy five -year old child with persistent glycosuria of renal cause. The investigation showed the coexistence of elevated renal excretion of glycine. Discussion : Familiar renal glycosuria and hyperglycinuria are caused by genetic defects in different renal tubular membrane transporters. The rare association of glycosuria and glycinuria was only described in one family in the 1960’s.The authors discuss the possible pathophysiologic mechanisms of this association and the importance of studying other tubulopathies in a child with glycosuria as it has prognostic and clinical management implications.

A Novel Mutation in the GLUT2 Gene Case Report of Fanconi-Bickel Syndrome in a Female Indian Patient

A female infant born out of 3rd degree consanguineous parents presented at 1 year of age with polyuria, polydipsia and glycosuria for 6 months. History revealed motor developmental delay. Investigations showed fasting hypoglycemia, postprandial hyperglycemia, renal glycosuria, generalized aminoaciduria, and renal rickets. Genetic evaluation revealed a novel mutation in exon2 of SLC2A2 a T-to-G substitution (c56T>G) confirming the diagnosis of Fanconi Bickel syndrome (FBS).

An unusual cause of severe rickets: Answers

Given the history of failure to thrive and finding of severe rickets with normal anion gap metabolic acidosis with glucosuria, phosphaturia and aminoaciduria, the diagnosis of Fanconi syndrome was made. In the presence of hepatosplenomegaly and abnormal liver function test results, the differential diagnosis of tyrosinemia type 1, cystinosis, glycogen storage disease, Fanconi–Bickel syndrome was considered.

PS19 Treatment of femoral deformity of a patient with Fanconi–Bickel syndrome using a retrograde tibia intramedullary nail: a case report

closed fixation and early mobilisation of 3 scaphoid fractures that were displaced 2mm or less. Material and Methods: Percutaneous fixation is done for 3 male patients at mean 7 days (3–11) after initial trauma. Mean age was 23 and it was all dominant right hands. One fracture was at proximal pole, the two others were body fractures. MRI images were seen both pre and postoperatively for the pole fracture.WeusedAcutrak screws for 2 patients and Herbert for the other. We didnot use any bone grafts. We used only simple elastic bandage after surgery allowing instant range of motion exercises and delay athletic activities until after the union was achieved. We passed our guide wires from distal to proximal at neutral ulnar deviation used image intensification to make sure that the guide Kwire is at correct axis within the bone.We confirmed the reduction and screw positon by direct radiographies. Results:Mean operation timewas 15.6minutes (14–18) All fractures united without any complications. Return to work was achieved at 6 weeks mean (5–7) without any postoperative rehabilitation programme. Full range of motion were achieved at mean 4 weeks (3–5) and it was equal compared to other nonaffected wrists. Mean union time was 6 weeks (4–8). We didnot face avascular necrosis of the scaphoid after 1 year and we didnot remove any screws. Conclusion:Westrongly recommendpercutaneous closed fixation of scaphoid fractures to gain more rapid motion and early return back to work.