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GATM-related Fanconi renotubular syndrome 1 (FRTS1) is a form of renal Fanconi syndrome (RFS), which is a disorder of solute and water reabsorption caused by defects in the function of the entire proximal tubule. Recent findings reveal the molecular basis of FRTS1: Intramitochondrial fiber aggregation triggered by mutant GATM provides a starting point for proximal tubule damage and drives disease progression. As a rare and newly recognized inherited kidney disease, the complex manifestations of FRTS1 are easily underdiagnosed or misdiagnosed. We discuss the complex phenotype of a 26-year-old woman with onset in infancy and a long history of hypophosphatemic rickets. We also identified a novel heterozygous missense variant in the GATM gene in this patient. The novel variant and phenotype we report expand the disease spectrum of FRTS1. We recommend screening for GATM in children with RFS, especially in patients with resistant rickets who have previously had negative genetic testing. In addition, we found pathological deposition of mutant GATM proteins within mitochondria in the patient's urinary sediment cells by a combination of electron microscopy and immunofluorescence. This unique urine cytology experiment has the potential to be a valuable tool for identifying patients with RRTS1., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Fanconi's syndrome (FS) is characterized by type-2 renal tubular acidosis, short stature, and renal rickets, along with glycosuria, aminoaciduria, hypophosphaturia, and urinary bicarbonate wasting. The genetic form of FS has been linked to HNF4A variants. Although additional clinical features such as hearing impairment have recently been associated with HNF4A-linked FS, its ocular manifestation has not been described., Material and Methods: Presenting a case of a 5-year-old male child with bilateral progressive corneal opacification and the presence of bilateral greyish-white deposits in the interpalpebral region since infancy. A next-generation sequencing (NGS)-based genetic testing was performed for the child followed by parental genetic testing for the identified variant. Furthermore, relevant works of literature were reviewed related to this condition., Results: Detailed corneal findings showed a bilateral band-shaped keratopathy (BSK) in the patient. Physical and systemic findings showed signs consistent with FS. Sequencing analysis revealed a novel heterozygous c.635C>T, (p.Pro212Leu) variant in the HNF4A gene in the proband and mother, while the father had a normal genotype., Conclusions: Our case highlights the occurrence of BSK in an exceptionally rare manifestation of hereditary FS linked to HNF4A gene variant. The variant exists both in proband and asymptomatic mother. Therefore, the variable penetrance which is known to exist in HNF4A is acknowledged in this context. This report suggests the first documented instance establishing a plausible connection between BSK and HNF4A-associated FS, characterized by the variable penetrance attributed to the HNF4A gene.

Background: Fanconi-Bickel syndrome is characterized by hepatorenal disease caused by anomalous glycogen storage. It occurs due to variants in the SLC2A2 gene. We present a male patient of 2 years 7 months old, with failure to thrive, hepatomegaly, metabolic acidosis, hypophosphatemia, hypokalemia, hyperlactatemia., Results: Exome sequencing identified the homozygous pathogenic variant NM_000340.2(SLC2A2):c.1093 C > T (p.Arg365Ter), related with Fanconi-Bickel syndrome. He received treatment with bicarbonate, amlodipine, sodium citrate and citric acid solution, enalapril, alendronate and zolendronate, and nutritional management with uncooked cornstarch, resulting in an improvement of one standard deviation in weight and height., Conclusions: The importance of knowing the etiology in rare genetic disease is essential, not only to determine individual and familial recurrence risk, but also to establish the treatment and prognosis; in this sense, access to a new genomic technology in low- and middle-income countries is essential to shorten the diagnostic odyssey., (© 2024. The Author(s).)

Introduction: Fanconi renotubular syndromes (FRTS) are a rare group of inherited phosphaturic disorders with limited Indian as well as global data on this condition. Here, we describe the experience of a single Endocrinology center from Western India on FRTS., Materials and Methods: Comprehensive clinical, biochemical, radiological, management, and genetic details of FRTS patients managed between 2010 and 2023 were collected and analyzed., Results: FRTS probands had mutations (eight novel) in six genes [CLCN5 (n = 4), SLC2A2 (n = 2), GATM, EHHADH, HNF4A, and OCRL (1 each)]. Among 15 FRTS patients (11 families), rickets/osteomalacia was the most common (n = 14) presentation with wide inter- and intra-familial phenotypic variability. Delayed diagnosis (median: 8.8 years), initial misdiagnosis (8/11 probands), and syndrome-specific discriminatory features (8/11 probands) were commonly seen. Hypophosphatemia, elevated alkaline phosphatase, normal parathyroid hormone (median: 36 pg/ml), high-normal/elevated 1,25(OH) 2 D (median: 152 pg/ml), hypercalciuria (median spot urinary calcium to creatinine ratio: 0.32), and variable proximal tubular dysfunction(s) were observed. Elevated C-terminal fibroblast growth factor 23 in two probands was misleading, till the genetic diagnosis was reached. Novel observations in our FRTS cohort were preserved renal function (till sixth decade) and enthesopathy in FRTS1 and FRTS3 families, respectively., Conclusion: Our findings underscore frequent under- and misdiagnosis of FRTS; hence, a high index of suspicion for FRTS in phosphopenic rickets/osteomalacia, with early consideration of genetic testing is essential to ensure timely diagnosis of FRTS. The novel variants and phenotypic manifestations described here expand the disease spectrum of FRTS., (© 2024. The Japanese Society Bone and Mineral Research.)

Background: Fanconi-Bickel syndrome (FBS) is a rare autosomal recessive disorder characterized by impaired glucose and galactose utilization as well as proximal renal tubular dysfunction., Methods: Clinical, biochemical, genetic, treatment, and follow-up data for 11 pediatric patients with FBS were retrospectively analysed., Results: Hepatomegaly (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 (HCO 3 - ) 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 HCO 3 - 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., Conclusions: Early 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., (© 2024. The Author(s).)

Glycogen storage disease XI, also known as Fanconi-Bickel syndrome (FBS), is a rare autosomal recessive disorder caused by mutations in the SLC2A2 gene that encodes the glucose-facilitated transporter type 2 (GLUT2). Patients develop a life-threatening renal proximal tubule dysfunction for which no treatment is available apart from electrolyte replacement. To investigate the renal pathogenesis of FBS, SLC2A2 expression was ablated in mouse kidney and HK-2 proximal tubule cells. GLUT2 Pax8Cre+ mice developed time-dependent glycogen accumulation in proximal tubule cells and recapitulated the renal Fanconi phenotype seen in patients. In vitro suppression of GLUT2 impaired lysosomal autophagy as shown by transcriptomic and biochemical analysis. However, this effect was reversed by exposure to a low glucose concentration, suggesting that GLUT2 facilitates the homeostasis of key cellular pathways in proximal tubule cells by preventing glucose toxicity. To investigate whether targeting proximal tubule glucose influx can limit glycogen accumulation and correct symptoms in vivo, we treated mice with the selective SGLT2 inhibitor dapagliflozin. Dapagliflozin reduced glycogen accumulation and improved metabolic acidosis and phosphaturia in the animals by normalizing the expression of Napi2a and NHE3 transporters. In addition, in a patient with FBS, dapagliflozin was safe, improved serum potassium and phosphate concentrations, and reduced glycogen content in urinary shed cells. Overall, this study provides proof of concept for dapagliflozin as a potentially suitable therapy for FBS.

Fanconi syndrome is a disorder of the proximal renal tubule. Recently, advanced genetic analysis technology has revealed that several genes cause familial Fanconi syndrome. We identified a family with autosomal dominant Fanconi syndrome and chronic kidney disease with a novel glycine amidinotransferase (GATM) variant. Case 1 was a 57-year-old Japanese woman. Her father and two siblings had Fanconi syndrome or chronic kidney disease. She presented to our hospital at the age of 34 years with recurrent glucosuria. Her height and weight were 151 cm and 46.6 kg, respectively. Laboratory tests showed glucosuria, hypophosphatemia, hypouricemia, and normal renal function. Her serum creatinine level gradually increased over the following next two decades, and she developed end-stage renal disease. Case 2, the daughter of Case 1, was a 26-year-old woman. Her height and weight were 151 cm and 37.5 kg, respectively. Glucosuria was detected at the age of 13 years, which led to a referral to our hospital. Urinalysis showed low-molecular-weight proteinuria. She was diagnosed with Fanconi syndrome. At the age of 26 years, she had glucosuria, low-molecular-weight proteinuria, hypouricemia, and normal renal function. Genetic testing of both cases revealed a novel missense variant in GATM. The heterozygous missense variants in GATM have been reported to cause familial Fanconi syndrome, which manifests early in life and progresses to renal glomerular failure by mid-adulthood. The novel GATM variant detected in our cases was suspected to be associated with the development of Fanconi syndrome. GATM variants should be tested in patients with idiopathic Fanconi syndrome.

Background: Fanconi-Debré-de Toni syndrome (also known as Fanconi renotubular syndrome, or FRST) profoundly increased the understanding of the functions of the proximal convoluted tubule (PCT) and provided important insights into the pathophysiology of several kidney diseases and drug toxicities., Data Sources: We searched Pubmed and Scopus databases to find relevant articles about FRST. This review article focuses on the physiology of the PCT, as well as on the physiopathology of FRST in children, its diagnosis, and treatment., Results: FRST encompasses a wide variety of inherited and acquired PCT alterations that lead to impairment of PCT reabsorption. In children, FRST often presents as a secondary feature of systemic disorders that impair energy supply, such as Lowe's syndrome, Dent's disease, cystinosis, hereditary fructose intolerance, galactosemia, tyrosinemia, Alport syndrome, and Wilson's disease. Although rare, congenital causes of FRST greatly impact the morbidity and mortality of patients and impose diagnostic challenges. Furthermore, its treatment is diverse and considers the ability of the clinician to identify the correct etiology of the disease., Conclusion: The early diagnosis and treatment of pediatric patients with FRST improve the prognosis and the quality of life., (© 2023. Children's Hospital, Zhejiang University School of Medicine.)

Alport syndrome (AS) is a progressive renal disease characterized by hematuria and progressive renal failure. X-linked dominant (XLAS) is the major inheritance form, accounting for almost 80% of the cases, caused by mutations in COL4A5 genes. Klinefelter syndrome (KS) is the most common genetic cause of human male gonadal dysgenesis. AS and KS are both rare disease, there are only three cases of combined AS and KS in the literatures. Fanconi syndrome (FS) caused by AS is also very rare. We report here the first case combined AS, KS and FS in a Chinese boy. We suggest that the severe renal phenotype and FS might be due to the two homozygous COL4A5 variants in our boy, and cases of AS combined KS will be good research objects for X chromosome inactivation., (© 2023 Asian Pacific Society of Nephrology.)

Renal Fanconi syndrome (RFS) is a generalised disorder of the proximal convoluted tubule. Many genes have been associated with RFS including those that cause systemic disorders such as cystinosis, as well as isolated RFS. We discuss the case of a 10-year-old female who presented with leg pain and raised creatinine on a screening blood test. Her mother has RFS and required a kidney transplant in her thirties. Further investigations confirmed RFS in the daughter. Exome sequencing was performed on the affected mother, child, and unaffected father. We identified a novel variant in GATM; c.965G>C p.(Arg322Pro) segregating dominantly in the mother and daughter. We validated our finding with molecular dynamics simulations and demonstrated a dynamic signature that differentiates our variant and two previously identified pathogenic variants in GATM from wildtype. Genetic testing has uncovered a novel pathogenic variant that predicts progression to end stage kidney failure and has important implications for family planning and cascade testing. We recommend that GATM is screened for in children presenting with RFS, in addition to adults, particularly with kidney failure, who may have had previous negative gene testing., (© 2022 The Authors. Clinical Genetics published by John Wiley & Sons Ltd.)

The present paper reports 10 patients (9 families) with Fanconi-Bickel syndrome managed during 2010-2021. Patients presented with polyuria, polydipsia, hepatomegaly, rickets, and stunting at a median of 5 (3, 7.3) mo; one had transient neonatal diabetes. Glucosuria, generalized aminoaciduria, β 2 -microglobinuria, urinary phosphate wasting, and hypercalciuria were present in all patients; 3 patients had nephrocalcinosis. Other metabolic abnormalities included hypertriglyceridemia (n = 5/6), fasting hypoglycemia (n = 5/8), and postprandial hyperglycemia (n = 3/6). Genetic analysis showed 7 homozygous or compound heterozygous variants in SLC2A2. A pathogenic variant c.952G>A, common to 4 patients (3 families), might be a potential hotspot. At a median follow-up of 43 mo, 4 patients died at a median of 25 mo; short stature persisted in all except one patient who showed catch-up growth with uncooked corn-starch diet. The present findings suggest that the Fanconi-Bickel syndrome has a severe phenotype with an unsatisfactory outcome. A high index of suspicion for diagnosis and efforts for facilitation of dietary therapy are necessary., (© 2022. The Author(s), under exclusive licence to Dr. K C Chaudhuri Foundation.)

Background: Nephropathic cystinosis is an autosomal recessive disease caused by a mutation in the CTNS gene which encodes cystinosin, a lysosomal cystine transporter. The spectrum of mutations in the CTNS gene is not well defined in the North African population. Here, we investigated twelve patients with nephropathic cystinosis belonging to eight Tunisian families in order to analyze the clinical and genetic characteristics of Tunisian children with infantile nephropathic cystinosis., Methods: Clinical data were collected retrospectively. Molecular analysis of the CTNS gene was performed by Sanger sequencing., Results: We describe a new splicing mutation c.971-1G > C in the homozygous state in 6/12 patients which seems to be a founder mutation. The reported deletion of 23nt c.771&#95;793 Del (p.Gly258Serfs*30) was detected in a homozygous state in one patient and in a heterozygous compound state with the c.971-1G > C mutation in 3/12 patients. Two of 12 patients have a deletion of exons 4 and 5 of the CTNS gene. None of our patients had the most common 57-kb deletion., Conclusions: The mutational spectrum in the Tunisian population is different from previously described populations. Thus, a molecular diagnostic strategy must be implemented in Tunisia, by targeting as a priority the common mutations described in this country. Such a strategy will allow a cost-effective diagnosis confirmation as well as early administration of treatment with oral cysteamine. A higher resolution version of the Graphical abstract is available as Supplementary information., (© 2022. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Infantile nephropathic cystinosis (INC) is an inheritable lysosomal storage disorder characterized by lysosomal cystine accumulation, progressive kidney disease, and multiple extrarenal complications (ERCs). Cysteamine postpones the onset of end-stage kidney disease (ESKD) and reduces the incidence of ERCs; however, cysteamine is generally initiated upon establishment of the renal Fanconi syndrome (FS) and partial loss of kidney function, whereas data on long-term effects of cysteamine administered from neonatal age are lacking. An international multicenter retrospective cohort study of siblings with INC was set up to investigate the outcome in relation to age at initiation of cysteamine versus CTNS genotype, with attention to patients treated with cysteamine from neonatal age. None of the siblings treated from neonatal age (n = 9; age 10 ± 6 years) had reached ESKD, while 22% of their index counterparts (n = 9; age 14 ± 5 years) had commenced renal replacement therapy. Siblings treated with cysteamine from the onset of symptoms at a younger age compared with their index counterparts, reached ESKD at a significant older age (13 ± 3 vs. 10 ± 3 years, p = 0.002). In contrast, no significant difference in ERCs was observed between sibling and index patients, independently from the age at initiation of cysteamine. The CTNS genotype had no impact on the overall outcome in this cohort. In INC, presymptomatic treatment with cysteamine results in a better renal outcome in comparison to treatment initiated from the onset of symptoms. This justifies including cystinosis into newborn screening programs. SYNOPSIS: In infantile nephropathic cystinosis, presymptomatic treatment with cysteamine improves the renal outcome which justifies the inclusion of cystinosis into newborn screening programs., (© 2022 SSIEM.)

Background: Hereditary renal tubular disorders (HRTD) represent a group of genetic diseases characterized by disturbances in fluid, electrolyte, and acid-base homeostasis. There is a paucity of studies on pediatric HRTD in Egypt. In this study, we aimed to study the pattern, characteristics, and growth outcome of HRTD at an Egyptian medical center., Methods: This study included children from one month to < 18-years of age with HRTD who were diagnosed and followed up at the Pediatric Nephrology Unit of Sohag University Hospital from January 2015 to December 2021. Data on patients` demographics, clinical features, growth profiles, and laboratory characteristics were collected., Results: Fifty-eight children (57% males; 72% parental consanguinity; 60% positive family history) were diagnosed with seven HRTD types. The most commonly encountered disorders were distal renal tubular acidosis (distal renal tubular acidosis [RTA] 27 cases, 46.6%) and Bartter syndrome (16 cases 27.6%). Other identified disorders were Fanconi syndrome (6 cases with cystinosis), isolated proximal RTA (4 cases), nephrogenic diabetes insipidus (3 cases), and one case for each RTA type IV and Gitelman syndrome. The median age at diagnosis was 17 months with a variable diagnostic delay. The most common presenting features were failure to thrive (91.4%), developmental delay (79.3%), and dehydration episodes (72.4%). Most children showed marked improvement in growth parameters in response to appropriate management, except for cases with Fanconi syndrome. Last, only one case (with cystinosis) developed end-stage kidney disease., Conclusions: HRTD (most commonly distal RTA and Bartter syndrome) could be relatively common among Egyptian children, and the diagnosis seems challenging and often delayed.

Introduction: Nephropathic cystinosis (NC) is a rare, autosomal recessive disorder leading to lysosomal accumulation of cystine. It is caused by mutations in the CTNS gene encoding a cystine cotransporter cystinosin. The infantile (INC) and juvenile (JNC) forms are distinguished. The former, responsible for 95% of cases, is characterized by development of renal Fanconi syndrome, end-stage kidney disease (ESKD), and extrarenal complications. A therapy with cysteamine significantly improves outcomes. There are limited data on NC in the Central Eastern European countries., Objectives: We aimed to evaluate the prevalence, genetic background, and clinical course of NC in the Polish population., Patients and Methods: We performed a retrospective analysis of data of all identified NC patients in Poland., Results: Between 1982 and 2017, 15 patients with NC (13 ICN, 2 JCN) were identified. The most common mutations of the CTNS gene were c.18&#95;c.21delGACT and c.681+1G>A, whereas only 2 patients carried the 57 kb deletion. The majority (11/13) of INC patients with limited access to the cysteamine therapy developed ESKD at a median age of 11 years and 9 of them received kidney transplants. Three INC patients died at a median age of 24 years. In contrast, 2 INC patients treated adequately present normal kidney function and growth at the age of 13 and 11 years. Two JNC patients presented a milder course., Conclusions: The prevalence of NC in Poland is much lower than in the Western countries and its molecular background appears to be different. The unfavorable course in the majority of INC patients was caused by a limited access to the cysteamine treatment.

The lysosomal storage disease cystinosis is caused by mutations in CTNS , encoding the cystine transporter cystinosin, and in its severest form leads to proximal tubule dysfunction followed by kidney failure. Patients receive the drug-based therapy cysteamine from diagnosis. However, despite long-term treatment, cysteamine only slows the progression of end-stage renal disease. Preclinical testing in cystinotic rodents is required to evaluate new therapies; however, the current models are suboptimal. To solve this problem, we generated a new cystinotic rat model using CRISPR/Cas9-mediated gene editing to disrupt exon 3 of Ctns and measured various parameters over a 12-mo time course. Ctns -/- rats display hallmarks of cystinosis by 3-6 mo of age, as demonstrated by a failure to thrive, excessive thirst and urination, cystine accumulation in tissues, corneal cystine crystals, loss of LDL receptor-related protein 2 in proximal tubules, and immune cell infiltration. High levels of glucose, calcium, albumin, and protein were excreted at 6 mo of age, consistent with the onset of Fanconi syndrome, with a progressive diminution of urine urea and creatinine from 9 mo of age, indicative of chronic kidney disease. Kidney histology and immunohistochemistry showed proximal tubule atrophy and glomerular damage as well as classic "swan neck" lesions. Overall, Ctns -/- rats show a disease progression that more faithfully recapitulates nephropathic cystinosis than existing rodent models. The Ctns -/- rat provides an excellent new rodent model of nephropathic cystinosis that is ideally suited for conducting preclinical drug testing and is a powerful tool to advance cystinosis research. NEW & NOTEWORTHY Animal models of disease are essential to perform preclinical testing of new therapies before they can progress to clinical trials. The cystinosis field has been hampered by a lack of suitable animal models that fully recapitulate the disease. Here, we generated a rat model of cystinosis that closely models the human condition in a timeframe that makes them an excellent model for preclinical drug testing as well as being a powerful tool to advance research.

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Sharari, Aouida, Mohammed, Haris, Bhat, Hawari, Nisar, Pavlovski, Biswas, Syed, Maacha, Grivel, Saifaldeen, Ericsson and Hussain.)

Background: Cystinosis is a lysosomal storage disease that affects many tissues. Its prognosis depends predominantly on kidney involvement. Cystinosis has three clinical forms: nephropathic infantile, nephropathic juvenile and non-nephropathic adult. Proximal tubular dysfunction is prominent in the infantile form, whereas a combination of glomerular and tubular alterations are observed in the juvenile form., Methods: Thirty-six children with nephropathic cystinosis were included in the study. Clinical features, molecular genetic diagnoses, and kidney outcomes of the patients were evaluated., Results: Twenty-one children (58.3%) were male. The median age at diagnosis was 18.5 months. Twenty-eight patients (77.8%) had infantile nephropathic cystinosis, while eight (22.2%) had juvenile nephropathic cystinosis. An acute rapid deterioration of the kidney function with proteinuria, hypoalbuminemia, and nephrotic syndrome, was observed in 37.5% of patients with the juvenile form. The mean estimated glomerular filtration rate (eGFR) was 82.31 ± 37.45 ml/min/1.73m 2 at diagnosis and 63.10 ± 54.60 ml/min/1.73m 2 at the last visit (p = 0.01). Six patients (16.6%) had kidney replacement therapy (KRT) at the last visit. The median age of patients with kidney failure was 122 months. Patients with a spot urine protein/creatinine ratio < 6 mg/mg at the time of diagnosis had better kidney outcomes (p = 0.01). The most common allele was c.451A>G (32.6%). The patients with the most common mutation tended to have higher mean eGFR and lower leukocyte cystine levels than patients with other mutations., Conclusion: Glomerulonephritis may be a frequent finding in addition to the well-known tubular dysfunction in patients with cystinosis. Furthermore, our results highlight that the presence of severe proteinuria at the time of diagnosis is a relevant prognostic factor for kidney survival., (© 2021. Italian Society of Nephrology.)

Fanconi syndrome is a functional disorder of the proximal tubule, characterized by pan-aminoaciduria, glucosuria, hypophosphatemia, and metabolic acidosis. With the advancements in gene analysis technologies, several causative genes are identified for Fanconi syndrome. Several mitochondrial diseases cause Fanconi syndrome and various systemic symptoms; however, it is rare that the main clinical symptoms in such disorders are Fanconi syndrome without systematic active diseases like encephalomyopathy or cardiomyopathy. In this study, we analyzed two families exhibiting Fanconi syndrome, developmental disability and mildly elevated liver enzyme levels. Whole-exome sequencing (WES) detected compound heterozygous known and novel BCS1L mutations, which affect the assembly of mitochondrial respiratory chain complex III, in both cases. The pathogenicity of these mutations has been established in several mitochondria-related functional analyses in this study. Mitochondrial diseases with isolated renal symptoms are uncommon; however, this study indicates that mitochondrial respiratory chain complex III deficiency due to BCS1L mutations cause Fanconi syndrome with developmental disability as the primary indications., (© 2021. The Author(s), under exclusive licence to The Japan Society of Human Genetics.)

Objective: The phenotype mediated by HNF4A/HNF1A mutations is variable and includes diazoxide-responsive hyperinsulinaemic hypoglycaemia (HH) and maturity-onset diabetes of the young (MODY)., Design: We characterised an international multicentre paediatric cohort of patients with HNF4Aor HNF1Amutations presenting with HH over a 25-year period (1995-2020)., Methods: Clinical and genetic analysis data from five centres were obtained. Diazoxide responsiveness was defined as the ability to maintain normoglycaemia without intravenous glucose. Macrosomia was defined as a birth weight ≥90th centile. SPSS v.27.1 was used for data analysis., Results: A total of 34 patients (70.6% female, n = 24) with a mean age of 7.1 years (s.d. 6.4) were included. A total of 21 different heterozygous HNF4Amutations were identified in 29 patients (four novels). Four different previously described heterozygous HNF1A mutations were detected in five patients. Most (97.1%, n = 33) developed hypoglycaemia by day 2 of life. The mean birth weight was 3.8 kg (s.d. 0.8), with most infants macrosomic (n = 21, 61.8%). Diazoxide was commenced in 28 patients (82.3%); all responded. HH resolved in 20 patients (58.8%) following a median of 0.9 years (interquartile range (IQR): 0.2-6.8). Nine patients (n = 9, 26.5%) had developmental delay. Two patients developed Fanconi syndrome (p.Arg63Trp, HNF4A) and four had other renal or hepatic findings. Five (14.7%) developed MODY at a median of 11.0 years (IQR: 9.0-13.9). Of patients with inherited mutations (n = 25, 73.5%), a family history of diabetes was present in 22 (88.0%)., Conclusions: We build on the knowledge of the natural history and pancreatic and extra-pancreatic phenotypes of HNF4A/HNF1Amutations and illustrate the heterogeneity of this condition.

Fanconi-Bickel syndrome (FBS) is a very rare but distinct clinical entity with the combined features of hepatic glycogen storage disease, generalized proximal renal tubular dysfunction with disproportionately severe glucosuria, and impaired galactose tolerance. Here, we report five cases (out of 93 diagnosed in our lab) with pathogenic variants on both GLUT2 ( SLC2A2 ) alleles. They come from 3 families and presented with an exceptionally mild clinical course. This course was correlated to data from old and most recent expression and transport studies in Xenopus oocytes. GLUT2 genotype in patients 1 and 2 was p.[153&#95;4delLI];[P417R] with the first variant exhibiting normal membrane expression and partially retained transport activity (5.8%) for 2-deoxyglucose. In patient 3, the very first GLUT2 variant ever detected (p.V197I) was found, but for the first time it was present in a patient in the homozygous state. This variant had also shown unaffected membrane expression and remarkable residual activity (8%). The genotype in patient 4, p.[153&#95;4delLI];[(E440A)], again included the 2-amino-acid deletion with residual transporter function, and patient 5 is the first found to be homozygous for this variant. Our results provide further evidence for a genotype-phenotype correlation in patients with GLUT2 variants; non-functional variants result in the full picture of FBS while dysfunctional variants may result in milder presentations, even glucosuria only, without other typical signs of FBS.

Fanconi-Bickel syndrome (FBS) is a rare autosomal recessive disease, resulting from mutations in the SLC2A2 gene, causing impaired glucose transporter 2 protein transporter protein function, impaired glucose and galactose utilisation, hepatorenal glycogen accumulation and organ dysfunction. Clinical features include failure to thrive, hepatomegaly, rickets, short stature and delayed puberty. Therapy includes electrolyte supplementation and uncooked cornstarch. We present a 15-year-old boy diagnosed with FBS in infancy. Growth velocity was normal on standard treatment until age 8.5 years, at which time growth failure led to a diagnosis of acquired growth hormone (GH) deficiency. Initiation of recombinant human GH (rhGH) replacement of 0.25 μg/kg/week resulted in marked improvement in growth velocity and height. While short stature is expected in FBS, growth velocity that falls below the normal range despite adequate therapy should prompt further evaluation. Our case suggests that acquired GH deficiency can arise in FBS and benefits from rhGH therapy., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Cystinosis is an autosomal recessive lysosomal storage disorder caused by CTNS gene mutations. The CTNS gene encodes the protein cystinosin, which transports free cystine from lysosomes to cytoplasm. In cases of cystinosin deficiency, free cystine accumulates in lysosomes and forms toxic crystals that lead to tissue and organ damage. Since CTNS gene mutations were first described, many variations have been identified that vary according to geographic region, although the phenotype remains the same. Cystinosis is a hereditary disease that can be treated with the cystine-depleting agent cysteamine. Cysteamine slows organ deterioration, but cannot treat renal Fanconi syndrome or prevent eventual kidney failure; therefore, novel treatment modalities for cystinosis are of great interest to researchers. The present review aims to highlight the geographic differences in cystinosis-specifically in terms of its genetic aspects, clinical features, management, and long-term complications.

Purpose: Tumor-induced osteomalacia (TIO) is an acquired form of hypophosphatemia caused by tumors with excess production of fibroblast growth factor 23 (FGF23). Some reports showed that TIO patients had renal Fanconi syndrome (FS) with unidentified mechanism. In this study, we investigated the association between genetic polymorphisms of phosphate transporters in renal proximal tubules and TIO with FS., Methods: We recruited 30 TIO patients with FS (TIO-FS) as well as 30 TIO patients (TIO-nonFS) without any urine abnormalities matched by age and gender. We collected clinical manifestations and conducted targeted sequencing of SLC34A1, SLC34A3 and XPR1 genes and the association analysis between variants in TIO with FS and phenotypes., Results: TIO-FS group had lower levels of serum phosphate (0.44 ± 0.12 vs. 0.51 ± 0.07 mmol/L, p < 0.05) than TIO-nonFS group. Among the 16 SNPs in SLC34A1, SLC34A3 and XPR1 genes, GG/GC genotypes of rs148196667 in XPR1 and AA/TA genotypes of rs35535797 in SLC34A3 were associated with a reduced susceptibility to have FS. The G allele of rs148196667 in XPR1 decreased the risk of FS. The GGAA haplotype in SLC34A3 and GCT haplotype in XPR1 were associated with a decreased risk for FS., Conclusions: The polymorphisms of XPR1 and SCL34A3 are associated with TIO patients with Fanconi syndrome. It provides novel insight to the relationship of phosphate transportation and general functions of renal proximal tubules.

The various forms of Fanconi renotubular syndromes (FRTS) offer significant challenges for clinicians and present unique opportunities for scientists who study proximal tubule physiology. This review will describe the clinical characteristics, genetic underpinnings, and underlying pathophysiology of the major forms of FRST. Although the classic forms of FRTS will be presented (e.g., Dent disease or Lowe syndrome), particular attention will be paid to five of the most recently discovered FRTS subtypes caused by mutations in the genes encoding for L-arginine:glycine amidinotransferase ( GATM ), solute carrier family 34 (type Ii sodium/phosphate cotransporter), member 1 ( SLC34A1 ), enoyl-CoAhydratase/3-hydroxyacyl CoA dehydrogenase ( EHHADH ), hepatocyte nuclear factor 4A ( HNF4A ), or NADH dehydrogenase complex I, assembly factor 6 ( NDUFAF6 ). We will explore how mutations in these genes revealed unexpected mechanisms that led to compromised proximal tubule functions. We will also describe the inherent challenges associated with gene discovery studies based on findings derived from small, single-family studies by focusing the story of FRTS type 2 ( SLC34A1 ). Finally, we will explain how extensive alternative splicing of HNF4A has resulted in confusion with mutation nomenclature for FRTS type 4.

Background: Dent disease is an X-linked form of progressive renal disease. This rare disorder was characterized by hypercalciuria, low molecular weight (LMW) proteinuria and proximal tubular dysfunction, caused by pathogenic variants in CLCN5 (Dent disease 1) or OCRL (Dent disease 2) genes. Fanconi syndrome is a consequence of decreased water and solute resorption in the proximal tubule of the kidney. Fanconi syndrome caused by proximal tubular dysfunction such as Dent disease might occur in early stage of the disease., Case Presentation: Three cases reported in this study were 3-, 10- and 14-year-old boys, and proteinuria was the first impression in all the cases. All the boys presented with LMW proteinuria and elevated urine albumin-to-creatinine ratio (ACR). Case 1 revealed a pathogenic variant in exon 11 of CLCN5 gene [NM&#95;001127899; c.1444delG] and a nonsense mutation at nucleotide 1509 [p.L503*], and he was diagnosed as Dent disease 1. Case 2 carried a deletion of exon 3 and 4 of OCRL1 gene [NM&#95;000276.4; c.120-238delG … A] and a nonsense mutation at nucleotide 171 in exon 5 [p.E57*], and this boy was diagnosed as Dent disease 2. Genetic analysis of Case 3 showed a missense mutation located in exon 2 of HNF4A gene [EF591040.1; c.253C > T; p.R85W] which is responsible for Fanconi syndrome. All of three pathogenic variants were not registered in GenBank., Conclusions: Urine protein electrophoresis should be performed for patients with proteinuria. When patients have LMW proteinuria and/or hypercalciuria, definite diagnosis and identification of Dent disease and Fanconi syndrome requires further genetic analyses.

Background: Hepatocyte NF 4α (Hnf4a) is a major regulator of renal proximal tubule (PT) development. In humans, a mutation in HNF4A impairs PT functions and is associated with Fanconi renotubular syndrome (FRTS). In mice, mosaic deletion of Hnf4a in the developing kidney reduces the population of PT cells, leading to FRTS-like symptoms. The molecular mechanisms underlying the role of Hnf4a in PT development remain unclear., Methods: The gene deletion tool Osr2Cre removed Hnf4a in developing nephrons in mice, generating a novel model for FRTS. Immunofluorescence analysis characterized the mutant phenotype, and lineage analysis tested whether Cadherin-6 (Cdh6)-expressing cells are PT progenitors. Genome-wide mapping of Hnf4a binding sites and differential gene analysis of Hnf4a mutant kidneys identified direct target genes of Hnf4a., Results: Deletion of Hnf4a with Osr2Cre led to the complete loss of mature PT cells, lethal to the Hnf4a mutant mice. Cdh6 high , lotus tetragonolobus lectin-low (LTL low ) cells serve as PT progenitors and demonstrate higher proliferation than Cdh6 low , LTL high differentiated PT cells. Additionally, Hnf4a is required for PT progenitors to differentiate into mature PT cells. Genomic analyses revealed that Hnf4a directly regulates the expression of genes involved in transmembrane transport and metabolism., Conclusions: Hnf4a promotes the differentiation of PT progenitors into mature PT cells by regulating the expression of genes associated with reabsorption, the major function of PT cells., (Copyright © 2020 by the American Society of Nephrology.)

Autosomal recessively inherited pathogenic variants in genes associated with the renin-angiotensin-aldosterone system (RAAS) result in early onset oligohydramnios and clinical features of the Potter sequence, typically in association with proximal renal tubules dysgenesis. We describe two siblings and a first cousin who had severe oligohydramnios in the second trimester, and presented at birth with loose skin, wide fontanelles and sutures, and pulmonary insufficiency. Two had refractory hypotension during their brief lives and one received palliative care after birth. All were found to have a homozygous nonsense variant, REN: c.891delG; p.Tyr287*, on exome sequencing. Autopsy limited to the genitourinary system in two of the children revealed normal renal tubular histology in both. Immunoblotting confirmed diminished expression of renin within cultured skin fibroblasts. To our knowledge, this is the first identification of an association between biallelic variants in REN and oligohydramnios in the absence of renal tubular dysgenesis. Due to its role in the RAAS, it has previously been proposed that the decreased expression of REN results in hypotension, ischemia, and decreased urine production. We suggest sequencing of genes in the RAAS, including REN, should be considered in cases of severe early onset oligohydramnios, even when renal morphology and histology are normal., (© 2020 Wiley Periodicals LLC.)

Drug induced kidney injury (DIKI) is a common reason for compound attrition in drug development pipelines with proximal tubule epithelial cells (PTECs) most commonly associated with DIKI. Here, we investigated freshly isolated human (hPTECs) as an in vitro model for assessing renal tubular toxicity. The freshly isolated hPTECs were first characterized to confirm gene expression of important renal transporters involved in drug handling which was further corroborated by confirming the functional activity of organic cation transporter 2 and organic anion transporter 1 by using transporter specific inhibitors. Additionally, functionality of megalin/cubilin endocytic receptors was also confirmed. A training set of 36 compounds was used to test the ability of the model to classify them using six different endpoints which included three biomarkers (Kidney Injury Molecule-1, Neutrophil gelatinase-associated lipocalin, and Clusterin) and three non-specific injury endpoints (ATP depletion, LDH leakage, and barrier permeability via transepithelial electrical resistance) in a dose-dependent manner across two independent kidney donors. In general, biomarkers showed higher predictivity than non-specific endpoints, with Clusterin showing the highest predictivity (Sensitivity/Specificity - 65.0/93.8 %). By using the thresholds generated from the training set, nine candidate internal Takeda compounds were screened where PTEC toxicity was identified as one of the findings in preclinical animal studies. The model correctly classified four of six true positives and two of three true negatives, showing validation of the in vitro model for detection of tubular toxicants. This work thus shows the potential application of freshly isolated primary hPTECs using translational biomarkers in assessment of tubular toxicity within the drug discovery pipeline., (Copyright © 2020. Published by Elsevier B.V.)

The kidney proximal tubule function relies on oxidative phosphorylation (OXPHOS), thus mitochondrial dysfunction is characteristic of acute kidney injury (AKI). Maleic acid (MA) can induce an experimental model of Fanconi syndrome that is associated to oxidative stress and decreased oxygen consumption. Sulforaphane (SF) is an antioxidant known to protect against MA-induced AKI. The molecular basis by which SF maintains the bioenergetics in MA-induced AKI is not fully understood. To achieve it, rats were submitted to a protective scheme: SF (1 mg/kg/day i.p.) for four days and, at the fourth day, they received a single dose of MA (400 mg/kg i.p.), getting four main experimental groups: (1) control (CT), (2) MA-nephropathy (MA), (3) SF-protected and (4) SF-control (SF). Additionally, a similar protective schema was tested in cultured NRK-52E cells with different concentrations of SF and MA. In the animal model, SF prevented the MA-induced alterations: decrease in fatty acid-related oxygen consumption rate, OXPHOS capacity, mitochondrial membrane potential (Ψ mt ), and the activity of complex I (CI) as its monomeric and supercomplexes forms; the antioxidant also increased the activity of cytochrome c oxidase as well as mitochondrial biogenesis markers. Thus, SF prevented the MA-induced increase in fission, mitophagy and autophagy markers. In NRK-52E cells, we found that SF prevented the MA-induced cell death, increased mitochondrial mass and ameliorated the loss of Ψ mt . We concluded that SF-induced biogenesis protects against mitochondrial dysfunction maintaining Ψ mt , activities of mitochondrial complexes and supercomplexes, and prevents the extensive fission and mitophagy., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Inherited and acquired disorders that affect proximal tubule endocytosis and lysosomal processing manifest with improper loss of solutes and proteins. The zebrafish pronephros is conserved with humans and is used to model numerous renal conditions, but has few quantitative measures for proximal tubule function. Here, Chen et al. developed a high-throughput assay to quantify proteinuria and lysosomal processing in transgenic zebrafish by labeling vitamin D protein, allowing for precise reporting of proximal tubule function., (Copyright © 2020 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Fanconi-Bickel syndrome (FBS) is a rare autosomal recessive disorder characterised by impaired glucose liver homeostasis and proximal renal tubular dysfunction. It is caused by pathogenic variants in SLC2A2 coding for the glucose transporter GLUT2. Main clinical features include hepatomegaly, fasting hypoglycaemia, postprandial hyperglycaemia, Fanconi-type tubulopathy occasionally with rickets, and a severe growth disorder. While treatment for renal tubular dysfunction is well established, data regarding optimal nutritional therapy are scarce. Similarly, detailed clinical evaluation of treated FBS patients is lacking. These unmet needs were an incentive to conduct the present pilot study. We present clinical findings, laboratory parameters and molecular genetic data on 11 FBS patients with emphasis on clinical outcome under various nutritional interventions. At diagnosis, the patients' phenotypic severity could be classified into two categories: a first group with severe growth failure and rickets, and a second group with milder signs and symptoms. Three patients were diagnosed early and treated because of family history. All patients exhibited massive glucosuria at diagnosis and some in both groups had fasting hypoglycaemic episodes. Growth retardation improved drastically in all five patients treated by intensive nutritional intervention (nocturnal enteral nutrition) and uncooked cornstarch with final growth parameters in the normal range. The four severely affected patients who were treated with uncooked cornstarch alone did not catch up growth. All patients received electrolytes and l-carnitine supplementation to compensate for the tubulopathy. This is one of the largest series of FBS on therapeutic management with evidence that nocturnal enteral nutrition rescues growth failure., (© 2019 SSIEM.)

HNF4A is a nuclear hormone receptor that binds DNA as an obligate homodimer. While all known human heterozygous mutations are associated with the autosomal-dominant diabetes form MODY1, one particular mutation (p.R85W) in the DNA-binding domain (DBD) causes additional renal Fanconi syndrome (FRTS). Here, we find that expression of the conserved fly ortholog dHNF4 harboring the FRTS mutation in Drosophila nephrocytes caused nuclear depletion and cytosolic aggregation of a wild-type dHNF4 reporter protein. While the nuclear depletion led to mitochondrial defects and lipid droplet accumulation, the cytosolic aggregates triggered the expansion of the endoplasmic reticulum (ER), autophagy, and eventually cell death. The latter effects could be fully rescued by preventing nuclear export through interfering with serine phosphorylation in the DBD. Our data describe a genomic and a non-genomic mechanism for FRTS in HNF4A-associated MODY1 with important implications for the renal proximal tubule and the regulation of other nuclear hormone receptors., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Fanconi-Bickel syndrome (FBS) is a rare autosomal recessive carbohydrate metabolism disorder caused by mutations in SLC2A2 encoding the glucose transporter 2 (GLUT2) protein. The clinical manifestations include hepatomegaly, conditional hypo/hyperglycemia, rickets, short stature and proximal renal tubular dysfunction. GLUT2 regulates monosaccharide homeostasis through sugar sensing and transmembrane transportation during high/low glucose levels. In the current study, we present two siblings suffering from FBS. The patients presented with doll-like facies, failure to gain weight and height, abdominal distension and firm hepatomegaly. The family had a history of deaths of twin male siblings in the neonatal period and twin female siblings at ages 10 months and 2.5 years, respectively. Clinical presentation and biochemical investigations including a complete blood count, electrolytes, liver and renal function tests suggested FBS. Mutation screening of SLC2A2 confirmed the diagnosis with identification of a novel homozygous splice site variant predicting an in-frame deletion [p.(Gly166-S169del)] in the GLUT2 protein. The in-silico analysis predicted the variant to affect the three-dimensional conformation of the fourth transmembrane helix of the encoded protein, rendering the non-functionality of GLUT2 in both patients of the family under study.

Background: Neonatal diabetes mellitus (NDM) is a rare condition that occurs within the first six months of life. Permanent NDM (PNDM) is caused by mutations in specific genes that are known for their expression at early and/or late stages of pancreatic beta- cell development, and are either involved in beta-cell survival, insulin processing, regulation, and release. The native population in Qatar continues to practice consanguineous marriages that lead to a high level of homozygosity. To our knowledge, there is no previous report on the genomics of NDM among the Qatari population. The aims of the current study are to identify patients with NDM diagnosed between 2001 and 2016, and examine their clinical and genetic characteristics., Methods: To calculate the incidence of PNDM, all patients with PNDM diagnosed between 2001 and 2016 were compared to the total number of live births over the 16-year-period. Whole Genome Sequencing (WGS) was used to investigate the genetic etiology in the PNDM cohort., Results: PNDM was diagnosed in nine (n = 9) patients with an estimated incidence rate of 1:22,938 live births among the indigenous Qatari. Seven different mutations in six genes (PTF1A, GCK, SLC2A2, EIF2AK3, INS, and HNF1B) were identified. In the majority of cases, the genetic etiology was part of a previously identified autosomal recessive disorder. Two novel de novo mutations were identified in INS and HNF1B., Conclusion: Qatar has the second highest reported incidence of PNDM worldwide. A majority of PNDM cases present as rare familial autosomal recessive disorders. Pancreas associated transcription factor 1a (PTF1A) enhancer deletions are the most common cause of PNDM in Qatar, with only a few previous cases reported in the literature., (© 2019 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

Summary Mitochondrial DNA（mtDNA） deletion is a rare occurrence that results in defects to oxidative phosphorylation. The common clinical presentations of mtDNA deletion vary but include mitochondrial myopathy, Pearson syndrome, Kearns-Sayre syndrome, and progressive external ophthalmoplegia. However, in clinical practice, some cases cannot be classified as any typical syndrome due to the absence or overlap of phenotypes. Here, we report one case of a 5-year-old girl who presented with progressive deterioration of her clinical status, which included systemic electrolyte disturbance, Fanconi syndrome and sensorineural hearing loss. Through a combination of systematic examinations and molecular analyses, mitochondrial disease was confirmed. A novel 6991-base pair deletion（deletion of mtDNA nt 7808-14798） was identified which confirmed molecular pathogeny of patient. Following treatment, the patient was stabilized and her hearing loss improved by hearing aid. This paper provided an important reference for the diagnosis and treatment of similar patients in clinical practice., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright© by the Editorial Department of Journal of Clinical Otorhinolaryngology Head and Neck Surgery.)

Deleterious variants in SLC2A2 cause Fanconi-Bickel Syndrome (FBS), a glycogen storage disorder, whereas less common variants in SLC2A2 associate with numerous metabolic diseases. Phenotypic heterogeneity in FBS has been observed, but its causes remain unknown. Our goal was to functionally characterize rare SLC2A2 variants found in FBS and metabolic disease-associated variants to understand the impact of these variants on GLUT2 activity and expression and establish genotype-phenotype correlations. Complementary RNA-injected Xenopus laevis oocytes were used to study mutant transporter activity and membrane expression. GLUT2 homology models were constructed for mutation analysis using GLUT1, GLUT3, and XylE as templates. Seventeen FBS variants were characterized. Only c.457&#95;462delCTTATA (p.Leu153&#95;Ile154del) exhibited residual glucose uptake. Functional characterization revealed that only half of the variants were expressed on the plasma membrane. Most less common variants (except c.593 C>A (p.Thr198Lys) and c.1087 G>T (p.Ala363Ser)) exhibited similar GLUT2 transport activity as the wild type. Structural analysis of GLUT2 revealed that variants affect substrate-binding, steric hindrance, or overall transporter structure. The mutant transporter that is associated with a milder FBS phenotype, p.Leu153&#95;Ile154del, retained transport activity. These results improve our overall understanding of the underlying causes of FBS and impact of GLUT2 function on various clinical phenotypes ranging from rare to common disease., (© 2019 Wiley Periodicals, Inc.)

Different nephron tubule segments perform distinct physiological functions, collectively acting as a blood filtration unit. Dysfunction of the proximal tubule segment can lead to Fanconi renotubular syndrome (FRTS), with major symptoms such as excess excretion of water, glucose, and phosphate in the urine. It has been shown that a mutation in HNF4A is associated with FRTS in humans and that Hnf4a is expressed specifically in proximal tubules in adult rat nephrons. However, little is known about the role of Hnf4a in nephrogenesis. Here, we found that Hnf4a is expressed in both presumptive and differentiated proximal tubules in the developing mouse kidney. We show that Hnf4a is required for the formation of differentiated proximal tubules but is dispensable for the formation of presumptive proximal tubules. Furthermore, we show that loss of Hnf4a decreased the expression of proximal tubule-specific genes. Adult Hnf4a mutant mice presented with FRTS-like symptoms, including polyuria, polydipsia, glycosuria, and phosphaturia. Analysis of the adult Hnf4a mutant kidney also showed proximal tubule dysgenesis and nephrocalcinosis. Our results demonstrate the critical role of Hnf4a in proximal tubule development and provide mechanistic insight into the etiology of FRTS.

Background: The p.R63W mutation in hepatocyte nuclear factor-4 alpha (HNF4A) leads to a heterogeneous group of disorders with various clinical presentations. Recently, patients with congenital hyperinsulinism and Fanconi syndrome due to the p.R63W mutation in HNF4A have been described. Although other clinical variations such as liver dysfunction have been associated with HNF4A mutations, hearing impairment has not previously been associated. We report the case of a patient with Fanconi syndrome and hyperinsulinemic hypoglycemia caused by the mutation of HNF4A presenting with additional auditory phenotypes., Case Presentation: We present a case report of a 10-year-old girl of Chinese Han ethnicity who presented with renal Fanconi syndrome, infantile hyperinsulinemic hypoglycemia, and transient cholestasis. In addition, she presented with bilateral severe hearing loss. Gene analysis showed a heterozygous p.R63W mutation in the HNF4A gene that is responsible for Fanconi syndrome and hyperinsulinemic hypoglycemia., Conclusions: This is the first case of HNF4A mutation associated with an auditory phenotype. It expands the clinical phenotypes and supports speculation in the literature that HNF4A may be a candidate gene for deafness. In conclusion, hearing loss may be found in children with HNF4A-related Fanconi syndrome, and auditory function should be assessed.

Proximal renal tubular acidosis (pRTA) is an inherited or acquired clinical syndrome in which there is a decreased bicarbonate reclamation in the proximal tubule resulting in normal anion gap hyperchloremic metabolic acidosis. In children, pRTA may be isolated but is often associated with a general proximal tubular dysfunction known as Fanconi syndrome which frequently heralds an underlying systemic disorder from which it arises. When accompanied by Fanconi syndrome, pRTA is characterized by additional renal wasting of phosphate, glucose, uric acid, and amino acids. The most common cause of inherited Fanconi syndrome in the pediatric age group is cystinosis, a disease with therapeutic implications. In this article, we summarize the clinical presentation and differential diagnosis of pRTA and Fanconi syndrome and provide a practical approach to their evaluation in children., (Copyright © 2018 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background For many patients with kidney failure, the cause and underlying defect remain unknown. Here, we describe a novel mechanism of a genetic order characterized by renal Fanconi syndrome and kidney failure. Methods We clinically and genetically characterized members of five families with autosomal dominant renal Fanconi syndrome and kidney failure. We performed genome-wide linkage analysis, sequencing, and expression studies in kidney biopsy specimens and renal cells along with knockout mouse studies and evaluations of mitochondrial morphology and function. Structural studies examined the effects of recognized mutations. Results The renal disease in these patients resulted from monoallelic mutations in the gene encoding glycine amidinotransferase (GATM), a renal proximal tubular enzyme in the creatine biosynthetic pathway that is otherwise associated with a recessive disorder of creatine deficiency. In silico analysis showed that the particular GATM mutations, identified in 28 members of the five families, create an additional interaction interface within the GATM protein and likely cause the linear aggregation of GATM observed in patient biopsy specimens and cultured proximal tubule cells. GATM aggregates-containing mitochondria were elongated and associated with increased ROS production, activation of the NLRP3 inflammasome, enhanced expression of the profibrotic cytokine IL-18, and increased cell death. Conclusions In this novel genetic disorder, fully penetrant heterozygous missense mutations in GATM trigger intramitochondrial fibrillary deposition of GATM and lead to elongated and abnormal mitochondria. We speculate that this renal proximal tubular mitochondrial pathology initiates a response from the inflammasome, with subsequent development of kidney fibrosis., (Copyright © 2018 by the American Society of Nephrology.)

Introduction: This case report describes a new genetic disease of the Braunvieh breed in Switzerland. The bovine disorder also occurs in German Fleckvieh, and corresponds to human Fanconi-Bickel syndrome which is an inherited glycogen storage disease caused by mutations of the SLC2A2 gene encoding the glucose transporter GLUT2. This case report describes a single affected Original Braunvieh calf genotyped as homozygous for the FH2-associated SLC2A2 frame shift mutation. The clinical examination showed stunted growth, polyuria and polydipsia, as well as poor claw horn and coat quality. Necropsy revealed a pale cortex of the kidneys and a unilateral renal hypoplasia. Histology showed tubulonephrosis of the proximal tubules with protein- and glucose-rich contents. Glycogen accumulation was not evident in any organ. This finding is different from the reported lesions in two previously described GLUT2-deficient Fleckvieh heifers. In the presented case, growth retardation mainly seems to be associated with renal dysfunction. A direct gene test is available to eliminate the mutant allele from the population.

Renal tubulopathies provide insights into the inner workings of the kidney, yet also pose therapeutic challenges. Because of the central nature of sodium in tubular transport physiology, disorders of sodium handling may affect virtually all aspects of the homeostatic functions of the kidney. Yet, owing to the rarity of these disorders, little clinical evidence regarding treatment exists. Consequently, treatment can vary widely between individual physicians and centers and is based mainly on understanding of renal physiology, reported clinical observations, and individual experiences. Salt-losing tubulopathies can affect all tubular segments, from the proximal tubule to the collecting duct. But the more frequently observed disorders are Bartter and Gitelman syndrome, which affect salt transport in the thick ascending limb of Henle's loop and/or the distal convoluted tubule, and these disorders generate the greatest controversies regarding management. Here, we review clinical and molecular aspects of salt-losing tubulopathies and discuss novel insights provided mainly by genetic investigations and retrospective clinical reviews. Additionally, we discuss controversial topics in the management of these disorders to highlight areas of importance for future clinical trials. International collaboration will be required to perform clinical studies to inform the treatment of these rare disorders., (Copyright © 2018 by the American Society of Nephrology.)

Context: NaPi-IIa, encoded by SLC34A1, is a key phosphate transporter in the mammalian proximal tubule and plays a cardinal role in renal phosphate handling. NaPi-IIa impairment has been linked to various overlapping clinical syndromes, including hypophosphatemic nephrolithiasis with osteoporosis, renal Fanconi syndrome with chronic kidney disease, and, most recently, idiopathic infantile hypercalcemia and nephrocalcinosis., Objectives: We studied the molecular basis of idiopathic infantile hypercalcemia with partial proximal tubulopathy in two apparently unrelated patients of Israeli and Turkish descent., Design: Genetic analysis in two affected children and their close relatives was performed using whole-exome sequencing, followed by in vitro localization and trafficking analysis of mutant NaPi-IIa., Results: Mutation and haplotype analyses in both patients revealed a previously described homozygous loss-of-function inserted duplication (p.I154&#95;V160dup) in NaPi-IIa, which is inherited identical-by-descent from a common ancestor. The shared mutation was originally reported by our team in two adult siblings with renal Fanconi syndrome, hypophosphatemic bone disease, and progressive renal failure who are family members of one of the infants reported herein. In vitro localization assays and biochemical analysis of p.I154&#95;V160dup and of additional NaPi-IIa mutants harboring a trafficking defect indicate aberrant retention at the endoplasmic reticulum in an immature and underglycosylated state, leading to premature proteasomal degradation., Conclusions: Our findings expand the phenotypic spectrum of NaPi-IIa disruption, reinforce its link with proximal tubular impairment, enable longitudinal study of the natural history of the disease, and shed light on cellular pathways associated with loss of function and impaired trafficking of NaPi-IIa mutants., (Copyright © 2017 Endocrine Society)

Background: Cystinosis is a rare autosomal recessive lysosomal disorder characterized by the accumulation of cystine in lysosomes. Cystinosis is much rarer in Asian than Caucasian populations. There are only 14 patients have with cystinosis alive in Japan. Most cystinosis is the nephropathic infantile form, as indicated by its apparent and severe clinical manifestations, including renal and ocular symptoms. Patients with the nephropathic juvenile form account for 5% of those with cystinosis. Their diagnosis is frequently delayed and difficult because of slower progression to end-stage renal disease and fewer cystine crystals in the cornea. Molecular analysis and a cysteine-binding protein assay should be performed when patients with proximal tubulopathy of an unknown origin are encountered., Case Presentation: A 12-year-old boy had been suffering from Fanconi syndrome since he was 3 years old. He was only recently diagnosed despite repeated ophthalmological examinations. Corneal cystine crystals were found when he was 12 years old, and he was diagnosed with cystinosis by high free cystine content in granulocytes (6.36 nmol half-cystine/mg protein, normal: <0.15). Analysis of the CTNS gene showed two novel heterozygous single nucleotide substitutions of c.329G > C and c.329 + 2 T > C. Both were splicing site variants causing exon 6 skipping proven by transcript analysis, although the functional prediction site showed c.329G > C, p.(Gly110Ala) as a benign missense substitution. The patient's estimated glomerular filtration rate was 66.8 mL/min/1.73 m 2 . He was immediately treated with cysteamine after diagnosis., Conclusions: Even if no ophthalmological abnormalities are present, nephropathic juvenile cystinosis should be suspected in children with Fanconi syndrome. Transcript analysis was useful to detect pathogenic splicing variants in this patient.

Megalin (or LRP2) is an endocytic receptor that plays a central role in embryonic development and adult tissue homeostasis. Loss of this receptor in congenital or acquired diseases results in multiple organ dysfunctions, including forebrain malformation (holoprosencephaly) and renal reabsorption defects (renal Fanconi syndrome). Here, we describe current concepts of the mode of receptor action that include co-receptors and a repertoire of different ligands, and we discuss how these interactions govern functional integrity of the kidney and the brain, and cause disease when defective.