Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0020438 (hypercalciuria)
 2,502 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dent's disease is a hereditary renal tubular disorder caused by mutations of the CLCN5 gene and is clinically characterized by low molecular weight proteinuria, hypercalciuria and nephrocalcinosis. This disease has been reported in several countries. However, there are some phenotypic differences between countries, such as hypophosphatemic rickets, progressive renal failure and hematuria. In this study, phenotypes were analyzed in three Korean boys with Dent's disease, and genetic diagnoses were performed using a new convenient method using peripheral blood RNA. Gene studies revealed two nonsense mutations, R637X in two patients and E609X in one patient. The phenotypes of the two patients with R637X were very similar to those of Japanese patients, i.e., they presented with asymptomatic proteinuria without rickets, renal failure or hematuria. The E609X patient was diagnosed genetically at 3 months of age before the onset of clinical symptoms because of superimposed furosemide-induced nephrolithiasis. This is the first report to characterize mutations in the CLCN5 gene in Korean patients with Dent's disease, and expands the spectrum of CLCN5 mutations by reporting a novel mutation, E609X. In addition, the mutational analysis using peripheral blood RNA can be easily applied in the clinical diagnosis.
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PMID:Phenotype and genotype of Dent's disease in three Korean boys. 1571 55

Although acute nonoliguric renal failure is a well-known nephrotoxic effect of aminoglycoside antibiotics, less recognized is acquired Bartter-like syndrome. Herein, we describe four female patients who presented with marked paresthesia, muscle weakness, and tetany following gentamicin therapy with total dose ranging from 1.2 g to 2.6 g. All were normotensive. Biochemical abnormalities included hypokalemia (K+ 1.8-2.3 mmol/L), metabolic alkalosis (HCO(3-) 31.9-34.2 mmol/L), hypomagnesemia (Mg2+ 0.9-1.2 mg/dL), hypermagnesiuria (fractional excretion of Mg 3-6%), hypocalcemia (free Ca2+ 2.0-4.1 mg/dL), and hypercalciuria (molar ratio of Ca2+/creatinine 0.23-0.53), all consistent with Bartter-like syndrome. Serum immunoreactive parathyroid hormone concentration was low despite the hypocalcemia. The Bartter-like syndrome lasted for 2 to 6 weeks after cessation of gentamicin, coupled with supplementation of K+, Ca2+, and Mg2+. These biochemical abnormalities resembled those seen in patients with gain-of-function mutations in the calcium-sensing receptor. We hypothesize that gentamicin, a polyvalent cationic molecule, induces the action of calcium-sensing receptor on the thick ascending loop of Henle and distal convoluted tubule to cause renal wasting of Na+, K+, Cl-, Ca2+, and Mg2+.
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PMID:Acquired bartter-like syndrome associated with gentamicin administration. 1576 21

ClC-5 is a member of the ClC family of voltage-gated chloride channels. Loss-of-function mutations of its corresponding gene (CLCN5) cause Dent's disease, an X-linked kidney disorder, characterized by low-molecular weight proteinuria, hypercalciuria, nephrocalcinosis/nephrolithiasis, and progressive renal failure. Here, we examined the effect of different mutations on function and cellular trafficking of the recombinant protein. Mutant CLCN5 cDNAs were generated by site directed mutagenesis for two premature stop codon variants (R347X and M517IfsX528), and several missense mutations (C221R, L324R, G462 V, and R516 W). We also tested L521R (instead of L521RfsX526 observed) and mutants G506E and R648X (previously reported by others). After heterologous expression in Xenopus oocytes, ClC-5 channel activity and surface expression were determined by two-electrode voltage-clamp analysis and ClC-5 surface ELISA, respectively. Except for the R516 W and R648X variants, none of the mutated proteins induced functional chloride currents or reached the plasma membrane. This is readily understandable for the truncation mutations. Yet, the tested missense mutations are distributed over different transmembrane regions, implying that correct channel structure and orientation in the membrane is not only a prerequisite for proper ClC-5 function but also for Golgi exit. Interestingly, the R648X mutant although functionally compromised, displayed a significant increase in surface expression. This finding might be explained by the deletion of a ClC-5 carboxy-terminal PY-like internalization signal, which in turn impairs channel removal from the membrane. Our observations further imply that recruitment of ClC-5 to alternative routes (plasma membrane or early endosomes) in the trans-Golgi network is mediated via different signal sequences.
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PMID:Functional evaluation of Dent's disease-causing mutations: implications for ClC-5 channel trafficking and internalization. 1589 57

Dent's disease (DD) involves nephrocalcinosis, urolithiasis, hypercalciuria, LMW proteinuria, and renal failure in various combinations. Males are affected. It is caused by mutations in the chloride channel CLCN5 gene. It has been suggested that DD is underdiagnosed, occurring in less overt forms, apparently without family history. A possible approach to this problem is to search for CLCN5 mutations in patients who may have a high prevalence of mutations: end-stage renal disease (ESRD) patients with previous calcium, struvite, or radio-opaque (CSR) stones. We looked for CLCN5 mutations in 25 males with ESRD-CSR stones selected from all of the patients (1,901 individuals, of which 1,179 were males) of 15 dialysis units in the Veneto region. One DD patient had a new DD mutation (1070 G > T) in exon 7. The new polymorphism IVS11-67 C > T was detected in intron 11 in one patient and one control. We also found 28 females with ESRD and stone history, and seven more males with ESRD and non-CSR stones. The prevalence of stone formers among dialysis patients in our region was 3.2%, much lower than the prevalence observed in older studies. Struvite stones continue to play a major role in causing stone-associated ESRD .
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PMID:Dent's disease and prevalence of renal stones in dialysis patients in Northeastern Italy. 1624 50

The rare Dent's disease manifests with medullary nephrocalcinosis, nephrolithiasis, hypercalciuria, low molecular weight proteinuria and other tubular dysfunctions, rickets or osteomalacia, and renal failure, in various combinations. It is a recessive X-linked condition. Clinicians consider family history a fundamental pointer to its diagnosis, but this is not invariably the case as clearly pointed out by the two reported cases.
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PMID:Family history may be misleading in the diagnosis of Dent's disease. 1641 11

Mutations in the gene for Claudin-16 (CLDN16) are linked to familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), a renal Mg2+ and Ca2+ wasting disorder that leads to progressive kidney failure. More than 20 mutations have been identified in CLDN16, which, with a single exception, affect one of two extracellular loops or one of four transmembrane domains of the encoded protein. Here, we describe a novel missense mutation, Cldn16 L203X, which deletes the entire C-terminal cytosolic domain of the protein. Surface expression of Cldn16 L203X is strongly reduced and the protein is instead found in the endoplasmic reticulum (ER) and lysosomes. ER-retained Cldn16 L203X is subject to proteasomal degradation. Cldn16 L203X present in lysosomes reaches this compartment following transport to the plasma membrane and endocytosis. Blocking clathrin-mediated endocytosis increases surface expression of Cldn16 L203X. Thus, endocytosis inhibitors may provide a novel therapeutic approach for FHHNC patients carrying particular Cldn16 mutations.
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PMID:Familial hypomagnesemia with hypercalciuria and nephrocalcinosis: blocking endocytosis restores surface expression of a novel Claudin-16 mutant that lacks the entire C-terminal cytosolic tail. 1650 Oct 1

We report a 66-year-old Chinese man with chronic renal insufficiency (creatinine 1.7 mg/dL) and gout suffering from slurred speech and right hemiplegia for 3 days. Acute cerebral infarction was confirmed by computed tomography. Conscious disturbance occurred on the tenth hospital day without significant changes on imaging study when compared with a previous scan. Hypercalcemia (total calcium 14.1 mg/dL) and acute exacerbation of chronic renal failure (serum creatinine 2.5 mg/dL) were noticed. Hypercalciuria (FECa 3.2%), and low serum levels of intact parathyroid hormone and 1,25(OH)2D3 suggested nonparathyroidal hypercalcemia. An extensive workup failed to identify any etiology of hypercalcemia. Hypercalcemia and renal failure were temporarily ameliorated after aggressive volume expansion and loop diuretic treatment but recurred 2 weeks later. Immobilization hypercalcemia was considered after the exclusion of other discernible causes and was successfully treated with rehabilitative exercises and bisphosphonates without further recurrence during a 2-year follow-up. Clinical alertness to immobilization as a possible cause of hypercalcemia may avoid unnecessary and invasive examinations, life-threatening complications and annoying recurrences.
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PMID:An unrecognized cause of recurrent hypercalcemia: immobilization. 1663 46

Genetic disorders of mineral metabolism cause urolithiasis, renal disease, and osteodystrophy. Most are rare, such that the full spectrum of clinical expression is difficult to appreciate. Diagnosis is further complicated by overlap of clinical features. Dent's disease and primary hyperoxaluria, inherited causes of calcium urolithiasis, are both associated with nephrocalcinosis and urolithiasis in early childhood and renal failure that can occur at any age but is seen more often in adulthood. Bone disease is an inconsistent feature of each. Dent's disease is caused by mutations of the CLCN-5 gene with impaired kidney-specific CLC-5 chloride channel expression in the proximal tubule, thick ascending limb of Henle, and the collecting ducts. Resulting hypercalciuria and proximal tubule dysfunction, including phosphate wasting, are primarily responsible for the clinical manifestations. Low-molecular-weight proteinuria is characteristic. Definitive diagnosis is made by DNA mutation analysis. Primary hyperoxaluria, type I, is due to mutations of the AGXT gene leading to deficient hepatic alanine-glyoxylate aminotransferase activity. Marked overproduction of oxalate by hepatic cells results in the hyperoxaluria responsible for clinical features. Definitive diagnosis is by liver biopsy with measurement of enzyme activity, with DNA mutation analysis used increasingly as mutations and their frequency are defined. These disorders of calcium urolithiasis illustrate the value of molecular medicine for diagnosis and the promise it provides for innovative and more effective future treatments.
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PMID:Stones, bones, and heredity. 1680 Nov 62

Hypercalciuria is regarded as a characteristic symptom of Dent disease, an X-linked recessive tubulopathy characterized by low molecular weight (LMW) proteinuria, nephrocalcinosis/nephrolithiasis, and progressive renal failure due to mutations in the CLCN5 gene. As the presence of hypercalciuria may affect the decision to consider a CLCN5 mutation in the differential diagnosis, the phenotypic spectrum and the relative frequency of hypercalciuria in patients with CLCN5 mutations was determined. We assessed renal calcium excretion in 34 male patients with proven CLCN5 mutations, who had been referred because of LMW proteinuria and at least one additional symptom of Dent disease. Hypercalciuria was defined as renal calcium excretion exceeding 0.1 mmol/kg per day. Data obtained were compared with all series of CLCN5-positive patients identified by a systematic literature survey. In 7 of our 19 families, at least 1 affected male had normal calcium excretion. Hypercalciuria was observed in 22 of 31 patients tested (71%) compared to 85 of 90 (94.4%) in series from Europe and North America and 74.4% from Japan. LMW proteinuria was present in all CLCN5-positive patients; 25% of the patients in European and North American series, 45% of the Japanese, and 41% in the present series had only two of the four principal symptoms of Dent disease. Therefore, a CLCN5 mutation should be considered irrespective of the presence of hypercalciuria in a patient with LMW proteinuria and one additional symptom of Dent disease.
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PMID:Hypercalciuria in patients with CLCN5 mutations. 1680 62

Familial Hypomagnesemia, Hypercalciuria with Nephrocalcinosis is a rare autosomal recessive inherited disease associated with renal failure. Two girls born of consanguineous parentage aged 16 and 17 presented to us with renal failure, nephrocalcinosis and bone deformities. On evaluation they were found to have hypomagnesemia, hypercalciuria, increased fractional excretion of magnesium, hypocitraturia, renal failure and elevated PTH. Their parental screening was normal. There were no extra-renal features in them. One sibling had nephrolithiasis and the stone analysis revealed calcium phosphate stones. Both were treated with sodium bicarbonate, thiazides, calcitriol and calcium carbonate. They did not require dialysis during hospital stay. Both of them were treated conservatively. They are on regular outpatient follow up. The primary defect in this syndrome is impaired paracellular reabsorption of magnesium and calcium in the medullary thick ascending limb. Mutations in the PCLN-1gene which encodes for the tight junction protein paracellin -1 is identified as the underlying genetic defect. Ocular abnormalities and deafness are the commonly reported associations. End stage renal failure usually occurs in second to third decade. Renal transplantation is the definite treatment.
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PMID:Nephrocalcinosis in siblings--familial hypomagnesemia, hypercalciuria with nephrocalcinosis (FHHNC syndrome). 1690 3


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