Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0035078 (renal failure)
 31,970 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Primary hyperoxaluria type 1 is an autosomal recessive inherited metabolic disease in which excessive oxalates are formed by the liver and excreted by the kidneys, causing a wide spectrum of phenotypes ranging from renal failure in infancy to mere renal stones in late adulthood. Mutations in the AGXT gene, encoding the liver-specific enzyme alanine:glyoxylate aminotransferase, are responsible for the disease. Seven mutations were detected in eight families in Israel. Four of these mutations are novel and three occur in children living in single-clan villages. The mutations are scattered along various exons (1, 4, 5, 7, 9, 10), and on different alleles comprising at least five different haplotypes. All but one of the mutations are in a homozygous pattern, reflecting the high rate of consanguinity in our patient population. Two affected brothers are homozygous for two different mutations expressed on the same allele. The patients comprise a distinct ethnic group (Israeli Arabs) residing in a confined geographic area. These results, which are supported by previous data, suggest for the first time that the phenomenon of multiple mutations in a relatively closed isolate is common and almost exclusive to the Israeli-Arab population. Potential mechanisms including selective advantage to heterozygotes, digenic inheritance, and the recent emergence of multiple mutations are discussed.
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PMID:Primary hyperoxaluria type I: a model for multiple mutations in a monogenic disease within a distinct ethnic group. 1054 Dec 94

Primary hyperoxaluria type I is an autosomal recessive metabolic disease in which excessive oxalates are formed by the liver and excreted by the kidneys, causing a wide spectrum of disease, ranging from renal failure in infancy to mere renal stones in late adulthood. The diagnosis may be suspected when clinical signs and increased urinary oxalate and glycolate excretion present, and is confirmed by the measurement of decreased alanine:glyoxylate aminotransferase activity in a liver sample. The enzymatic assay is not readily available to pediatric nephrologists in many parts of the world. We describe three families from Croatia in whom the diagnosis of primary hyperoxaluria was solely based on clinical findings that included nephrolithiasis and nephrocalcinosis accompanied by increased urinary oxalates and glycolate excretion, as enzymatic assays of liver samples could not be performed. Mutation analysis of the AGXT gene encoding the defective enzyme confirmed the diagnosis, revealing three alleles carrying the C156ins mutation and two the G630A mutation. Screening first-degree relatives for the relevant mutation disclosed an asymptomatic affected sibling. Mutation analysis of the AGXT gene is a non-invasive and accurate tool for the diagnosis of type I primary hyperoxaluria that may replace enzymatic assays of liver biopsies.
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PMID:Genetic analysis--a diagnostic tool for primary hyperoxaluria type I. 1268 63

Primary hyperoxaluria type 1 (PH1) is an autosomal recessive disorder of glyoxylate metabolism, in which excessive oxalates are formed by the liver and excreted by the kidneys, causing a wide spectrum of disease, ranging from renal failure in infancy to mere renal stones in late adulthood. This disease is caused by a deficiency of alanine:glyoxylate aminotransferase (AGT), which is encoded by a single copy gene, AGXT, located in 2q37.3. We identified an apparently homozygous, loss-of-function, mutation in a patient; the gene defect was present in the heterozygous mother but not in the patient's father. We performed a microsatellite repeat analysis using 13 specific chromosome 2 markers and non-chromosome 2 minisatellites. Six specific chromosome 2 markers showed an apparently homozygous maternal inheritance while four showed a biparental transmission consistent with paternity (confirmed by minisatellite analysis). Quantitative PCR of AGXT exons 1 and 3 on the patient's and parents genomic DNA revealed the presence of two copies of the gene. This is the first case of PH1 caused by segmental maternal isodisomy of 2q37.3.
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PMID:Maternal isodisomy of the telomeric end of chromosome 2 is responsible for a case of primary hyperoxaluria type 1. 1558 Jun 38

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

Primary hyperoxaluria type I (PH1) is an inborn error of metabolism caused by deficiency of the hepatic enzyme alanine-glyoxylate aminotransferase (AGXT or AGT) which leads to overproduction of oxalate by the liver and subsequent urolithiasis and renal failure. The current therapy largely depends on liver transplantation, which is associated with significant morbidity and mortality. To explore an alternative treatment, we used somatic gene transfer in a mouse genetic model for PH1 (Agxt1KO). Recombinant adeno-associated virus (AAV) vectors containing the human AGXT complementary DNA (cDNA) were pseudotyped with capsids from either serotype 8 or 5, and delivered to the livers of Agxt1KO mice via the tail vein. Both AAV8-AGXT and AAV5-AGXT vectors were able to reduce oxaluria to normal levels. In addition, treated mice showed blunted increase of oxaluria after challenge with ethylene glycol (EG), a glyoxylate precursor. In mice, AGT enzyme activity in whole liver extracts were restored to normal without hepatic toxicity nor immunogenicity for the 50 day follow-up. In summary, this study demonstrates the correction of primary hyperoxaluria in mice treated with either AAV5 or AAV8 vectors.
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PMID:Phenotypic correction of a mouse model for primary hyperoxaluria with adeno-associated virus gene transfer. 2111 25

Primary hyperoxaluria type 1 (PH1) and type 2 (PH2) are rare genetic diseases that result from deficiencies in glyoxylate metabolism. The increased oxalate synthesis that occurs can lead to kidney stone formation, deposition of calcium oxalate in the kidney and other tissues, and renal failure. Hydroxyproline (Hyp) catabolism, which occurs mainly in the liver and kidney, is a prominent source of glyoxylate and could account for a significant portion of the oxalate produced in PH. To determine the sensitivity of mouse models of PH1 and PH2 to Hyp-derived oxalate, animals were fed diets containing 1% Hyp. Urinary excretions of glycolate and oxalate were used to monitor Hyp catabolism and the kidneys were examined to assess pathological changes. Both strains of knockout (KO) mice excreted more oxalate than wild-type (WT) animals with Hyp feeding. After 4 wk of Hyp feeding, all mice deficient in glyoxylate reductase/hydroxypyruvate reductase (GRHPR KO) developed severe nephrocalcinosis in contrast to animals deficient in alanine-glyoxylate aminotransferase (AGXT KO) where nephrocalcinosis was milder and with a lower frequency. Plasma cystatin C measurements over 4-wk Hyp feeding indicated no significant loss of renal function in WT and AGXT KO animals, and significant and severe loss of renal function in GRHPR KO animals after 2 and 4 wk, respectively. These data suggest that GRHPR activity may be vital in the kidney for limiting the conversion of Hyp-derived glyoxylate to oxalate. As Hyp catabolism may make a major contribution to the oxalate produced in PH patients, Hyp feeding in these mouse models should be useful in understanding the mechanisms associated with calcium oxalate deposition in the kidney.
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PMID:Hydroxyproline metabolism in mouse models of primary hyperoxaluria. 2249 66

Background. Primary hyperoxaluria belongs to a group of rare metabolic disorders with autosomal recessive inheritance. It results from genetic mutations of the AGXT gene, which is more common due to higher consanguinity rates in the developing countries. Clinical features at presentation are heterogeneous even in children from the same family; this study was conducted to determine the clinical characteristics, type of AGXT mutation, and outcome in children diagnosed with PH1 at a tertiary referral center in Oman. Method. Retrospective review of children diagnosed with PH1 at a tertiary hospital in Oman from 2000 to 2013. Result. Total of 18 children were identified. Females composed 61% of the children with median presentation age of 7 months. Severe renal failure was initial presentation in 39% and 22% presented with nephrocalcinosis and/or renal calculi. Family screening diagnosed 39% of patients. Fifty percent of the children underwent hemodialysis. 28% of children underwent organ transplantation. The most common mutation found in Omani children was c.33-34insC mutation in the AGXT gene. Conclusion. Due to consanguinity, PH1 is a common cause of ESRD in Omani children. Genetic testing is recommended to help in family counseling and helps in decreasing the incidence and disease burden; it also could be utilized for premarital screening.
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PMID:Primary hyperoxaluria type 1 in 18 children: genotyping and outcome. 2591 46

Primary hyperoxaluria type 1 is a rare autosomal-recessive disease caused by the deficient activity of the liver specific enzyme alanine-glyoxylate aminotransferase. Increased endogenous oxalate production induces severe hyperoxaluria, recurrent urolithiasis, progressive nephrocalcinosis and renal failure. Here we report a 6 month old boy who presented with vomiting and decreased urine volume. He was diagnosed with chronic kidney failure at 4 months of age and peritoneal dialysis was introduced at a local hospital. His parents were third degree cousins and family history revealed 2 maternal cousins who developed end stage renal disease during childhood. When he was admitted to our hospital, laboratory studies were consistent with end stage renal disease, ultrasound showed bilateral massive nephrocalcinosis. As clinical presentation was suggestive for primary hyperoxaluria type 1, plasma oxalate was determined and found extremely elevated. Genetic testing proved diagnosis by showing a disease causing homozygous mutation (AGXT-gene: c.971_972delT). The patient was put on pyridoxine treatment and aggressive dialysis programme. In conclusion; progressive renal failure in infancy with massive nephrocalcinosis, especially if accompanied by consanguinity and family history, should always raise the suspicion of PH type 1. Increased awareness of the disease would help physicians in both treating the patients and guiding the families who have diseased children and plan to have further pregnancies.
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PMID:Primary Hyperoxaluria Type 1: A Cause for Infantile Renal Failure and Massive Nephrocalcinosis. 2609 Sep 95

Primary hyperoxaluria type I (PH1), the most severe form of primary hyperoxalurias, is a liver disease of the metabolic defect in glyoxylate detoxification that can be corrected by liver transplantation. A 21-year-old man presented to our center after 4 months of regular hemodialysis for kidney failure caused by nephrolithiasis. A diagnosis of PH1 was confirmed by mutations of the AGXT gene. Left lateral sectionectomy of the native liver was performed; and auxiliary partial orthotopic liver transplantation (APOLT) and kidney transplantation were carried out synchronously using a living donor. After transplantation, the patient's plasma oxalate and creatinine levels substantially decreased and the patient recovered well with good dual grafts function. APOLT and kidney transplantation can compensate the liver deficient in liver enzyme production and aid the renal elimination of oxalate, thus serving as an effective treatment option for patients with PH1. In conclusion, left lateral sectionectomy of the native liver and combined living-related liver-kidney transplantation can be a surgical option for PH1.
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PMID:Left Lateral Sectionectomy of the Native Liver and Combined Living-Related Liver-Kidney Transplantation for Primary Hyperoxaluria Type 1. 2625 91

Primary hyperoxaluria is a genetic disorder in glyoxylate metabolism that leads to systemic overproduction of oxalate. Functional deficiency of alanine-glyoxylate aminotransferase in this disease leads to recurrent nephrolithiasis, nephrocalcinosis, systemic oxalosis, and kidney failure. The aim of this study was to determine the molecular etiology of kidney transplant loss in a young Tunisian individual. We present a young man with end-stage renal disease who received a kidney allograft and experienced early graft failure. There were no improvement in kidney function; he required hemodialysis and graft biopsy revealed calcium oxalate crystals, which raised suspicion of primary hyperoxaluria. Genetic study in the AGXT gene by PCR direct sequencing identified three missense changes in heterozygote state: the p. Gly190Arg mutation next to two other novels not previously described. The classification of the deleterious effect of the missense changes was developed using the summered results of four different mutation assessment algorithms, SIFT, PolyPhen, Mutation Taster, and Align-GVGD. This system classified the changes as polymorphism in one and as mutation in other. The patient was compound heterozygous mutations. Structural analysis showed that the novel mutation, p.Pro28Ser mutation, affects near the dimerization interface of AGT and positioned on binding site instead of the inhibitor, amino-oxyacetic acid (AOA). With the novel AGXT mutation, the mutational spectrum of this gene continues to broaden in our population. The diagnosis of PH1 was not recognized until after renal transplant with fatal consequences, which led us to confirm the importance of screening before planning for kidney transplantation in population with a relatively high frequency of AGXT mutation carriers.
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PMID:Identification of a novel AGXT gene mutation in primary hyperoxaluria after kidney transplantation failure. 2756 36


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