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Clinical Journal of the American... Dec 2016Dent disease is a rare X-linked disorder characterized by low molecular weight proteinuria and often considered a renal tubular disease. However, glomerulosclerosis was...
BACKGROUND AND OBJECTIVES
Dent disease is a rare X-linked disorder characterized by low molecular weight proteinuria and often considered a renal tubular disease. However, glomerulosclerosis was recently reported in several patients. Thus, Dent disease renal histopathologic features were characterized and assessed, and their association with kidney function was assessed.
DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS
Clinical renal pathology reports and slides (where available) were collected from 30 boys and men in eight countries who had undergone clinical renal biopsy between 1995 and 2014.
RESULTS
Median (25th, 75th percentiles) age at biopsy was 7.5 (5, 19) years with an eGFR of 69 (44, 94) ml/min per 1.73 m and a 24-hour urine protein of 2000 (1325, 2936) mg. A repeat biopsy for steroid-resistant proteinuria was performed in 13% (four of 30) of the patients. Prominent histologic findings included focal global glomerulosclerosis in 83% (25 of 30; affecting 16%±19% glomeruli), mild segmental foot process effacement in 57% (13 of 23), focal interstitial fibrosis in 60% (18 of 30), interstitial lymphocytic infiltration in 53% (16 of 30), and tubular damage in 70% (21 of 30). Higher percentages of globally sclerotic glomeruli, foot process effacement, and interstitial inflammation were associated with lower eGFR at biopsy, whereas foot process effacement was associated with steeper annual eGFR decline.
CONCLUSIONS
These associations suggest a potential role for glomerular pathology, specifically involving the podocyte, in disease progression, which deserves further study. Furthermore, Dent disease should be suspected in boys and men who have unexplained proteinuria with focal global glomerulosclerosis and segmental foot process effacement on renal biopsy.
Topics: Adolescent; Adult; Biopsy; Child; Child, Preschool; Dent Disease; Fibrosis; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Humans; Infant; Kidney Glomerulus; Kidney Tubules; Lymphocytes; Male; Middle Aged; Young Adult
PubMed: 27697782
DOI: 10.2215/CJN.03710416 -
Nephron. Physiology 2005Dent's disease is a hereditary renal tubular disorder characterized by low-molecular weight (LMW) proteinuria, hypercalciuria and nephrolithiasis. The disease is due to... (Review)
Review
Dent's disease is a hereditary renal tubular disorder characterized by low-molecular weight (LMW) proteinuria, hypercalciuria and nephrolithiasis. The disease is due to mutations of ClC-5, a member of the family of voltage-gated CLC chloride channels. ClC-5 is expressed in part in cells lining the proximal tubule (PT) of the kidney, where it colocalizes with albumin-containing endocytic vesicles belonging to the receptor-mediated endocytic pathway that ensures efficient reabsorption of ultrafiltrated LMW proteins. Since progression along the endocytic apparatus requires endosomal acidification, it has been suggested that dysfunction of ClC-5 in endosomes may lead to inefficient reabsorption of LMW proteins and dysfunction of PT cells. Analysis of a ClC-5 knockout (KO) mouse model, displaying all the characteristic renal tubular defects of Dent's disease, showed evidence of a severe LMW proteinuria. Cytochemical studies with the endocytic tracer, peroxidase, showed poor transfer into early endocytic vesicles, suggesting that impairment of receptor-mediated endocytosis in PT cells is the basis for the defective uptake of LMW proteins in patients with Dent's disease. Endocytosis and processing of LMW proteins involve the multiligand tandem receptors, megalin and cubilin, that are abundantly expressed at the brush border of PT cells. Characterization of the endocytic defect in ClC-5 KO mice revealed that ligands of both megalin and cubilin were affected. The total kidney content of megalin and especially cubilin at the protein level was decreased but, more importantly, using analytical subcellular fractionation and quantitative immunogold labelling we demonstrated a selective disappearance of megalin and cubilin at the brush border of PT cells. These observations allowed us to conclude that defective protein endocytosis linked to ClC-5 inactivation is due at least in part to a major and selective loss of megalin and cubilin at the brush border, reflecting a trafficking defect in renal PT cells. These results improve our understanding of Dent's disease, taken as a paradigm for renal Fanconi syndrome and nephrolithiasis, and demonstrate multiple roles for ClC-5 in the kidney. These studies also provided insights into important functions such as apical endocytosis, handling of proteins by renal tubular cells, calcium metabolism, and urinary acidification.
Topics: Animals; Chloride Channels; Endocytosis; Ion Channel Gating; Kidney Calculi; Kidney Tubules, Proximal; Low Density Lipoprotein Receptor-Related Protein-2; Mice; Mice, Knockout; Tubulin
PubMed: 15637424
DOI: 10.1159/000083210 -
Bulletin Et Memoires de L'Academie... 2004Dent's disease is an hereditary renal tubular disorder characterized by low-molecular-weight (LMW) proteinuria, hypercalciuria and nephrolithiasis. The disease is due to... (Review)
Review
Dent's disease is an hereditary renal tubular disorder characterized by low-molecular-weight (LMW) proteinuria, hypercalciuria and nephrolithiasis. The disease is due to mutations of CLC-5, a member of the family of voltage-gated CLC chloride channels. CLC-5 is distributed in cells lining the proximal tubule (PT) of the kidney, where it co-localizes with albumin-containing endocytic vesicles that form part of the receptor-mediated endocytic pathway that mediates the reabsorption of low-molecular-weight (LMW) proteins filtered at the glomerular level. Since progression along the endocytic apparatus requires endosomal acidification, it has been suggested that dysfunction of CLC-5 in endosomes may lead to inefficient reabsorption of LMW proteins and dysfunction of PT cells. Investigations conducted in a CLC-5 knockout (KO) mouse model harbouring all the characteristic renal tubular defects of Dent's disease showed a severe impairment of endocytosis by PT cells, such that the endocytic tracer peroxidase was poorly transferred into early endocytic vesicles. These data demonstrated that an impairment of receptor-mediated endocytosis in PT cells is the basis for the defective uptake of LMW proteins in patients with Dent's disease. The endocytosis and processing of LMW proteins involves the multiligand tandem receptors, megalin and cubilin, that are abundantly expressed at the brush border of PT cells. The characterization of the endocytic defect in CLC-5 KO mice revealed that ligands of both megalin and cubilin were affected, whereas a decrease in total kidney content of megalin and cubilin at the protein level was detected. Using analytical subcellular fractionation and quantitative immunogold labelling, we demonstrated a selective disappearance of megalin and cubilin at the brush border of PT cells. These observations allowed us to conclude that defective protein endocytosis linked to CLC-5 inactivation is due to a major and selective loss of megalin and cubilin at the brush border, reflecting a trafficking defect in renal PT cells. These results improve our understanding of Dent's disease, taken as a paradigm for renal Fanconi syndrome and nephrolithiasis, and demonstrate multiple roles for CLC-5 in the kidney. These studies also provided insights in important functions such as apical endocytosis, handling of proteins by renal tubular cells, calcium metabolism, and urinary acidification.
Topics: Animals; Calcium; Chloride Channels; Disease Models, Animal; Endocytosis; Kidney Calculi; Mice; Mice, Knockout
PubMed: 15615095
DOI: No ID Found -
Intractable & Rare Diseases Research Feb 2017Dent disease is a rare X-linked recessive proximal tubular disorder that affects mostly male patients in childhood or early adult life. Dent disease is clinically...
Dent disease is a rare X-linked recessive proximal tubular disorder that affects mostly male patients in childhood or early adult life. Dent disease is clinically characterized by the presence of low molecular weight proteinuria (LMWP), hypercalciuria, medullary nephrocalcinosis, nephrolithiasis, and progressive renal failure. The clinical features, diagnosis, and treatment of Dent disease were examined in 10 Chinese boys. All 10 childhood cases of Dent disease in China presented with tubular proteinuria in the nephrotic range and hypercalciuria. The ratio of α1-microglobulinuria to microalbuminuria, if close to or above 1, can be used as a diagnostic criterion for tubuloproteinuria. Lotensin was ineffective at treating proteinuria while dihydrochlorothiazide reduced urine calcium excretion.
PubMed: 28357180
DOI: 10.5582/irdr.2016.01088 -
Zhejiang Da Xue Xue Bao. Yi Xue Ban =... Apr 2023Renal calculus is a common disease with complex etiology and high recurrence rate. Recent studies have revealed that gene mutations may lead to metabolic defects which... (Review)
Review
Renal calculus is a common disease with complex etiology and high recurrence rate. Recent studies have revealed that gene mutations may lead to metabolic defects which are associated with the formation of renal calculus, and single gene mutation is involved in relative high proportion of renal calculus. Gene mutations cause changes in enzyme function, metabolic pathway, ion transport, and receptor sensitivity, causing defects in oxalic acid metabolism, cystine metabolism, calcium ion metabolism, or purine metabolism, which may lead to the formation of renal calculus. The hereditary conditions associated with renal calculus include primary hyperoxaluria, cystinuria, Dent disease, familial hypomagnesemia with hypercalciuria and nephrocalcinosis, Bartter syndrome, primary distal renal tubular acidosis, infant hypercalcemia, hereditary hypophosphatemic rickets with hypercalciuria, adenine phosphoribosyltransferase deficiency, hypoxanthine-guanine phosphoribosyltransferase deficiency, and hereditary xanthinuria. This article reviews the research progress on renal calculus associated with inborn error of metabolism, to provide reference for early screening, diagnosis, treatment, prevention and recurrence of renal calculus.
Topics: Infant; Humans; Hypercalciuria; Kidney Calculi; Urolithiasis; Nephrocalcinosis; Metabolism, Inborn Errors
PubMed: 37283101
DOI: 10.3724/zdxbyxb-2022-0698 -
Genetics Research 2022Both Lowe syndrome and Dent-2 disease are caused by variants in the gene. However, the reason why patients with similar gene mutations presented with different...
BACKGROUND
Both Lowe syndrome and Dent-2 disease are caused by variants in the gene. However, the reason why patients with similar gene mutations presented with different phenotypes remains uncertain.
METHODS
Children with hemizygous pathogenic or likely pathogenic variants in were compiled from published and unpublished consecutive cases from China. Furthermore, a Chi-square test was employed to analyze the correlation of the location and types of mutations on the phenotype of children with Lowe syndrome or Dent-2 disease.
RESULTS
Among the total 83 patients, 70.8% (34/48) cases of Lowe syndrome presented with truncating mutations, while only 31.4% (11/35) cases of Dent-2 disease presented with truncating mutation (Χ = 12.662; < 0.001). Meanwhile, the majority of mutations in Dent-2 disease are located in Exon 2-12 (21/35, 60.0%), while the majority of mutations in Lowe syndrome are located in Exon 13-23 (39/48, 81.3%; Χ = 14.922; < 0.001).
CONCLUSIONS
Truncating mutations of the gene were more common in patients with Lowe syndrome than in Dent-2 disease, while mutation is more likely located at exon 2-12 in Dent-2 disease than that in Lowe syndrome. The type and location of mutation are important indicators for the phenotypes in patients with mutation. This is a large cohort study analyzing the genotype-phenotype correlation in patients with Lowe syndrome and Dent-2 disease in China. Our data may improve the interpretation of new variants and genetic counseling. Furthermore, a large international study would be necessary to illustrate the genotype-phenotype correlation in patients with mutations.
Topics: Cohort Studies; Genetic Association Studies; Humans; Mutation; Oculocerebrorenal Syndrome; Phosphoric Monoester Hydrolases
PubMed: 35919034
DOI: 10.1155/2022/1473260 -
Dent disease presenting with nyctalopia and electroretinographic correlates of vitamin A deficiency.American Journal of Ophthalmology Case... Mar 2023To report a unique case of Dent Disease presenting with nyctalopia associated with vitamin A deficiency and abnormal electroretinogram findings without prior systemic...
PURPOSE
To report a unique case of Dent Disease presenting with nyctalopia associated with vitamin A deficiency and abnormal electroretinogram findings without prior systemic symptomatology.
OBSERVATIONS
A 16-year-old male presented with a several month history of nyctalopia and peripheral vision deficits. Central visual acuity, anterior and posterior segment examinations, and macular optical coherence tomography were unremarkable. Electroretinogram (ERG) testing revealed a rod-cone dystrophic pattern, with further workup demonstrating serum vitamin A deficiency (VAD). Laboratory evaluation revealed renal dysfunction and proteinuria with a significantly elevated urinary retinol-binding protein (RBP). Kidney biopsy showed glomerular and tubular disease.Genetic screening for inherited renal disease was performed identifying a hemizygous pathogenic variant c.2152C>T (p.Arg718*) in the ( gene, confirming the diagnosis of X-linked Dent Disease. Following vitamin A supplementation, our patient reported resolution of nyctalopia and reversal of abnormal ERG findings were demonstrated.
CONCLUSIONS AND IMPORTANCE
To our knowledge, this is the first case in the literature describing Dent disease solely presenting with ophthalmic symptoms of nyctalopia and abnormal electroretinogram findings that later reversed with vitamin A repletion. This case stresses the importance for clinicians to consider renal tubular disorders in the differential for VAD.
PubMed: 36578800
DOI: 10.1016/j.ajoc.2022.101781 -
Pediatric Nephrology (Berlin, Germany) Oct 2013Adenine phosphoribosyltransferase (APRT) deficiency, cystinuria, Dent disease, familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), and primary... (Review)
Review
Adenine phosphoribosyltransferase (APRT) deficiency, cystinuria, Dent disease, familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), and primary hyperoxaluria (PH) are rare but important causes of severe kidney stone disease and/or chronic kidney disease in children. Recurrent kidney stone disease and nephrocalcinosis, particularly in pre-pubertal children, should alert the physician to the possibility of an inborn error of metabolism as the underlying cause. Unfortunately, the lack of recognition and knowledge of the five disorders has frequently resulted in an unacceptable delay in diagnosis and treatment, sometimes with grave consequences. A high index of suspicion coupled with early diagnosis may reduce or even prevent the serious long-term complications of these diseases. In this paper, we review the epidemiology, clinical features, diagnosis, treatment, and outcome of patients with APRT deficiency, cystinuria, Dent disease, FHHNC, and PH, with an emphasis on childhood manifestations.
Topics: Adenine Phosphoribosyltransferase; Animals; Child; Cystinuria; Dent Disease; Genetic Predisposition to Disease; Heredity; Humans; Hypercalciuria; Hyperoxaluria, Primary; Kidney Calculi; Metabolism, Inborn Errors; Nephrocalcinosis; Phenotype; Prognosis; Renal Insufficiency, Chronic; Renal Tubular Transport, Inborn Errors; Risk Factors; Urolithiasis
PubMed: 23334384
DOI: 10.1007/s00467-012-2329-z -
Swiss Dental Journal 2015TMJ-like symptoms as first sign of a tumorous disease. Metastasis as an uncommon origin of the symptoms (in German).
TMJ-like symptoms as first sign of a tumorous disease. Metastasis as an uncommon origin of the symptoms (in German).
PubMed: 26470719
DOI: No ID Found -
Genes Oct 2021Dent disease is a rare X-linked renal tubulopathy due to and (DD2) mutations. mutations also cause Lowe syndrome (LS) involving the eyes, brain and kidney. DD2 is...
Dent disease is a rare X-linked renal tubulopathy due to and (DD2) mutations. mutations also cause Lowe syndrome (LS) involving the eyes, brain and kidney. DD2 is frequently described as a mild form of LS because some patients may present with extra-renal symptoms (ESs). Since DD2 is a rare disease and there are a low number of reported cases, it is still unclear whether it has a clinical picture distinct from LS. We retrospectively analyzed the phenotype and genotype of our cohort of 35 DD2 males and reviewed all published DD2 cases. We analyzed the distribution of mutations along the gene and evaluated the type and frequency of ES according to the type of mutation and localization in OCRL protein domains. The frequency of patients with at least one ES was 39%. Muscle findings are the most common ES (52%), while ocular findings are less common (11%). Analysis of the distribution of mutations revealed (1) truncating mutations map in the PH and linker domain, while missense mutations map in the 5-phosphatase domain, and only occasionally in the ASH-RhoGAP module; (2) five mutations cause both DD2 and LS phenotypes; (3) codon 318 is a DD2 mutational hot spot; (4) a correlation was found between the presence of ES and the position of the mutations along OCRL domains. DD2 is distinct from LS. The mutation site and the mutation type largely determine the DD2 phenotype.
Topics: Adolescent; Biological Variation, Population; Child; Child, Preschool; Female; Genetic Association Studies; Genetic Diseases, X-Linked; Genetic Pleiotropy; Genotype; Humans; Kidney; Male; Mutation, Missense; Nephrolithiasis; Oculocerebrorenal Syndrome; Phenotype; Phosphoric Monoester Hydrolases
PubMed: 34680992
DOI: 10.3390/genes12101597