1H NMR-based metabonomics for the diagnosis of inborn errors of metabolism in urine

Constantinou, Maria; Papakonstantinou, Evangelos; Spraul, Manfred; Sevastiadou, Sophia; Costalos, Christos; Koupparis, Michael A.; Shulpis, K; Tsantili‐Kakoulidou, Anna; Mikros, Emmanuel

doi:10.1016/j.aca.2005.03.059

Cited by 67 publications

(51 citation statements)

References 18 publications

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“…14−16 The noninvasive collection of newborn urine and subsequent ease to address large cohorts, compared to newborn blood, makes it a particularly interesting biofluid in the present context. This has indeed been recognized in reports on the newborn urinary impact of prematurity, 17−20 IUGR, 21−23 large for gestational age (LGA), 22,23 GDM, 3 asphyxia, 11,24,25 respiratory distress syndrome (RDS), 24 meconium aspiration syndrome (MAS), 24 bronchopulmonary dysplasia, 26 IEM, 27 neonatal sepsis, 28 postnatal bacterial, 19 cytomegalovirus, 29 and fungal 30 infections. Most of these studies have considered relatively small cohorts (up to ca.…”

Section: ■ Introductionmentioning

confidence: 99%

Newborn Urinary Metabolic Signatures of Prematurity and Other Disorders: A Case Control Study

et al. 2015

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This work assesses the urinary metabolite signature of prematurity in newborns by nuclear magnetic resonance (NMR) spectroscopy, while establishing the role of possible confounders and signature specificity, through comparison to other disorders. Gender and delivery mode are shown to impact importantly on newborn urine composition, their analysis pointing out at specific metabolite variations requiring consideration in unmatched subject groups. Premature newborns are, however, characterized by a stronger signature of varying metabolites, suggestive of disturbances in nucleotide metabolism, lung surfactants biosynthesis and renal function, along with enhancement of tricarboxylic acid (TCA) cycle activity, fatty acids oxidation, and oxidative stress. Comparison with other abnormal conditions (respiratory depression episode, large for gestational age, malformations, jaundice and premature rupture of membranes) reveals that such signature seems to be largely specific of preterm newborns, showing that NMR metabolomics can retrieve particular disorder effects, as well as general stress effects. These results provide valuable novel information on the metabolic impact of prematurity, contributing to the better understanding of its effects on the newborn's state of health.

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Section: ■ Introductionmentioning

confidence: 99%

Newborn Urinary Metabolic Signatures of Prematurity and Other Disorders: A Case Control Study

et al. 2015

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“…Several of the IEM are associated with the accumulation of amino acids as metabolites in serum and urine. 1 H NMR studies on urinary excretion of diagnostic amino acids such as phenylalanine in phenylketonuria (PKU), branched chain amino acids (leucine, valine, isoleucine) in maple syrup urine disease, N-acetyl aspartic acid in Canavan disease, and tyrosine and N-acetyl tyrosine in tyrosinemia type I have been reported (18,19). However, the diversity of the detectable metabolites found in intact biofluids and their highly variable concentrations often results in the severe overlap of amino acid signals in 1 H NMR spectra with those from several other metabolites, thus alternatives are highly sought (20).…”

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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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“…In addition, the chemical shift of TSP has been shown to vary with pH (De Marco 1977), temperature (Farrant et al 1994;Wishart et al 1995) and protein concentration (Shimizu et al 1994). Consequently, although both compounds are frequently used for NMR analysis of urine, tissue extract (Constantinou et al 2005;Le Belle et al 2002;Lenz et al 2004) and potentially deproteinised serum extract, neither compound is ideal as an internal standard for biofluids containing high levels of macromolecules.…”

Section: Resultsmentioning

confidence: 99%

“…Internal chemical shift standards such as 3-(trimethylsilyl)-1-propane sulfonic acid sodium salt (DSS) and 3-(trimethylsilyl)propionic acid sodium salt (TSP) are commonly used for NMR studies in urine (Constantinou et al 2005;Gartland et al 1990; Lenz et al 2004). However, due to interactions with proteins and associated NMR line-broadening, these compounds are not suitable as either quantitative or qualitative tools in proteinaceous solutions such as blood plasma or serum (Bell et al 1989;Nowick et al 2003).…”

Section: Introductionmentioning

confidence: 99%

4,4-Dimethyl-4-silapentane-1-ammonium trifluoroacetate (DSA), a promising universal internal standard for NMR-based metabolic profiling studies of biofluids, including blood plasma and serum

et al. 2008

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Nuclear magnetic resonance (NMR)-based metabolic profiling of biofluids and tissues are of key interest to enhance biomarker discovery for disease, drug efficacy and toxicity studies. Urine and blood plasma/ serum are the biofluids of most interest as they are the most accessible in both clinical and preclinical studies. However, proteinaceous fluids, such as blood serum or plasma, represent the greatest technical challenge since the chemical shift (d) and line-width (m 1/2 ) of internal standards currently used for aqueous NMR samples are greatly affected by protein binding. We have therefore investigated the suitability of 4,4-dimethyl-4-silapentane-1-ammonium trifluoroacetate (DSA) as a universal internal standard for biofluids. Proton ( 1 H) NMR spectroscopy was used to determine the effect of serum pH (3, 7.4 and 10) and DSA concentration on the overall lineshape and position of the trimethylsilyl resonance of DSA. The results were compared to that of 3-(trimethylsilyl)propionic acid sodium salt (TSP). Both the chemical shift and line-width of the DSA peak were not significantly affected by pH or DSA concentration, whereas these parameters for TSP showed large variations due to protein binding. Furthermore, the peak area of DSA correlated linearly with its concentration under all pH conditions, whilst no linear correlation was observed with TSP. Overall, in contrast to TSP, these results support the use of DSA as an accurate universal internal chemical shift reference and concentration/normalisation standard for biofluids. In the case of proteinaceous biofluids such as serum, where no current standard is available, this offers a considerable saving in both operator and spectrometer time.

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1H NMR-based metabonomics for the diagnosis of inborn errors of metabolism in urine

Cited by 67 publications

References 18 publications

Newborn Urinary Metabolic Signatures of Prematurity and Other Disorders: A Case Control Study

Newborn Urinary Metabolic Signatures of Prematurity and Other Disorders: A Case Control Study

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

4,4-Dimethyl-4-silapentane-1-ammonium trifluoroacetate (DSA), a promising universal internal standard for NMR-based metabolic profiling studies of biofluids, including blood plasma and serum

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1H NMR-based metabonomics for the diagnosis of inborn errors of metabolism in urine

Cited by 67 publications

References 18 publications

Newborn Urinary Metabolic Signatures of Prematurity and Other Disorders: A Case Control Study

Newborn Urinary Metabolic Signatures of Prematurity and Other Disorders: A Case Control Study

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

4,4-Dimethyl-4-silapentane-1-ammonium trifluoroacetate (DSA), a promising universal internal standard for NMR-based metabolic profiling studies of biofluids, including blood plasma and serum

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