Fanconi-Bickel Syndrome: Two Pakistani Patients Presenting with Hypophosphatemic Rickets.
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ABSTRACT:
SUBMITTER: Afroze B
PROVIDER: S-EPMC4999332 | biostudies-literature | 2016 Sep
REPOSITORIES: biostudies-literature
Publications
Fanconi-Bickel Syndrome: Two Pakistani Patients Presenting with Hypophosphatemic Rickets.
Afroze Bushra B Chen Margaret M
Journal of pediatric genetics 20160603 3
Fanconi-Bickel syndrome is a rare inherited disorder characterized by hepatorenal glycogen accumulation, renal tubular dysfunction, growth failure, and impaired utilization of glucose and galactose. We report the first two children with Fanconi-Bickel syndrome from Pakistan who presented with classical features of Fanconi-Bickel Syndrome. Both patients were found to be homozygous for a single nucleotide deletion in the SLC2A2 gene defined as c.339delC. This mutation was previously described in a ...[more]
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Project description:Fanconi-Bickel Syndrome (FBS) is a rare variety of glycogen storage disease (GSD). Characterized by massive hepatomegaly due to glycogen accumulation, severe hypophosphatemic rickets, and marked growth retardation due to proximal renal tubular dysfunction. We report a young boy presented as hypophosphatemic rickets with hepatomegaly and subsequently diagnosed as FBS.
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Project description:OBJECTIVE:To describe the phenotypic features of an ethnically homogenous group of patients with Fanconi-Bickel syndrome harboring the p.R310X mutation. METHODS:The study group consisted of eight patients from a single Bedouin family with clinically and molecularly diagnosed Fanconi-Bickel syndrome who had been followed at the same tertiary medical center for 8 years or more. All were homozygous for the p.R310X mutation. The medical files were reviewed for presenting signs and symptoms, laboratory and imaging findings, treatment regimens, and disease severity over time. RESULTS:Seven patients were diagnosed at our center before age 1 year, and one transferred from another center at age 16 years. Most patients presented with failure to thrive and/or hepatomegaly. All had short stature and doll-like facies. Most had biochemical abnormalities. Evaluation of the long-term findings revealed a wide spectrum of disease severity according to the following parameters: growth patterns, maximal electrolyte replacement therapy, skeletal and renal complications, frequency of follow-up visits, and hospitalizations for disease exacerbations. There was no apparent association of the clinical picture at presentation and later disease severity. CONCLUSION:Fanconi-Bickel syndrome has a broad phenotypic variability in patients harboring the same homozygous p.R301X mutation. This finding might be explained by genetic elements such as modifier genes and epigenetic factors, as well as the effects of still-undetermined environmental and nutritional factors.
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Project description:BackgroundFanconi-Bickel syndrome (FBS, OMIM 227810) is a rare autosomal recessive disease caused by a deficiency of glucose transporter 2 (GLUT2), a member of the facilitative glucose transporter family (Santer et al. J Inherit Metab Dis 21:191-194, 1998). The typical clinical picture is characterized by hepatorenal glycogen accumulation resulting in hepato- and nephromegaly, impaired utilization of glucose and galactose, proximal renal tubular dysfunction, rickets and severe short stature.Case presentationWe report 2 Palestinian patients from 2 families who were homozygous for the mutation p.R301X (C>T) in exon 7of GLUT2 gene. Patient 1 showed clinical and laboratory improvement with age characterized by normal growth and resolution of rickets. Patient 2 had severe phenotype characterized by progressive weight loss, persistent metabolic acidosis, marked polyuria and clinical and laboratory findings of rickets progressing to death at age 10 months.ConclusionThis report further expands the clinical spectrum of FBS even with identical mutations. Other yet unknown genetic, environmental or stochastic factors may be responsible for phenotypic variability.
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Project description:Tight control of extracellular and intracellular inorganic phosphate (Pi) levels is critical to most biochemical and physiologic processes. Urinary Pi is freely filtered at the kidney glomerulus and is reabsorbed in the renal tubule by the action of the apical sodium-dependent phosphate transporters, NaPi-IIa/NaPi-IIc/Pit2. However, the molecular identity of the protein(s) participating in the basolateral Pi efflux remains unknown. Evidence has suggested that xenotropic and polytropic retroviral receptor 1 (XPR1) might be involved in this process. Here, we show that conditional inactivation of Xpr1 in the renal tubule in mice resulted in impaired renal Pi reabsorption. Analysis of Pi transport in primary cultures of proximal tubular cells or in freshly isolated renal tubules revealed that this Xpr1 deficiency significantly affected Pi efflux. Further, mice with conditional inactivation of Xpr1 in the renal tubule exhibited generalized proximal tubular dysfunction indicative of Fanconi syndrome, characterized by glycosuria, aminoaciduria, calciuria, and albuminuria. Dramatic alterations in the renal transcriptome, including a significant reduction in NaPi-IIa/NaPi-IIc expression, accompanied these functional changes. Additionally, Xpr1-deficient mice developed hypophosphatemic rickets secondary to renal dysfunction. These results identify XPR1 as a major regulator of Pi homeostasis and as a potential therapeutic target in bone and kidney disorders.
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Project description:Renal tubular acidosis (RTA) encompasses many renal tubular disorders characterized by hyperchloremic metabolic acidosis with a normal anion gap. Untreated patients usually complain of growth failure, osteoporosis, rickets, nephrolithiasis and eventually renal insufficiency. Fanconi-Bickel syndrome (FBS) is an example of proximal RTA due to a single gene disorder; it is caused by defects in the facilitative glucose transporter 2 gene that codes for the glucose transporter protein 2 expressed in hepatocytes, pancreatic β-cells, enterocytes and renal tubular cells. It is a rare inherited disorder of carbohydrate metabolism manifested by huge hepatomegaly [hence it is classified as glycogen storage disease (GSD) type XI; GSD XI], severe hypophosphatemic rickets and failure to thrive due to proximal renal tubular dysfunction leading to glucosuria, phosphaturia, generalized aminoaciduria, bicarbonate wasting and hypophosphatemia. The disorder has been reported from all parts of Europe, Turkey, Israel, Arabian countries, Japan and North America. Many mutant alleles have been described, its exact frequency is unknown and there is no single mutation found more frequently than the others. The presence of consanguinity in affected families suggests an autosomal recessive pattern of inheritance. New cases of FBS have been recently reported in the Middle and Far East in collaboration with specialized centers. Two novel mutations have been discovered in two unrelated Egyptian families. The first was two bases deletion, guanine and adenine, (c.253_254delGA) causing a frameshift mutation (p. Glu85fs) and the second is mutation in exon6 in splicing acceptor site with intron5 (c.776-1G>C or IVS5-1G>A). Moreover, a new different mutation was described in a 3 year old Indian boy.
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Project description: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.
| S-EPMC9159359 | biostudies-literature
Project description:BackgroundFanconi-Bickel syndrome (FBS) is a rare autosomal recessive disorder characterized by impaired glucose and galactose utilization as well as proximal renal tubular dysfunction.MethodsClinical, biochemical, genetic, treatment, and follow-up data for 11 pediatric patients with FBS were retrospectively analysed.ResultsHepatomegaly (10/11), short stature (10/11) and hypophosphataemic rickets (7/11) were the most common initial symptoms. At diagnosis, all patients had decreased fasting blood glucose (FBG), plasma bicarbonate (HCO3-) and serum phosphorus, as well as elevated liver transaminases, alkaline phosphatase (AKP) and proximal renal tubular dysfunction. Two infant patients were misdiagnosed with transient neonatal diabetes mellitus. After therapy with uncooked cornstarch and conventional rickets treatment, remission of hepatomegaly was observed in all patients, with significant improvements in pre-prandial blood glucose, liver transaminases, triglyceride, plasma HCO3- and AKP (p < 0.05). At the last follow-up, 5/7 patients with elevated AKP had nephrocalcinosis. The mean height standard deviation score (Ht SDS) of eight patients with regular treatment increased from - 4.1 to -3.5 (p = 0.02). Recombinant human growth hormone (rhGH) was administered to 4/9 patients, but their Ht SDS did not improve significantly (p = 0.13). Fourteen variants of the SLC2A2 gene were identified, with six being novel, among which one was recurrent: c.1217T > G (p.L406R) (allele frequency: 4/22, 18%). Patients with biallelic missense variants showed milder metabolic acidosis than those with null variants. Two of five patients from nonconsanguineous families with rare homozygous variations showed 5.3 Mb and 36.6 Mb of homozygosity surrounding the variants, respectively; a region of homozygosity (ROH) involving the entire chromosome 3 covering the SLC2A2 gene, suggesting uniparental disomy 3, was detected in one patient.ConclusionsEarly diagnosis of FBS is difficult due to the heterogeneity of initial symptoms. Although short stature is a major issue of treatment for FBS, rhGH is not recommended in FBS patients who have normal GH stimulation tests. Patients with biallelic null variants may require alkali supplementation since urine bicarbonate loss is genetically related. ROH is a mechanism for rare homozygous variants of FBS in nonconsanguineous families.
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Project description: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 ?-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.
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Project description: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.
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Project description:ObjectiveX-linked dominant hypophosphatemia (XLH) is the most prevalent form of inherited rickets/osteomalacia in humans. The aim of this study was to identify PHEX gene mutations and describe the clinical features observed in 6 unrelated Chinese families and 3 sporadic patients with hypophosphatemic rickets/osteomalacia.MethodsFor this study, 45 individuals from 9 unrelated families of Chinese Han ethnicity (including 16 patients and 29 normal phenotype subjects), and 250 healthy donors were recruited. All 22 exons and exon-intron boundaries of the PHEX gene were amplified by polymerase chain reaction (PCR) and directly sequenced.ResultsThe PHEX mutations were detected in 6 familial and 3 sporadic hypophosphatemic rickets/osteomalacia. Altogether, 2 novel mutations were detected: 1 missense mutation c.1183G>C in exon 11, resulting in p.Gly395Arg and 1 missense mutation c.1751A>C in exon 17, resulting in p.His584Pro. No mutations were found in the 250 healthy controls.ConclusionsOur study increases knowledge of the PHEX gene mutation types and clinical phenotypes found in Chinese patients with XLH, which is important for understanding the genetic basis of XLH. The molecular diagnosis of a PHEX genetic mutation is of great importance for confirming the clinical diagnosis of XLH, conducting genetic counseling, and facilitating prenatal intervention, especially in the case of sporadic patients.
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