NMR-based newborn urine screening for optimized detection of inherited errors of metabolism

Abstract

Inborn errors of metabolism (IEMs) are rare diseases produced by the accumulation of abnormal amounts of metabolites, toxic to the newborn. When not detected on time, they can lead to irreversible physiological and psychological sequels or even demise. Metabolomics has emerged as an efficient and powerful tool for IEM detection in newborns, children, and adults with late onset. In here, we screened urine samples from a large set of neonates (470 individuals) from a homogeneous population (Basque Country), for the identification of congenital metabolic diseases using NMR spectroscopy. Absolute quantification allowed to derive a probability function for up to 66 metabolites that adequately describes their normal concentration ranges in newborns from the Basque Country. The absence of another 84 metabolites, considered abnormal, was routinely verified in the healthy newborn population and confirmed for all but 2 samples, of which one showed toxic concentrations of metabolites associated to ketosis and the other one a high trimethylamine concentration that strongly suggested an episode of trimethylaminuria. Thus, a non-invasive and readily accessible urine sample contains enough information to assess the potential existence of a substantial number (>70) of IEMs in newborns, using a single, automated and standardized 1H- NMR-based analysis.

The Urinary Metabolome of Healthy Newborns

“…In our study, the interquartile (IQ) range for taurine was 74.64-2841 µmol/mmol creatinine. The reference value reported in the UMDB was 250-910 µmol/mmol creatinine (using NMR) [24]. The abnormal concentration quoted for taurine in the HMDB is 1261 µmol/mmol creatinine, associated with molybdenum cofactor deficiency [25].…”

Study of the Metabolomics of Equine Preovulatory Follicular Fluid: A Way to Improve Current In Vitro Maturation Media

“…For assignment purposes, a battery of experiments including 2D-1 H, 13 C-HSQC, 2D-1 H, 1 H-TOCSY, and 2D 1 H-1 H-NOESY were recorded in a Bruker Avance III 800 MHz spectrometer (Figure S1). The chemical shift, multiplet type, and number of contributing nuclei to each metabolite are provided in Table 1 and were determined following previously validated methods [10][11][12].…”

1H-Nuclear Magnetic Resonance Analysis of Urine as Diagnostic Tool for Organic Acidemias and Aminoacidopathies

“…For the last 30 years, efforts have been made to evaluate the utility of urinary 1 H-NMR spectroscopic profiles for detecting a wide range of smIEMs in a single assay. In fact, based on the biochemical complexity of urine samples, most diagnostic evidence has been obtained using high-resolution spectrometers of >500 MHz, which have proven to be useful for discriminating potentially pathological samples [12][13][14][15][16][17]21]. Indeed, this technology has recently been applied to newborn screening scenarios through quantitative and multivariate analyses of 1 H-NMR spectral data [12,13].…”

“…Accordingly, various research groups have introduced the use of 1 H-NMR-based metabolomics using high-resolution equipment (>500 MHz) to obtain promising results; however, the accessibility to such technology might be limited in some contexts [12][13][14][15][16][17]. Therefore, in this work, we aimed to establish a 1 H-NMR-based metabolomics approach using equipment with a field strength of 400 MHz as an initial screening technique for the urine diagnostic approximation of smIEM in combination with GC-MS.…”