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World Journal of Pediatrics : WJP Feb 2021Dent disease is a rare tubulopathy characterized by manifestations of proximal tubular dysfunction, which occurs almost exclusively in males. It mainly presents symptoms... (Review)
Review
BACKGROUND
Dent disease is a rare tubulopathy characterized by manifestations of proximal tubular dysfunction, which occurs almost exclusively in males. It mainly presents symptoms in early childhood and may progress to end-stage renal failure between the 3rd and 5th decades of human life. According to its various genetic basis and to clinical signs and symptoms, researchers define two forms of Dent disease (Dent diseases 1 and 2) and suggest that these forms are produced by mutations in the CLCN5 and OCRL genes, respectively. Dent diseases 1 and 2 account for 60% and 15% of all Dent disease cases, and their genetic cause is generally understood. However, the genetic cause of the remaining 25% of Dent disease cases remains unidentified.
DATA SOURCES
All relevant peer-reviewed original articles published thus far have been screened out from PubMed and have been referenced.
RESULTS
Genetic testing has been used greatly to identify mutation types of CLCN5 and OCRL gene, and next-generation sequencing also has been used to identify an increasing number of unknown genotypes. Gene therapy may bring new hope to the treatment of Dent disease. The abuse of hormones and immunosuppressive agents for the treatment of Dent disease should be avoided to prevent unnecessary harm to children.
CONCLUSIONS
The current research progress in classification, genetic heterogeneity, diagnosis, and treatment of Dent disease reviewed in this paper enables doctors and researchers to better understand Dent disease and provides a basis for improved prevention and treatment.
Topics: Dent Disease; Humans; Mutation
PubMed: 32248351
DOI: 10.1007/s12519-020-00357-1 -
Pediatric Clinics of North America Feb 2019Dent disease is an X-linked form of chronic kidney disease characterized by hypercalciuria, low molecular weight proteinuria, nephrocalcinosis, and proximal tubular... (Review)
Review
Dent disease is an X-linked form of chronic kidney disease characterized by hypercalciuria, low molecular weight proteinuria, nephrocalcinosis, and proximal tubular dysfunction. Clinical presentation is highly variable. Male patients may present with early-onset rickets, recurrent nephrolithiasis, or insidiously with asymptomatic proteinuria or chronic kidney disease. Mutations in both the CLCN5 and OCRL1 genes have been associated with the Dent phenotype and are now classified as Dent-1 and Dent-2, respectively. This article describes the clinical presentation, laboratory evaluation, genetics, pathophysiology, management, and future therapies of Dent disease.
Topics: Child; Dent Disease; Diagnosis, Differential; Disease Progression; Humans
PubMed: 30454742
DOI: 10.1016/j.pcl.2018.09.003 -
Orphanet Journal of Rare Diseases Oct 2010Dent's disease is a renal tubular disorder characterized by manifestations of proximal tubule dysfunction, including low-molecular-weight proteinuria, hypercalciuria,... (Review)
Review
Dent's disease is a renal tubular disorder characterized by manifestations of proximal tubule dysfunction, including low-molecular-weight proteinuria, hypercalciuria, nephrolithiasis, nephrocalcinosis, and progressive renal failure. These features are generally found in males only, and may be present in early childhood, whereas female carriers may show a milder phenotype. Prevalence is unknown; the disorder has been reported in around 250 families to date. Complications such as rickets or osteomalacia may occur. The disease is caused by mutations in either the CLCN5 (Dent disease 1) or OCRL1 (Dent disease 2) genes that are located on chromosome Xp11.22 and Xq25, respectively. CLCN5 encodes the electrogenic Cl⁻/H(+) exchanger ClC-5, which belongs to the CLC family of Cl⁻ channels/transporters. OCRL1 encodes a phosphatidylinositol bisphosphate (PIP₂) 5-phosphatase and mutations are also associated with Lowe Syndrome. The phenotype of Dent's disease is explained by the predominant expression of ClC-5 in the proximal tubule segments of the kidney. No genotype-phenotype correlation has been described thus far, and there is considerable intra-familial variability in disease severity. A few patients with Dent's disease do not harbour mutations in CLCN5 and OCRL1, pointing to the involvement of other genes. Diagnosis is based on the presence of all three of the following criteria: low-molecular-weight proteinuria, hypercalciuria and at least one of the following: nephrocalcinosis, kidney stones, hematuria, hypophosphatemia or renal insufficiency. Molecular genetic testing confirms the diagnosis. The differential diagnosis includes other causes of generalized dysfunction of the proximal tubules (renal Fanconi syndrome), hereditary, acquired, or caused by exogenous substances. Antenatal diagnosis and pre-implantation genetic testing is not advised. The care of patients with Dent's disease is supportive, focusing on the treatment of hypercalciuria and the prevention of nephrolithiasis. The vital prognosis is good in the majority of patients. Progression to end-stage renal failure occurs between the 3rd and 5th decades of life in 30-80% of affected males.
Topics: Chloride Channels; Dent Disease; Female; Humans; Hypercalciuria; Kidney Diseases; Male; Mutation; Nephrocalcinosis; Nephrolithiasis; Phosphoric Monoester Hydrolases; Proteinuria
PubMed: 20946626
DOI: 10.1186/1750-1172-5-28 -
Function (Oxford, England) 2020Dent disease (DD) is a rare kidney disorder caused by mutations in the Cl/H exchanger ClC-5. Extensive physiologic characterization of the transporter has begun to... (Review)
Review
Dent disease (DD) is a rare kidney disorder caused by mutations in the Cl/H exchanger ClC-5. Extensive physiologic characterization of the transporter has begun to illuminate its role in endosomal ion homeostasis. Nevertheless, we have yet to understand how loss of ClC-5 function in the kidney proximal tubule impairs membrane traffic of megalin and cubilin receptors to cause the low molecular weight proteinuria characteristic of DD. This review identifies open questions that remain to be answered, evaluates the current literature addressing these questions, and suggests new testable models that may link loss of ClC-5 function to tubular proteinuria in DD.
Topics: Humans; Dent Disease; Endocytosis; Chloride Channels; Kidney Tubules, Proximal; Proteinuria
PubMed: 33015630
DOI: 10.1093/function/zqaa017 -
Journal of Cellular and Molecular... Nov 2019This review examines calcium and phosphate transport in the kidney through the lens of the rare X-linked genetic disorder Dent disease. Dent disease type 1 (DD1) is... (Review)
Review
This review examines calcium and phosphate transport in the kidney through the lens of the rare X-linked genetic disorder Dent disease. Dent disease type 1 (DD1) is caused by mutations in the CLCN5 gene encoding ClC-5, a Cl /H antiporter localized to early endosomes of the proximal tubule (PT). Phenotypic features commonly include low molecular weight proteinuria (LMWP), hypercalciuria, focal global sclerosis and chronic kidney disease; calcium nephrolithiasis, nephrocalcinosis and hypophosphatemic rickets are less commonly observed. Although it is not surprising that abnormal endosomal function and recycling in the PT could result in LMWP, it is less clear how ClC-5 dysfunction disturbs calcium and phosphate metabolism. It is known that the majority of calcium and phosphate transport occurs in PT cells, and PT endocytosis is essential for calcium and phosphorus reabsorption in this nephron segment. Evidence from ClC-5 KO models suggests that ClC-5 mediates parathormone endocytosis from tubular fluid. In addition, ClC-5 dysfunction alters expression of the sodium/proton exchanger NHE3 on the PT apical surface thus altering transcellular sodium movement and hence paracellular calcium reabsorption. A potential role for NHE3 dysfunction in the DD1 phenotype has never been investigated, either in DD models or in patients with DD1, even though patients with DD1 exhibit renal sodium and potassium wasting, especially when exposed to even a low dose of thiazide diuretic. Thus, insights from the rare disease DD1 may inform possible underlying mechanisms for the phenotype of hypercalciuria and idiopathic calcium stones.
Topics: Animals; Calcium; Dent Disease; Humans; Ion Channels; Ion Transport; Phosphates
PubMed: 31472005
DOI: 10.1111/jcmm.14590 -
Pediatric Nephrology (Berlin, Germany) Oct 2017Dent disease is a rare X-linked recessive proximal tubulopathy caused by mutations in CLCN5 (Dent-1) or OCRL (Dent-2). As a rule, total protein excretion (TPE) is low in... (Review)
Review
BACKGROUND
Dent disease is a rare X-linked recessive proximal tubulopathy caused by mutations in CLCN5 (Dent-1) or OCRL (Dent-2). As a rule, total protein excretion (TPE) is low in tubular proteinuria compared with glomerular disease. Several authors have reported nephrotic-range proteinuria (NP) and glomerulosclerosis in Dent disease. Therefore, we aimed to analyze protein excretion in patients with documented CLCN5 or OCRL mutations in a systematic literature review.
DESIGN
PubMed and Embase were searched for cases with documented CLCN5 or OCRL mutations and (semi-)quantitative data on protein excretion. The most reliable data (i.e., TPE > protein-creatinine ratio > Albustix) was used for NP classification.
RESULTS
Data were available on 148 patients from 47 reports: 126 had a CLCN5 and 22 an OCRLmutation. TPE was not significantly different between both forms (p = 0.11). Fifty-five of 126 (43.7 %) Dent-1 vs 13/22 (59.1 %) Dent-2 patients met the definition of NP (p = 0.25). Serum albumin was normal in all reported cases (24/148). Glomerulosclerosis was noted in 20/32 kidney biopsies and was strongly related to tubulointerstitial fibrosis, but not to kidney function or proteinuria.
CONCLUSION
More than half of the patients with both forms of Dent disease have NP, and the presence of low molecular weight proteinuria in a patient with NP in the absence of edema and hypoalbuminemia should prompt genetic testing. Even with normal renal function, glomerulosclerosis and tubulointerstitial fibrosis are present in Dent disease. The role of proteinuria in the course of the disease needs to be examined further in longitudinal studies.
Topics: Biopsy; Chloride Channels; Dent Disease; Genetic Testing; Humans; Kidney; Mutation; Nephritis, Interstitial; Phosphoric Monoester Hydrolases; Proteinuria; Renal Elimination; Serum Albumin
PubMed: 27757584
DOI: 10.1007/s00467-016-3499-x -
Intractable & Rare Diseases Research Feb 2023Dent disease is an X-linked recessive renal tubular disorder, which is mainly caused by mutations of the gene and gene. It is characterized by low molecular weight...
Dent disease is an X-linked recessive renal tubular disorder, which is mainly caused by mutations of the gene and gene. It is characterized by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis or nephrolithiasis, and progressive renal failure. Nephrotic syndrome is a glomerular disorder characterized by massive proteinuria, hypoalbuminemia, edema, and hyperlipidemia. In this study, we report two cases of Dent disease manifesting as nephrotic syndrome. Two patients were initially diagnosed with nephrotic syndrome due to edema, nephrotic range proteinuria, hypoalbuminemia, and hyperlipidemia, and responded to prednisone and tacrolimus therapy. Genetic testing revealed mutations in the and genes. They were eventually diagnosed with Dent disease. Nephrotic syndrome is a rare and insidious phenotype of Dent disease, and its pathogenesis is not fully understood. Patients with nephrotic syndrome are recommended to routinely undergo urinary protein classification and urinary calcium testing, especially those with frequently recurrent nephrotic syndrome and poor response to steroid and immunosuppressive therapy. To date, there is no effective drug treatment for Dent disease. About 30% to 80% of patients progress to end-stage renal disease at the age of 30-50.
PubMed: 36873671
DOI: 10.5582/irdr.2022.01125 -
Clinical Kidney Journal Aug 2014Dent-Wrong disease, an X-linked recessive disorder of the proximal tubules, presents with hypercalciuria, nephrocalcinosis, nephrolithiasis, renal insufficiency,... (Review)
Review
Dent-Wrong disease, an X-linked recessive disorder of the proximal tubules, presents with hypercalciuria, nephrocalcinosis, nephrolithiasis, renal insufficiency, low-molecular-weight proteinuria, rickets and/or osteomalacia. Dent and Friedman initially characterized the disorder in 1964 following studies of two patients with rickets who presented with hypercalciuria, hyperphosphaturia, proteinuria and aminoaciduria. Since then, extensive investigation identified two genetic mutations (CLCN5 and OCRL1) to be associated with Dent-Wrong disease. Clinical features supported by laboratory findings consistent with proximal tubule dysfunction help diagnose Dent-Wrong disease. Genetic analysis supports the diagnosis; however, these two genes can be normal in a small subset of patients. The differential diagnosis includes other forms of the Fanconi syndrome, which can be hereditary or acquired (e.g. those related to exposure to exogenous substances). Treatment is supportive with special attention to the prevention of nephrolithiasis and treatment of hypercalciuria. We review the rare forms of Fanconi syndrome with special attention to Dent-Wrong disease.
PubMed: 25852908
DOI: 10.1093/ckj/sfu070 -
Gene Jul 2020Proteinuria is a well-known risk factor, not only for renal disorders, but also for several other problems such as cardiovascular diseases and overall mortality. In the... (Review)
Review
Proteinuria is a well-known risk factor, not only for renal disorders, but also for several other problems such as cardiovascular diseases and overall mortality. In the kidney, the chloride channel Cl/H exchanger ClC-5 encoded by the CLCN5 gene is actively involved in preventing protein loss. This action becomes evident in patients suffering from the rare proximal tubulopathy Dent disease because they carry a defective ClC-5 due to CLCN5 mutations. In fact, proteinuria is the distinctive clinical sign of Dent disease, and mainly involves the loss of low-molecular-weight proteins. The identification of CLCN5 disease-causing mutations has greatly improved our understanding of ClC-5 function and of the ClC-5-related physiological processes in the kidney. This review outlines current knowledge regarding the CLCN5 gene and its protein product, providing an update on ClC-5 function in tubular and glomerular cells, and focusing on its relationship with proteinuria and Dent disease.
Topics: Animals; Chloride Channels; Dent Disease; Endocytosis; Humans; Kidney; Mutation; Phenotype
PubMed: 32289351
DOI: 10.1016/j.gene.2020.144662