Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033687 (proteinuria)
 24,015 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Renal stone disease, which affects 12% of males and 5% of females by the seventh decade, occurs as an inherited disorder in 45% of patients and is most commonly associated with hypercalciuria. The biochemical basis for hereditary nephrolithiasis and hypercalciuria is unknown, and this has therefore been investigated by a "positional cloning" approach. As a first step in this approach, the chromosomal locations of two disorders referred to as Dent's disease and X-linked recessive nephrolithiasis (XRN) were determined. These two disorders, which represent unusual forms of the renal Fanconi syndrome, are characterized by a low molecular weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis and renal failure. An X-linked inheritance for XRN was established by studies of a North American kindred, and a similar inheritance for Dent's disease was indicated by the observation of a greater disease severity in males and an absence of male-to-male transmission in five British families. X-linked polymorphic genetic markers were used in linkage studies of these families, and the genes causing Dent's disease and XRN were mapped to Xp11. In addition, in one family with Dent's disease, a microdeletion involving the DNA probe M27 beta was identified. This microdeletion was further characterized by using yeast artificial chromosomes (YACs) and its size was estimated to be 515 Kb. A search for renal-expressed genes from this region identified a novel gene encoding a chloride channel (CLCN5) with similarities to a family of voltage-gated chloride channels. Molecular genetic studies of CLCN5 demonstrated that mutations, which resulted in a functional loss, were associated with Dent's disease and XRN. In addition, such CLCN5 mutations that would result in a functional loss have also been demonstrated in Japanese children with idiopathic low molecular weight proteinuria, hypercalciuria and nephrocalcinosis, and an Italian kindred with X-linked recessive hypophosphatemic rickets (XLRH) and hypercalciuria. Thus, four hereditary disorders of nephrolithiasis are due to mutations of the novel chloride channel, CLCN5.
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PMID:Pathogenesis of Dent's disease and related syndromes of X-linked nephrolithiasis. 1072 Sep 30

ClC-5 is a chloride channel whose gene mutations have been reported to be associated with X-linked nephrolithiasis (XRN), X-linked recessive hypophosphatemic rickets (XLRH), Dent disease, and idiopathic low-molecular-weight proteinuria (ILMWP) in Japanese children. To establish more efficient screening for CLCN5 abnormalities, we developed a new diagnostic method using reverse transcription and polymerase chain reaction (RT-PCR) of cultured renal tubular cells from the urine of patients. Using this new method, we successfully detected microdeletion of ClC-5 mRNA in a patient and splicing abnormality of the CLCN5 Cl channel.
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PMID:A new approach to mRNA in proximal tubule cells of patients with CLCN5 channelopathy. 1126 75

Incidental findings of rare diseases in organ donors can be seen in allograft biopsies that may have profound implications for the recipient and for the donor and their family. Fabry disease is an X-linked recessive lipid storage disease with cardiovascular, renal and lenticular abnormalities. Phenotypic expression in female heterozygote carriers depends on lyonization. Minimal data exists on outcomes of transplanted kidneys from carriers of Fabry disease. We report a patient with ESRD secondary to focal sclerosis who received a HLA-identical transplant from her sister whose pretransplant donor work up was completely negative. Post-transplant, while pregnant, the recipient developed increasing proteinuria and was biopsied. The biopsy showed extensive myelin figures consistent with Fabry disease. Subsequent genetic, enzymatic and pedigree analysis confirmed the diagnosis in the recipient, the donor and the donor's son. Two years post-transplant the patient continues to have non-nephrotic range proteinuria with normal serum creatinine.
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PMID:Fabry disease in a renal allograft. 1285 41

Mutations in the CLCN5 gene have been detected in Dent's disease and its phenotypic variants (X-linked recessive nephrolithiasis, X-linked recessive hypophosphatemic rickets, and idiopathic low-molecular-weight proteinuria of Japanese children). Dent's disease is a tubular disorder characterized by low-molecular-weight proteinuria, and nephrolithiasis associated with nephrocalcinosis and hypercalciuria. ClC-5 is the first chloride channel for which a definitive role in the trafficking and acidification-dependent recycling of apical membrane proteins has been established. In the course of CLCN5 SSCP analysis in patients with hypercalciuric nephrolithiasis, we detected a novel mutation at intron 2 of the CLCN5 gene, a T-to-G substitution, located 17 bp upstream of the AG acceptor site. To determine the effect of IVS2-17 T>G mutation on the correct splicing of intron 2, we studied ClC-5 transcripts in a patient's peripheral blood leukocytes by means of quantitative comparative RT/PCR, and found a new ClC-5 5' UTR isoform characterized by the untranslated exon 1b and by retention of intron 1b. This new isoform--isoform B1--was not correlated with mutation since it was detected also in control leukocytes and in renal tissues of kidney donors, thus confirming its physiological role. By RACE analysis we determined the putative transcriptional start site which is located at intron 1a, 251 nt upstream of the first nucleotide of the untranslated exon 1b. ORF analysis revealed that intron 1b retention in isoform B1 stabilizes the initiation of translation to the AGT at position 297 of the ClC-5 cDNA coding region.
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PMID:Identification of a novel splice site mutation of CLCN5 gene and characterization of a new alternative 5' UTR end of ClC-5 mRNA in human renal tissue and leukocytes. 1467 7

Fabry disease is an under-recognized X-linked recessive lysosomal storage disorder resulting from the deficient activity of the enzyme alpha-galactosidase A (alpha-Gal A). The first case of Fabry disease in Slovenia was diagnosed in 1991. This 46 year-old male was referred for dermatologic evaluation of a purpura on his abdomen. He was being treated for proteinuria and cardiac symptoms. The diagnosis of angiokeratoma corporis diffusa (Fabry disease) was made clinically and confirmed by demonstration of the deficient leukocyte alpha-Gal A activity. The patient subsequently developed cerebrovascular symptoms, coronary disease, and renal failure, and died from a recurrent myocardial infarction. Family studies identified several other affected males and carrier female relatives with this X-linked recessive disorder. This case illustrates the typical multi-manifestations of this inherited disease which now can be safely and effectively treated by enzyme replacement therapy. Early diagnosis is important for the most effective treatment of this disease.
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PMID:Fabry disease. A case report. 1581 41

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

Fabry disease is an X-linked recessive lysosomal storage disorder resulting from the deficiency of alpha-galactosidase. This disease causes endothelial vasculopathy and affects multiple organ systems. Hemizygous male patients represent the classical renal, cardiac and neurological symptoms of disease. Heterozygous female carriers are frequently asymptomatic, but cerebrovascular events in females are as frequent as in males. Even if rarely seen, neurological damage is an important cause of morbidity. Severe neurological signs that are due to multifocal small vessel occlusions may be present without major thrombosis. In this report, we present a 33-year-old female patient with recurrent neurological deficits secondary to multifocal small vessel involvements. The case had previously been misdiagnosed as multiple sclerosis. Cerebral MRI revealed hyperintense lesions located in bilateral thalamus, supratentorial areas, and left cerebellum. Laboratory and radiological investigations were performed for differential diagnosis, but the etiology could not be identified. During follow-up period, skin lesions and proteinuria were detected. The dermatological, neurological, laboratory, and radiological findings were all suggestive of Fabry disease and the diagnosis was confirmed by subsequent enzyme assays. Fabry disease should be considered in young patients with unexplained stroke-like episodes, especially in those who have infarction in the vertebrobasilar arterial system, angiokeratomas, and proteinuria.
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PMID:Fabry disease mimicking multiple sclerosis. 1723 36

Fabry disease (FD), the second most common type of lysosomal storage disease (LSD), is one of 41 disorders characterized by accumulation of substances normally degraded within lysosomes. It is an X-linked recessive disorder characterized by a deficiency of lysosomal alpha-galactosidase A (alpha-Gal A). The locus for human alpha-Gal A is located on the Xq22 chromosome. Most FD mutations are confined to a single family. Although FD is an X-linked disorder, up to one third of female carriers develop clinical manifestations of the disease. It typically presents during infancy or adolescence with crisis of neuropathic pain (acroparesthesia), angiokeratomas, and asymptomatic corneal lesions. As Gb3 deposition progresses, clinical manifestations occur in other organs. Patients typically die in the fourth or fifth decade of life due to cardiac, renal or cerebrovascular complications. Usually, there is diffuse deposition of glycosphingolipid in the renal glomeruli, tubules, interstitium, and vasculature. Clinically, the renal disease manifests with hypertension, microscopic hematuria (rare), moderate proteinuria, which can be in the nephrotic range, and lipiduria. End-stage renal disease can be treated with either dialysis or transplantation. Thegene for (x-Gal A was cloned and sequenced, which eventually led to production of enzyme for therapeutic use by either recombinant DNA technology or gene activation.
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PMID:Fabry kidney disease. 1765 9

Fabry disease, an X-linked recessive glycolipid storage disease, is caused by a deficiency of the lysosomal enzyme alpha-galactosidase A (alpha-Gal A), which cleaves a fatty substance called globotriaosylceramide (GL3). The abnormal storage of GL3 in blood vessel walls leads to ischemia and necrosis, particularly in blood vessels of the skin, kidneys, heart, brain, and nervous system. The aim of our study was to present the results of cadaveric kidney transplantation with enzyme alpha-Gal A therapy in a patient with Fabry disease. The patient was diagnosed with Fabry disease at the age of 33 years, based on enzymatic tests. Renal manifestations occurred a year later as proteinuria. At the age of 35 years, the glomerular filtration rate (GFR) was within the normal range. The patient received supplemental enzyme treatment with alpha-Gal (1 mg/kg every 2 weeks). At 3 months after starting supplementation, renal function worsened with serum creatinine levels at 1.7 to 1.8 mg/dL. The following months of supplementation (alpha-Gal 1 mg/kg) concurred with progressive renal dysfunction. After 27 months of supplementation at 37 years, with a creatinine value of 5.5 mg/dL, hemodialysis began and months later the patient received a cadaveric kidney graft. The patient no longer required dialysis. On postoperative day 5 the serum creatinine was 3.9 mg/dL; on day 7, 2.2 mg/dL; on day 14, 1.5 mg/dL. Enzyme supplementation began on posttransplant day 13. Renal graft function has been good during 5 months of observation with creatinine levels at 1.2 to 1.3 mg/dL. The treatment does not interfere with tacrolimus metabolism. Simultaneous chronic enzyme supplementation is the optimal treatment in the fifth stage of end-stage renal disease in Fabry disease.
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PMID:Kidney transplantation and enzyme alpha-galactosidase A therapy in patient with Fabry disease: a case report. 1802 18

Fabry disease is an X-linked recessive inborn error of glycosphingolipid metabolism caused by the deficient activity of the lysosomal enzyme, alpha-galactosidase A. Enzyme replacement therapy (ERT) for this disorder has been available in Europe since 2001. However, its effect on advanced renal failure remains controversial. We report the case of a patient whose decline in renal function was reduced by the administration of ERT (agalsidase-alpha). This reduction was more pronounced after doubling the dose of the enzyme. The rate of deterioration of eGFR went from 6.3 ml/min/year prior to the start of ERT (0.2 mg/kg) to 2 ml/min/year (0.4 mg/kg). To our knowledge, this is the first reported case of a patient with moderately impaired renal function treated with high doses of ERT and follow-up of 6 years. The data shown here suggest that ERT may have a very positive impact on renal function even in advanced stages. The role of proteinuria and its control seem to have a clear responsibility for this favorable outcome.
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PMID:Preservation of renal function in a patient with Fabry nephropathy on enzyme replacement therapy. 1853 21


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