Characterization of carrier females and affected males with X-linked recessive nephrolithiasis.

Abstract

X-linked recessive nephrolithiasis (XRN) was described in a large kindred in which nephrolithiasis; proximal tubular dysfunction, proteinuria, nephrocalcinosis, and renal failure occur only in males. Carrier females are asymptomatic, but formal studies of them have not been done. The gene for XRN has been mapped to the pericentromeric region of the X chromosome, close to the loci for several eye disease genes. We studied six affected males, 13 carrier females, and 25 normal members of this family including 7 females whose genetic haplotype predicted them to be carriers. Studies were done in the Clinical Research Unit on a diet containing 400 mg of calcium and 2 g of sodium, and by an additional outpatient urine collection was obtained on a 1-g calcium intake. Hypercalciuria occurred in five of six affected males, 4 of 12 carrier females, and three of seven predicted carriers. Significant proteinuria was present in all affected males and in no other subjects. Low-molecular-weight proteinuria was present in all affected males: the excretion of alpha 1-microglobulin exceeded normal by 3- to 14-fold, of beta 2-microglobulin exceeded normal by 100- to 400-fold, and of retinol-binding protein exceeded normal by 1,000- to 3,000-fold. The excretion of these proteins was less strikingly elevated in carrier females, but the excretion of alpha 1-microglobulin was abnormal in 9 of 15 carriers, beta 2-microglobulin was abnormal in 12 of 15, and retinolbinding protein in was abnormal 12 of 13, and this pattern was similar in predicted carriers. The urinary concentrating ability was abnormal in four affected males with renal insufficiency but normal in all other subjects. Urinary wasting of potassium, phosphorous, and glucose occurred infrequently, and no subject was hypouricemic. Formal ophthalmologic studies were normal in five affected males. Thus, the most consistent urinary abnormalities in XRN are hypercalciuria and low-molecular-weight proteinuria, the latter of which appears to be a marker for the carrier state.

Dent’s disease as a rare cause of proteinuria

“…Choroba rozwija się zazwyczaj u chłopców i może rozpocząć się we wczesnym dzieciństwie. U kobiet niekiedy występuje łagodny fenotyp choroby [2]. Rozpoznanie choroby Denta oparte jest na stwierdzeniu trzech objawów: LMVP (low molecular weight protieinuria), hiperkalciurii oraz jednego z następujących objawów: nefrokalcynozy, kamicy nerkowej, hematurii, hipofosfatemii lub niewydolności nerek [3,4].…”

The Role of the Endosomal Chloride/Proton Antiporter ClC-5 in Proximal Tubule Endocytosis and Kidney Physiology

“…Dent's disease patients are affected by malfunctions of the proximal renal tubule, leading to progressive proteinuria, hyperphosphaturia, hypercalciuria and nephrolithiasis and consequent renal failure (Dent and Friedman, 1964, Fisher et al, 1994, Lloyd et al, 1996, Pook et al, 1993. Female carriers show in general a milder phenotype possibly due to random X chromosome inactivation (Wrong et al, 1994, Reinhart et al, 1995.…”

Characterization of pre-mRNA Splicing Defects Caused by CLCN5 and OCRL Mutations and Identification of Novel Variants Associated with Dent Disease

“…A minority of patients develop rickets or osteomalacia [6,7]. In the case of female carriers, the phenotype is usually mild, rarely presenting nephrocalcinosis or chronic renal failure, probably due to the random inactivation of one of the two X chromosomes [5,8,9].…”