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      The oculocerebrorenal syndrome of Lowe: an update

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          Abstract

          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.

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          Improved equations estimating GFR in children with chronic kidney disease using an immunonephelometric determination of cystatin C

          The Chronic Kidney Disease in Children study is a cohort of about 600 children with chronic kidney disease (CKD) in the United States and Canada. The independent variable for our observations was a measurement of glomerular filtration rate (GFR) by iohexol disappearance (iGFR) at the first two visits one year apart and during alternate years thereafter. In a previous report, we had developed GFR estimating equations utilizing serum creatinine, blood urea nitrogen, height, gender and cystatin C measured by an immunoturbidimetric method; however the correlation coefficient of cystatin C and GFR (-0.69) was less robust than expected. Therefore, 495 samples were re-assayed using immunonephelometry. The reciprocal of immunonephelometric cystatin C was as well correlated with iGFR as was height/serum creatinine (both 0.88). We developed a new GFR estimating equation using a random 2/3 of 965 person-visits and applied it to the remaining 1/3 as a validation data set. In the validation data set, the correlation of the estimated GFR with iGFR was 0.92 with high precision and no bias; 91% and 45% of eGFR values were within 30% and 10% of iGFR, respectively. This equation works well in children with CKD in a range of GFR from 15 to 75 ml/min per 1.73 m2. Further studies are needed to establish the applicability to children of normal stature and muscle mass, and higher GFR.
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            The Lowe's oculocerebrorenal syndrome gene encodes a protein highly homologous to inositol polyphosphate-5-phosphatase.

            Lowe's oculocerebrorenal syndrome (OCRL) is a human X-linked developmental disorder of unknown pathogenesis and has a pleiotropic phenotype affecting the lens, brain and kidneys. The OCRL locus has been mapped to Xq25-q26 by linkage and by finding de novo X; autosome translocations at Xq25-q26 in two unrelated females with OCRL. Here we use yeast artificial chromosomes with inserts that span the X chromosomal breakpoint from a female OCRL patient in order to isolate complementary DNAs for a gene that is interrupted by the translocation. We show that the transcript is absent in both female OCRL patients with X; autosome translocations and that it is absent or abnormally sized in 9 of 13 unrelated male OCRL patients with no detectable genomic rearrangement. The open reading frame encodes a new protein with 71% similarity to human inositol polyphosphate-5-phosphatase. Our results suggest that OCRL may be an inborn error of inositol phosphate metabolism.
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              Cystatin C--a new marker of glomerular filtration rate in children independent of age and height.

              Serum creatinine is the most common endogenous marker of renal function. The proportionality between creatinine production and muscle mass requires adjustment for height and body composition. The low molecular weight protein cystatin C is produced by all nucleated cells and eliminated by glomerular filtration. Therefore, cystatin C was studied as an alternative marker of glomerular filtration rate (GFR) in children. Cystatin C and creatinine were measured in sera from inulin clearance (CIn) examinations performed in 184 children aged 0.24 to 17.96 years. CIn ranged from 7 to 209 mL/min/1.73 m (median, 77). The reciprocal of cystatin C correlated better with CIn (r = 0.88) than the reciprocal of creatinine (r = 0.72). Stepwise regression analysis identified no covariates for the correlation between cystatin C and CIn, whereas height was a covariate for creatinine. Using an estimate of GFR from serum creatinine and height, correlation with CIn was similar to cystatin C, but female gender and dystrophy were associated with an overestimation of GFR. Diagnostic accuracy in the identification of reduced GFR measured as area under the receiver-operating characteristic plot was 0.970 +/- 0.135 (mean +/- SE) for cystatin C and 0.894 +/- 0.131 for creatinine (NS). A cutoff cystatin C concentration of 1.39 mg/L had 90% sensitivity and 86% specificity for detecting abnormal GFR. Unlike creatinine, serum cystatin C reflects renal function in children independent of age, gender, height, and body composition.
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                Author and article information

                Contributors
                +31-20-4444444 , a.bokenkamp@vumc.nl
                Journal
                Pediatr Nephrol
                Pediatr. Nephrol
                Pediatric Nephrology (Berlin, Germany)
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0931-041X
                1432-198X
                24 March 2016
                24 March 2016
                2016
                : 31
                : 12
                : 2201-2212
                Affiliations
                [1 ]Department of Pediatric Nephrology, VU University Medical Center, de Boelelaan 1112, 1081 HV Amsterdam, The Netherlands
                [2 ]Department of Clinical Chemistry and Clinical Pharmacology, University of Bonn, Bonn, Germany
                Article
                3343
                10.1007/s00467-016-3343-3
                5118406
                27011217
                c33dcb6f-ab14-4fb9-ba6b-140c469cf30d
                © The Author(s) 2016

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 11 January 2016
                : 28 January 2016
                : 1 February 2016
                Categories
                Review
                Custom metadata
                © IPNA 2016

                Nephrology
                congenital cataract,cognitive and behavioral impairment,ocrl gene,oculocerebrorenal syndrome,inositol-polyphosphate 5-phosphatase,proximal tubulopathy,renal fanconi syndrome

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