β‐Ureidopropionase deficiency: A novel inborn error of metabolism discovered using NMR spectroscopy on urine

Moolenaar, Sytske H.; Göhlich-Ratmann, G.; Engelke, Udo F. H.; Spraul, Manfred; Humpfer, Eberhard; Dvortsák, Péter; Voït, Thomas; Hoffmann, Georg F.; Bräutigam, Christa; Kuilenburg, A. B. van; Gennip, A. van; Vreken, P.; Wevers, Ron A.

doi:10.1002/mrm.1289.abs

Cited by 15 publications

(19 citation statements)

References 7 publications

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“…Metabolic profiling or metabolomics, defined as the analysis of multiple biofluid metabolites in parallel, holds the promise of earlier disease detection and improved understanding of systems biology (1)(2)(3). Early indications of this potential have been reported for the detection of several diseases, including inborn errors of metabolism, cardiovascular diseases, and cancer (4)(5)(6)(7).…”

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confidence: 99%

Class selection of amino acid metabolites in body fluids using chemical derivatization and their enhanced ¹³ C NMR

Shanaiah

DeSilva

Gowda

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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We report a chemical derivatization method that selects a class of metabolites from a complex mixture and enhances their detection by 13 C NMR. Acetylation of amines directly in aqueous medium with 1,1 -13 C2 acetic anhydride is a simple method that creates a high sensitivity and quantitative label in complex biofluids with minimal sample pretreatment. Detection using either 1D or 2D 13 C NMR experiments produces highly resolved spectra with improved sensitivity. Experiments to identify and compare amino acids and related metabolites in normal human urine and serum samples as well as in urine from patients with the inborn errors of metabolism tyrosinemia type II, argininosuccinic aciduria, homocystinuria, and phenylketonuria demonstrate the method. The use of metabolite derivatization and 13 C NMR spectroscopy produces data suitable for metabolite profiling analysis of biofluids on a time scale that allows routine use. Extension of this approach to enhance the NMR detection of other classes of metabolites has also been accomplished. The improved detection of low-concentration metabolites shown here creates opportunities to improve the understanding of the biological processes and develop improved disease detection methodologies.carbon-13 ͉ inborn errors of metabolism ͉ metabolite profiling ͉ metabolomics ͉ metabonomics T he metabolic profile in biofluids represents a snapshot of ongoing biological processes in the human body. The presence of a particular metabolite, panel of metabolites, or a certain ratio of metabolites can indicate normal homeostasis, a response to biological stress, or even a specific disease state. Conventional medical diagnostic methods are typically based on the selective detection of a single or a few biochemical parameters that are associated with a given disease. A major challenge in the present practice of clinical medicine is the lack of suitable biomarkers and bioanalytical technologies for earlier detection of numerous diseases. Metabolic profiling or metabolomics, defined as the analysis of multiple biofluid metabolites in parallel, holds the promise of earlier disease detection and improved understanding of systems biology (1-3). Early indications of this potential have been reported for the detection of several diseases, including inborn errors of metabolism, cardiovascular diseases, and cancer (4-7).NMR and mass spectrometry are the two most often used analytical methods for metabolite profiling because of their high resolution and rich data content (8)(9)(10)(11)(12)(13)(14). Although mass spectrometry is the more sensitive technique, NMR provides broad coverage of the metabolome by detecting all of the (hydrogencontaining) metabolites present in the biofluid simultaneously, with excellent reproducibility and only limited sample pretreatment. Thus, for example, many classic inborn errors of metabolism (IEM) can be diagnosed by the use of 1 H NMR spectroscopy of body fluids (15-17). Several of the IEM are associated with the accumulation of amino acids as metabolites in serum an...

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confidence: 99%

Class selection of amino acid metabolites in body fluids using chemical derivatization and their enhanced ¹³ C NMR

Shanaiah

DeSilva

Gowda

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…16 To our knowledge, however,ˇUPase deficiency has only been described in a single case in 2001. 16,17 The patient in the original case had developed severe clinical abnormalities in the neonatal period andˇUPase deficiency was identified by NMR spectroscopy of the urine when the patient was 11 months old. The present case ofˇUPase deficiency is the first to be discovered using GC/MS.…”

Section: Resultsmentioning

confidence: 99%

“…These highly polar compounds are not recovered by conventional organic solvent extraction methods, which is why the first case was identified by NMR. 15,17 Recently, however, a specific HPLC/tandem MS method has been reported for the identification of pyrimidine degradation defects. 18 A pilot study of neonatal screening for 22 inborn errors of metabolism (IEMs) using a simple diagnostic procedure involving the urease pretreatment of urine followed by GC/MS was initiated in 1995 in Japan.…”

Section: Introductionmentioning

confidence: 99%

Screening and diagnosis of β‐ureidopropionase deficiency by gas chromatographic/mass spectrometric analysis of urine

Ohse

Matsuo

Ishida³

et al. 2002

J. Mass Spectrom.

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Dihydropyrimidine dehydrogenase (DHPDase), dihydropyrimidinase (DHPase) and beta-ureidopropionase (betaUPase) are the enzymes that catalyze the first, second, and third steps of the degradation of pyrimidines, respectively. beta-Ureidopropionate (betaUP) and beta-ureidoisobutyrate (betaUIB) are increased in the urine of patients with betaUPase deficiency. The original case in which betaUPase deficiency was discovered by NMR spectroscopy was an 11-month-old patient who presented with hypotonia and dystonic movement. We detected a second but asymptomatic case during a pilot study of neonatal screening with filter-paper urine, urease pretreatment and gas chromatography/mass spectrometry (GC/MS). The urease pretreatment of urine without fractionation resulted in a high recovery of these polar ureide compounds and allowed the highly sensitive GC/MS detection and diagnosis of betaUPase deficiency. betaUP and betaUIB were identified using GC/MS techniques. In the urine of the neonate with betaUPase deficiency, betaUP and betaUIB were persistently increased. Thymine, 5,6-dihydrothymine and 5,6-dihydrouracil were increased only moderately but significantly. It is known that thymine and uracil increase markedly in DHPDase deficiency, and 5,6-dihydrothymine and 5,6-dihydrouracil increase in DHPase deficiency. Therefore, betaUPase deficiency can be differentially diagnosed from the first and second enzyme deficiencies. Application of this specific and sensitive diagnostic procedure will lead to an understanding of the clinical heterogeneity of betaUPase deficiency. Furthermore, the identification of patients with defects in pyrimidine metabolism will enable doctors to avoid cancer chemotherapy with pyrimidine analogues such as 5-fluorouracil, which could be dangerous for these patients.

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“…The technique can be used for rapid identification and quantification of metabolites in body fluids. Known, and also as yet unknown, inborn errors of metabolism have been diagnosed using NMR spectroscopy of body fluids (2)(3)(4). Aminoacylase 1 deficiency is a novel inborn error of metabolism (OMIM 609924).…”

Section: Introductionmentioning

confidence: 99%

NMR spectroscopy of aminoacylase 1 deficiency, a novel inborn error of metabolism

et al. 2008

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Aminoacylase 1 deficiency is a novel inborn error of metabolism. The clinical significance of the deficiency is under discussion, as well as the possible consequences of the defect for brain metabolism and function. This study includes the five originally published cases as well as three novel ones. NMR spectroscopy of urine, serum and cerebrospinal fluid has been used to study these patients. A typical profile with 11 accumulating N-acetylated amino acids was observed in urine from the patients. The concentration of most of the accumulating metabolites is typically 100-500 micromol/mmol creatinine. Two additional minor N-acetylated metabolites remain unidentified. The concentrations of the accumulating metabolites are <20 micromol/L in serum from the patients. Interestingly we found no evidence of an increased concentration of N-acetylated amino acids in the cerebrospinal fluid from one patient. Our data define aminoacylase 1 deficiency at the metabolite level providing a specific urinary profile of accumulating N-acetylated amino acids.

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β‐Ureidopropionase deficiency: A novel inborn error of metabolism discovered using NMR spectroscopy on urine

Cited by 15 publications

References 7 publications

Class selection of amino acid metabolites in body fluids using chemical derivatization and their enhanced ¹³ C NMR

Class selection of amino acid metabolites in body fluids using chemical derivatization and their enhanced ¹³ C NMR

Screening and diagnosis of β‐ureidopropionase deficiency by gas chromatographic/mass spectrometric analysis of urine

NMR spectroscopy of aminoacylase 1 deficiency, a novel inborn error of metabolism

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β‐Ureidopropionase deficiency: A novel inborn error of metabolism discovered using NMR spectroscopy on urine

Cited by 15 publications

References 7 publications

Class selection of amino acid metabolites in body fluids using chemical derivatization and their enhanced 13 C NMR

Class selection of amino acid metabolites in body fluids using chemical derivatization and their enhanced 13 C NMR

Screening and diagnosis of β‐ureidopropionase deficiency by gas chromatographic/mass spectrometric analysis of urine

NMR spectroscopy of aminoacylase 1 deficiency, a novel inborn error of metabolism

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Class selection of amino acid metabolites in body fluids using chemical derivatization and their enhanced ¹³ C NMR

Class selection of amino acid metabolites in body fluids using chemical derivatization and their enhanced ¹³ C NMR