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Query: UMLS:C0020500 (hyperoxaluria)
 912 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We examine the suitability of a rapid and sensitive liquid chromatographic technique to determine L-alanine:glyoxylate aminotransferase (AGT) activity in human liver. Homogenised tissue was incubated for 30 min in the presence of substrates and the generated pyruvate was converted into the corresponding phenylhydrazone which was determined using reversed-phase high-performance liquid chromatography (HPLC). The procedure allowed the detection of the enzyme activity expressed by 10 micrograms of liver protein and was rapid enough resulting more sensitive and less time-consuming than the previous colorimetric one. We found that AGT activity in two hyperoxaluria type 1 patients was reduced as compared with controls. Also, cirrhotic patients had very low enzyme activities, even in the absence of detectable disorders of oxalate metabolism and this was ascribed to abnormal liver morphology. This may represent a misleading drawback if diagnosis of type 1 primary hyperoxaluria (PH1) uniquely relies on AGT assay.
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PMID:High-performance liquid chromatographic microassay for L-alanine:glyoxylate aminotransferase activity in human liver. 149 37

In approximately one-third of primary hyperoxaluria type 1 patients, disease is associated with a unique protein sorting defect in which hepatic L-alanine:glyoxylate aminotransferase (AGT; EC 2.6.1.44), which is normally peroxisomal, is mistargeted to mitochondria. In all such patients analyzed to date, the gene encoding the aberrantly targeted AGT carries three point mutations, each of which specifies an amino acid substitution. In this paper we show that one of these substitutions, a proline-to-leucine at residue 11, is necessary and sufficient for the generation of a mitochondrial targeting sequence in the AGT protein. AGT with this substitution appears to interact specifically with the mitochondrial protein import machinery, via a discrete N-terminal domain of the AGT protein. The N-terminal 19 amino acids of AGT with this substitution are sufficient to direct mouse cytosolic dihydrofolate reductase to mitochondria, and a synthetic peptide corresponding to this same 19-amino acid region reversibly inhibits mitochondrial protein import, not only of AGT but also of ornithine transcarbamoylase, a genuine cytoplasmically synthesized mitochondrial protein. We have extended these studies to analyze a region of normal human AGT cDNA directly upstream of the coding region. This sequence appears to correspond to an ancestral mitochondrial targeting sequence deleted from the human coding region by point mutation at the initiation codon. We show that reestablishment of this initiation codon produces an active mitochondrial targeting sequence that is different to that found in the hyperoxaluria patients. These results are discussed with reference to the AGT targeting defect in primary hyperoxaluria and also in relation to the highly unusual species specificity of subcellular distribution of AGT among mammals.
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PMID:Mistargeting of peroxisomal L-alanine:glyoxylate aminotransferase to mitochondria in primary hyperoxaluria patients depends upon activation of a cryptic mitochondrial targeting sequence by a point mutation. 196 59

We have studied the characteristics of human liver alanine-glyoxylate aminotransferase, which is deficient in hyperoxaluria type I, an inherited disorder of glyoxylate metabolism. The enzyme was optimally active at pH 8.0 showing apparent Km values for L-alanine and glyoxylate of 8.3 and 1.3 mmol/l, respectively. Activity was found to proceed linearly for up to 4 h. Measurements under these optimal conditions enabled the biochemical diagnosis of hyperoxaluria type I to be made via enzyme activity measurements in percutaneous needle biopsy specimens of liver tissue.
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PMID:Human liver L-alanine-glyoxylate aminotransferase: characteristics and activity in controls and hyperoxaluria type I patients using a simple spectrophotometric method. 239 96

Considering the clinical heterogeneity of primary hyperoxaluria type I (PH1) and the fact that in many instances this diagnosis was made without enzymatic and immunohistochemical investigation, other disturbances of oxalate metabolism than those presently known can be expected in PH1. Using a gaschromatographic/mass spectrometric method that allows quantification of these acids, hyperoxaluria and hyperglycoluria was found repeatedly in two unrelated patients. The hyperoxaluria was unresponsive to pyridoxine. There was no nephrocalcinosis or urolithiasis. In the liver biopsy normal AGT activity and normal localization of this enzyme in the peroxisome was found. In one patient abnormal Km and maximal activity and mozaicism of AGT were excluded. Hyperoxaluria and hyperglycoluria were also found in other family members, suggesting autosomal dominant transmission. Although the underlying defect leading to hyperoxaluria and hyperglycoluria could not be identified in these patients, it is probable that they represent a separate type of primary hyperoxaluria.
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PMID:Hyperoxaluria with hyperglycoluria not due to alanine:glyoxylate aminotransferase defect: a novel type of primary hyperoxaluria. 891 45

The hyperoxaluria syndromes can be differentiated by the assessment of associated abnormalities in generation and urine excretion of metabolically related molecules. Based on the experience gained in our laboratory during the last decade, we have developed a comprehensive diagnostic work-up, which includes measurements of oxalate, glycolate and L-glycerate in plasma, urine and dialysis fluids, and an assay for AGT activity on liver biopsy. The availability of reliable assays for each of these parameters is indispensable for the recognition and differentiation of hyperoxalurias. Patients suspected to have abnormalities in oxalate metabolism are first screened by analysing spot urines and serum, and subsequently are subjected to more extensive studies using properly pre-treated blood samples and 24-hour urine collection. AGT activity, in the case of PH1, is assayed on few milligrams liver specimen by using a sensitive chromatographic procedure. Pertinent biochemistries will also assist in the long-term medical follow-up of these patients and in view of the choice of renal replacement or transplantation strategies.
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PMID:Biochemical approach to diagnosis and differentiation of primary hyperoxalurias: an update. 960 5

Urolithiasis is uncommon in adolescence and rare in early childhood. In pediatric populations, congenital urinary tract anomalies associated with stasis and infection, idiopathic urolithiasis (adolescents), and nephrocalcinosis (premature infants) account for the majority of urolithiasis patients. Inborn errors of metabolism, such as the primary hyperoxalurias, are rare causes of urolithiasis in childhood. We report six children (mean age at symptom onset 1.3 years; range 0.32-4.1 years) with moderate hyperoxaluria (mean 1.10 +/- 0.58 mmoL/1.73m2 per day; range 0.69-2.19 mmoL/1.73m2 per day). Urolithiasis was present in four. Stones from two children were comprised of calcium oxalate dihydrate. Calcium oxalate crystalluria was seen in two of the patients. Findings included a mean urine calcium concentration of 6.61 +/- 2.28 mg/kg per day, urine citrate of 925.5 +/- 291.29 mg/g of creatinine per day, and mean renal clearance of 99.83 +/- 23.27 mL/min. All children were born full term, none was receiving diuretics, and none had recurrent urinary tract infections. Secondary causes of hyperoxaluria, including dietary oxalate excess, pyridoxine deficiency, and malabsorption, were excluded. Urine glycolate and glycerate were normal in all patients. In one hyperoxaluric member of each sibship, hepatic alanine-glyoxylate aminotransferase and D-glycerate dehydrogenase/glyoxylate reductase activity were normal. The clinical and biochemical features of these children are unlike those in previously recognized hyperoxaluric states. Thus, our description of a separate hyperoxaluric entity, referred to as unclassified hyperoxaluria.
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PMID:Hyperoxaluria and urolithiasis in young children: an atypical presentation. 1060 14

Primary hyperoxaluria (PH1) is a condition caused by a hepatic-based enzyme defect which can lead to renal failure due to oxalate stone disease, obstructive uropathy and nephrocalcinosis. It has been shown that the underlying metabolic defect can be corrected by liver transplantation and in most cases (renal failure having already occurred) is accompanied by a kidney graft. This paper describes the current results of 127 liver transplants performed in 117 patients over a 20-year period from 1984 to 2004 in 35 European centres. The mean age at onset of symptoms was 5.6 +/- 7.8 years and the mean age at which a diagnosis was made was 8.8 +/- 9.5 years. The diagnosis was confirmed by liver biopsy proven decreased AGT activity in 68% of cases, hyperoxaluria in 74%, hyperglycolicaciduria in 37% and hyperoxalaemia in 50%. Patients were transplanted at a mean age of 16.5 +/- 11.4 years following a period of dialysis of 3.2 +/- 3.2 years (range 0-14.4 years). 1-, 5- and 10-year patient survival values were 86, 80 and 69%, respectively, and liver graft survival rates of 80, 72 and 60% at the same time intervals. There have been 27 deaths and 10 liver retransplants have been carried out. Patient outcomes are improved when prolonged periods on dialysis and the complications of systemic oxalosis have not occurred.
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PMID:A 20-year experience of combined liver/kidney transplantation for primary hyperoxaluria (PH1): the European PH1 transplant registry experience 1984-2004. 1596 48

We report herein a domino orthotopic liver transplantation (LT), from a 38-year-old woman undergoing liver-kidney transplantation (LKT) for primary hyperoxaluria type I (PH1) to a recipient with cirrhosis and hepatocellular carcinoma. Delayed onset of PH1 and renal failure and 10% residual alanine-glyoxylate aminotransferase (AGT) activity in domino liver justified its use for domino procedure. The clinical course after LKT was similar to that described in other series, including ours. Renal function started promptly and maintained despite sustained hyperoxaluria from dissolution of oxalotic deposits. Conversely, the domino recipient manifested severe hyperoxaluria and developed nephrolithiasis and renal insufficiency with rapid progression over 2 months. A new LT resulted in slow decrease of oxaluria and improvement of renal function. Therefore, PH1 behaved quite differently in these two patients, leading us to conclude that domino LT using livers from PH1 patients should be considered very carefully, only as a bridge to definitive LT in recipients with critical clinical conditions.
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PMID:Severe course of primary hyperoxaluria and renal failure after domino hepatic transplantation. 1609 18

In primary hyperoxaluria the deficiency or mistargeting of hepatic alanine-glyoxylate aminotransferase (AGT) leads to the overproduction of oxalate resulting in hyperoxaluria and renal damage due to urolithiasis and/or nephrocalcinosis. Presently, the cure of the metabolic defect can be achieved only by liver transplantation. While for patients with end-stage renal disease combined hepatorenal transplantation is recommended, the concept of preemptive liver transplantation (PLTX), i.e. cure of the metabolic defect before renal damage occurs, has received considerable attention. Due to the heterogenous clinical course in PH1, optimal timing of PLTX is a matter of debate. Advocators of PLTX would consider a patient with a slowly declining GFR, reaching levels of 40-60 ml/min/1.73 m(2), as an ideal candidate, while others would continue medical treatment in these patients and opt for rapid combined liver-kidney transplantation if GFR reaches even lower levels. This review will discuss the background and rationale of PLTX and gives an update on 11 patients with PLTX who have been reported in the literature to date.
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PMID:The role of preemptive liver transplantation in primary hyperoxaluria type 1. 1628 78

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


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