Urinary purines and pyrimidines in patients with hyperammonemia of various origins

Gennip, Albert H.; Bree-Blom, E.J. Van; Grift, J. Van Der; Bree, P.K. De; Wadman, S.K.

doi:10.1016/0009-8981(80)90200-4

Cited by 33 publications

(15 citation statements)

References 49 publications

(21 reference statements)

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“…In our study, all four patients with a defect in either ornithine transcarbamylase or argininosuccinase presented with highly increased concentrations of orotate and N-C-aspartate. In addition, some of these patients also had highly increased concentrations of orotidine, uridine, and uracil, which are in line with results obtained by others (7,9 ). Only two patients had moder- ately increased concentrations of dihydroorotate, which might be attributable to the fact that dihydroorotase favors the reverse reaction (12 ).…”

Section: Discussionsupporting

confidence: 89%

“…In contrast, a uracil concentration within reference values was observed for the patient with an argininosuccinase deficiency. This phenomenon has been observed before and can be explained by the high excretion of other nitrogen-containing metabolites in patients with an argininosuccinase deficiency (5,7 ). In patients suffering from a dihydropyrimidine dehydrogenase deficiency, the concentrations of the pyrimidine de novo metabolites were within reference values and only highly increased concentrations of uracil were present in the urine.…”

Section: Resultsmentioning

confidence: 59%

“…Patients with a deficiency of UMP synthetase excrete excessive amounts of orotate in their urine (5,6 ). In contrast, patients suffering from a urea-cycle disorder can, in addition to orotate, also excrete highly increased amounts of orotidine, uridine, and uracil (5,7 ). Several methods have been described for the detection of some of the metabolites of the pyrimidine de novo pathway, using colorimetry (8 ), thin-layer chromatography (9 ), enzymatic spectrophotometric assays (10 ), liquid-liquid chromatography (11 ), HPLC (6,12,13 ), gas chromatographymass spectrometry (14,15 ), HPLC-tandem mass spectrometry (HPLC-MS/MS) (16,17 ), and capillary electrophoresis (18,19 ).…”

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confidence: 99%

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Analysis of Pyrimidine Synthesis “de Novo” Intermediates in Urine and Dried Urine Filter- Paper Strips with HPLC–Electrospray Tandem Mass Spectrometry

et al. 2004

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Background:The concentrations of the pyrimidine "de novo" metabolites and their degradation products in urine are useful indicators for the diagnosis of an inborn error of the pyrimidine de novo pathway or a urea-cycle defect. Until now, no procedure was available that allowed the analysis of all of these metabolites in a single analytical run. We describe a rapid, specific method to measure these metabolites by HPLC-tandem mass spectrometry. Methods: Urine or urine-soaked filter-paper strips were used to measure N-carbamyl-aspartate, dihydroorotate, orotate, orotidine, uridine, and uracil. Reversed-phase HPLC was combined with electrospray ionization tandem mass spectrometry, and detection was performed by multiple-reaction monitoring. Stable-isotope-labeled reference compounds were used as internal standards. Results: All pyrimidine de novo metabolites and their degradation products were measured within a single analytical run of 14 min with lower limits of detection of 0.4 -3 mol/L. The intra-and interassay variation for urine with added compounds was 1.2-5% for urines and 2-9% for filter-paper extracts of the urines. Recoveries of the added metabolites were 97-106% for urine samples

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Section: Discussionsupporting

confidence: 89%

Section: Resultsmentioning

confidence: 59%

mentioning

confidence: 99%

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Analysis of Pyrimidine Synthesis “de Novo” Intermediates in Urine and Dried Urine Filter- Paper Strips with HPLC–Electrospray Tandem Mass Spectrometry

et al. 2004

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“…An increased excretion of uracil has been reported in the literature in five heterozygotes for OCT deficiency (12). Orotic acid and, less frequently, uridine were also increased in these camers.…”

Section: Van Acker Et Almentioning

confidence: 72%

Urinary Excretion of Purine and Pyrimidine Metabolites in the Neonate

et al. 1993

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ABSTRACT. Random urine samples from 614 neonates were screened for metabolites of purine and pyrimidine metabolism using an adapted column chromatographic method. A restricted number of metabolites and a number of unidentified peaks appeared on the chromatograms. No inborn errors of this metabolism were found. The chromatograms were identical in term and in premature or dysmature neonates, except for the presence of more unidentified peaks in the latter group. The pattern was not influenced by the type of feeding or i.v. nutrition. Metabolites of different medications were identified. One female neonate with an increased excretion of uracil was shown to be heterozygous for ornithine carbamyl transferase deficiency. (Pediatr Res 34: 762-766, 1993) Abbreviations OCT deficiency, ornithine carbamyltransferase deficiency Inherited disorders of purine and pyrimidine metabolism may be more prevalent than is currently believed (1). Some are associated with a severe clinical picture and a fatal outcome, whereas others have a discrete clinical expression and a relatively benign evolution. For some of them treatment is available, for others recognition is important for genetic counseling and prenatal diagnosis in subsequent pregnancies. The majority of these inherited disorders can now be identified from specific metabolites in the urine (Tables 1 and 2). Systematic screening of newborns has, however, not yet been performed. This paper reports the results of a screening of more than 600 newborns, on the 4th d of life, using an adapted column chromatographic method. MATERIALS AND METHODSA random urine sample was obtained from 6 14 neonates on the 4th d of life and stored at -20°C immediately after collection. Data concerning the perinatal period were collected; the diagnosis of hypoxia was made on the basis of data provided by monitoring during delivery, Apgar score, and blood gas analysis shortly after birth. Information was obtained on the feeding and the medication given to the mother shortly before delivery or during lactation or to the child. Two categories of neonates were investigated. Group A was formed by 510 neonates, born successively in the same maternity ward, who had a birth weight above 2800 g and were born after an uneventful pregnancy and delivery. There were 234 boys and 276 girls; 296 (58%) were breast fed, 199 (39%) were formula fed, and 15 (3%) received mixed feeding. An adapted start formula containing 1.4-1.9 g/ 100 mL protein, 5.2-7.1 g/100 mL lactose, and 3.2-3.6 g/100 mL fat was used. In this group, no medication was given to mother or child. Group B comprised 104 neonates, 62 boys and 42 girls, who were admitted to the neonatal intensive care unit of the same hospital. Ninety-four were born prematurely with a mean gestational age of 32 & 2.5 wk. Ten were considered to be dysmature on the basis of a low birth weight for gestational age: mean birth weight was 1822 f 585 g. Of the 104 neonates, 26 (25%) were breast fed, 39 (37%) were formula-fed, and seven (7%) had mixed feeding. The formula conta...

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“…[5][6][7][8][9][10][11][12][13] To date, orotic acid has been determined mostly by liquid chromatography (HPLC) with UV detection at 275 nm. 14 This approach is quite cumbersome in the subsequent integration and interpretation process.…”

mentioning

confidence: 99%

Rapid determination of orotic acid in urine by a fast liquid chromatography/tandem mass spectrometric method

Marca

Casetta²,

Zammarchi

2003

Rapid Comm Mass Spectrometry

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Quantification of orotic acid (uracil-6-carboxylic acid) in urine is an important tool to diagnose some inherited diseases, such as urea cycle disorder (OTCD) and hereditary orotic aciduria. New rapid analytical methods are necessary to provide high-throughput orotic acid analyses. A new analytical method has been developed for the rapid analysis of orotic acid in urine by liquid chromatography coupled with ion spray tandem mass spectrometry (LC/MS/MS). After a sample dilution 1:20, the analysis was performed in the selected reaction monitoring mode in which orotic acid was detected through the transition m/z 155 to 111. The retention time was 3.9 min in a 4.5-min analysis. The analysis of orotic acid (OA) is used in clinical chemistry to diagnose some diseases associated with urea cycle disorders; ornithine transcarbamylase deficiency (OTCD) 1 is the most common, and also hereditary orotic aciduria. 2 The urea cycle has three roles: it produces urea as the waste product incorporating nitrogen not used for biosynthetic purposes, it is involved in the biochemical reactions that degrade and synthesise arginine de novo, and it plays a fundamental role in pH homeostasis. 3 Ornithine transcarbamylase, a mitochondrial matrix enzyme, catalyses the synthesis of citrulline from carbamyl phosphate and ornithine. OTCD male patients show classical clinical symptoms such as vomiting, lethargy, and confusion; clinical laboratory indications are high values of glutamine and ammonia, low citrulline, and high urinary excretion of orotic acid. Also, female manifesting carriers generally have higher than normal values of urinary orotic acid excretion due to X-inactivation.Hereditary orotic aciduria is a pyrimidine synthesis defect caused by uridine-5 0 -monophosphate (UMP) synthase deficiency. 4 This multienzyme catalyses the synthesis of UMP starting from orotic acid via orotidine-5 0 -monophosphate. Some characteristic clinical features are anaemia, hematuria, pallor, diarrhoea, retarded and poor development, while laboratory indications include very high urinary orotic acid excretion.Therefore, determination of orotic acid levels in urine is becoming an assay routinely performed in clinical analysis. [5][6][7][8][9][10][11][12][13] To date, orotic acid has been determined mostly by liquid chromatography (HPLC) with UV detection at 275 nm. 14 This approach is quite cumbersome in the subsequent integration and interpretation process. Signals from a 'normal' specimen are quite difficult to quantify since the LC-UV peaks are very close to the baseline (lack of adequate sensitivity) and are sometimes not sufficiently resolved from other endogenous components owing to the nonspecific wavelength chosen for detection. In addition the chromatographic run is time demanding.In this paper we evaluate the possibility to take advantage of tandem mass spectrometry 15 (MS/MS) as the basis for a rapid method for determination of OA in urine with very simple preparation, which could be a candidate for highthroughput routine analyses. The main cr...

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Urinary purines and pyrimidines in patients with hyperammonemia of various origins

Cited by 33 publications

References 49 publications

Analysis of Pyrimidine Synthesis “de Novo” Intermediates in Urine and Dried Urine Filter- Paper Strips with HPLC–Electrospray Tandem Mass Spectrometry

Analysis of Pyrimidine Synthesis “de Novo” Intermediates in Urine and Dried Urine Filter- Paper Strips with HPLC–Electrospray Tandem Mass Spectrometry

Urinary Excretion of Purine and Pyrimidine Metabolites in the Neonate

Rapid determination of orotic acid in urine by a fast liquid chromatography/tandem mass spectrometric method

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