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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 -
Annual Review of Physiology Feb 2017Cells lining the proximal tubule (PT) of the kidney are highly specialized for apical endocytosis of filtered proteins and small bioactive molecules from the glomerular... (Review)
Review
Cells lining the proximal tubule (PT) of the kidney are highly specialized for apical endocytosis of filtered proteins and small bioactive molecules from the glomerular ultrafiltrate to maintain essentially protein-free urine. Compromise of this pathway results in low molecular weight (LMW) proteinuria that can progress to end-stage kidney disease. This review describes our current understanding of the endocytic pathway and the multiligand receptors that mediate LMW protein uptake in PT cells, how these are regulated in response to physiologic cues, and the molecular basis of inherited diseases characterized by LMW proteinuria.
Topics: Animals; Endocytosis; Humans; Kidney Glomerulus; Kidney Tubules, Proximal; Proteinuria; Receptors, Cell Surface
PubMed: 27813828
DOI: 10.1146/annurev-physiol-022516-034234 -
Cureus Apr 2022This case report describes a boy with a rare genetic disease that primarily affects the kidneys and has implications on growth and development. Dent disease type 1 is an...
This case report describes a boy with a rare genetic disease that primarily affects the kidneys and has implications on growth and development. Dent disease type 1 is an X-linked tubulopathy mainly caused by inactivating mutations in the chloride voltage-gated channel 5 (CLCN5) gene. It is a rare but important diagnosis for children with variable phenotypic presentations that can include low molecular weight proteinuria (LMWP), nephrocalcinosis, bony deformities and possible progression to early-onset renal failure. A delay in diagnosis is often encountered when it comes to Dent disease. This is due to the similarities in presentation of the disease to other commonly seen pediatric conditions (such as minimal change nephrotic syndrome, nutritional rickets, renal tubular acidosis [RTA], etc.) and also since it can present with variable phenotypes and has a great amount of allelic heterogeneity. In this case, it was diagnosed after 13 years from symptom onset. The patient was subjected to alternative forms of medicine, multiple working diagnoses and associated treatments at various hospitals which most likely contributed to a faster disease progression. In addition to the treatment of the disease, growth hormone (GH) therapy has proven to be beneficial but was not offered to this patient. In this case, we would also like to report some rare findings such as persistent hypercholesterolemia and steroid-resistant nephrotic syndrome (SRNS) biopsy pattern. We decided to pursue this particular disease to highlight the importance of having a high clinical suspicion with a view to attain a definitive diagnosis and instituting appropriate treatment as soon as possible. We also highlight the importance of keeping the patient informed about their disease, the possible therapeutic options and the importance of genetic counselling and patient education.
PubMed: 35530822
DOI: 10.7759/cureus.23910 -
Pathogens and Global Health Dec 2022Malaria and malnutrition are major public health problems in India, especially in the rural and tribal communities, and also remain primary causes of morbidity and...
Malaria and malnutrition are major public health problems in India, especially in the rural and tribal communities, and also remain primary causes of morbidity and mortality among children younger than five years. Both diseases are synergistic with each other. It is essential to have a better understanding of the intricate relationships between malnutrition and malaria to target interventions in areas where both diseases coexist. This article highlights the synergistic relationship between malnutrition and malaria, and how malnutrition and malaria play a significant role in disease severity and eventually hinder the elimination of these diseases by 2030. The government and several private sectors have made a substantial dent through various programmes and schemes. However, supplementing nutrition-sensitive measures, including easy accessibility to a healthy balanced diet, safe drinking water and improved sanitation, is necessary. Therefore, if India really aims to achieve its dream of disease elimination (malaria and all forms of malnutrition) by 2030, it is imperative that tribal regions are given more attention and all possible strategies are applied in the country's remotest corners.
Topics: Child; Humans; Malnutrition; Nutritional Status; Malaria; Sanitation; Disease Eradication; India
PubMed: 35818754
DOI: 10.1080/20477724.2022.2100190 -
World Journal of Nephrology Jan 2017Dent's disease is an X-linked renal tubulopathy characterized by low molecular weight proteinuria, hypercalciuria and progressive renal failure. Disease aetiology is... (Review)
Review
Dent's disease is an X-linked renal tubulopathy characterized by low molecular weight proteinuria, hypercalciuria and progressive renal failure. Disease aetiology is associated with mutations in the gene coding for the electrogenic 2Cl/H antiporter chloride channel 5 (CLC-5), which is expressed in the apical endosomes of renal proximal tubules with the vacuolar type H-ATPase (V-ATPase). Initially identified as a member of the CLC family of Cl channels, CLC-5 was presumed to provide Cl shunt into the endosomal lumen to dissipate H accumulation by V-ATPase, thereby facilitating efficient endosomal acidification. However, recent findings showing that CLC-5 is in fact not a Cl channel but a 2Cl/H antiporter challenged this classical shunt model, leading to a renewed and intense debate on its physiological roles. Cl accumulation CLC-5 is predicted to play a critical role in endocytosis, as illustrated in mice carrying an artificial Cl channel mutation E211A that developed defective endocytosis but normal endosomal acidification. Conversely, a recent functional analysis of a newly identified disease-causing Cl channel mutation E211Q in a patient with typical Dent's disease confirmed the functional coupling between V-ATPase and CLC-5 in endosomal acidification, lending support to the classical shunt model. In this editorial, we will address the current recognition of the physiological role of CLC-5 with a specific focus on the functional coupling of V-ATPase and CLC-5.
PubMed: 28101447
DOI: 10.5527/wjn.v6.i1.14 -
Kidney International Reports Jun 2023Dent disease is an X-linked recessive disorder associated with low molecular weight proteinuria (LMWP), nephrocalcinosis, kidney stones, and kidney failure in the third...
INTRODUCTION
Dent disease is an X-linked recessive disorder associated with low molecular weight proteinuria (LMWP), nephrocalcinosis, kidney stones, and kidney failure in the third to fifth decade of life. It consists of Dent disease 1 (DD1) (60% of patients) because of pathogenic variants in the gene and Dent disease 2 (DD2) with changes in .
METHODS
Retrospective review of 162 patients from 121 different families with genetically confirmed DD1 (82 different pathogenic variants validated using American College of Medical Genetics [ACMG] guidelines). Clinical and genetic factors were compared using observational statistics.
RESULTS
A total of 110 patients had 51 different truncating (nonsense, frameshifting, large deletions, and canonical splicing) variants, whereas 52 patients had 31 different nontruncating (missense, in-frame, noncanonical splicing, and stop-loss) changes. Sixteen newly described pathogenic variants were found in our cohort. Among patients with truncating variants, lifetime stone events positively correlated with chronic kidney disease (CKD) evolution. Patients with truncating changes also experienced stone events earlier in life and manifested a higher albumin excretion rate than the nontruncating group. Nevertheless, neither age of nephrocalcinosis nor CKD progression varied between the truncating versus nontruncating patients. A large majority of nontruncating changes (26/31; 84%) were clustered in the middle exons that encode the voltage ClC domain whereas truncating changes were spread across the protein. Variants associated with kidney failure were restricted to truncating (11/13 cases), plus a single missense variant previously shown to markedly reduce ClC-5 functional activity that was found in the other 2 individuals.
CONCLUSION
DD1 manifestations, including the risk of kidney stones and progression to kidney failure, may relate to the degree of residual ClC-5 function.
PubMed: 37284679
DOI: 10.1016/j.ekir.2023.03.012 -
Pediatric Nephrology (Berlin, Germany) Dec 2016The oculocerebrorenal syndrome of Lowe is a rare X-linked multisystemic disorder characterized by the triad of congenital cataracts, intellectual disability, and... (Review)
Review
The oculocerebrorenal syndrome of Lowe is a rare X-linked multisystemic disorder characterized by the triad of congenital cataracts, intellectual disability, and proximal renal tubular dysfunction. Whereas the ocular manifestations and severe muscular hypotonia are the typical first diagnostic clues apparent at birth, the manifestations of incomplete renal Fanconi syndrome are often recognized only later in life. Other characteristic features are progressive severe growth retardation and behavioral problems, with tantrums. Many patients develop a debilitating arthropathy. Treatment is symptomatic, and the life span rarely exceeds 40 years. The causative oculocerebrorenal syndrome of Lowe gene (OCRL) encodes the inositol polyphosphate 5-phosphatase OCRL-1. OCRL variants have not only been found in classic Lowe syndrome, but also in patients with a predominantly renal phenotype classified as Dent disease type 2 (Dent-2). Recent data indicate that there is a phenotypic continuum between Dent-2 disease and Lowe syndrome, suggesting that there are individual differences in the ability to compensate for the loss of enzyme function. Extensive research has demonstrated that OCRL-1 is involved in multiple intracellular processes involving endocytic trafficking and actin skeleton dynamics. This explains the multi-organ manifestations of the disease. Still, the mechanisms underlying the wide phenotypic spectrum are poorly understood, and we are far from a causative therapy. In this review, we provide an update on clinical and molecular genetic findings in Lowe syndrome and the cellular and physiological functions of OCRL-1.
Topics: Adolescent; Child; Child, Preschool; Chromosome Deletion; Chromosomes, Human, Pair 11; Humans; Infant; Infant, Newborn; Molecular Biology; Mutation; Oculocerebrorenal Syndrome; WAGR Syndrome
PubMed: 27011217
DOI: 10.1007/s00467-016-3343-3 -
Journal of Pediatric Genetics Jun 2013The oculocerebrorenal syndrome of Lowe is a rare X-linked multisystemic disorder characterized by the triad of congenital cataracts, cognitive and behavioral impairment... (Review)
Review
The oculocerebrorenal syndrome of Lowe is a rare X-linked multisystemic disorder characterized by the triad of congenital cataracts, cognitive and behavioral impairment and a renal proximal tubulopathy in almost all of the patients. Whereas the ocular manifestations and severe hypotonia are present at birth, the renal involvement appears within the first months of life. Patients show progressive growth retardation and may develop a debilitating arthropathy. Treatment is symptomatic and life span rarely exceeds 40 yr. The causative OCRL gene, encodes an inositol polyphosphate 5-phosphatase. OCRL mutations were not only found in classic Lowe syndrome, but also in milder affected patients, classified as having Dent-2 disease. There is a phenotypic continuum within patients with Dent-2 disease and Lowe syndrome, suggesting that there are individual differences in the ability to compensate for loss of enzyme function. Researchers have conducted a large amount of work to understand the etiology responsible for the disease. However, the mechanisms leading to the clinical manifestations are still poorly understood and we are far from an effective therapy. In this review, we have included well-established findings and the most recent progress in understanding Lowe syndrome and Dent-2 disease.
PubMed: 27625841
DOI: 10.3233/PGE-13049 -
The Dental Register Nov 1867
PubMed: 33696823
DOI: No ID Found -
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