Novel NMR Screening Assay for Inborn Errors of Metabolism Demonstrated in a Clinical Trial

A novel Inborn Errors of Metabolism (IEM) screening assay was successfully demonstrated during a clinical study in Turkey, in which more than 1,000 newborn babies were screened by nuclear magnetic resonance (NMR) spectroscopy in an effort to establish a method for a non-invasive, efficient, and reliable assessment of absolute and relative metabolite concentrations in newborns, allowing pediatricians to assess their health, and to detect a multitude of inborn metabolic errors simultaneously.

The comprehensive urine-screening program included 14 hospitals in Turkey, integrating both targeted and non-targeted screening techniques in a high-throughput method requiring only approximately 12 minutes of NMR measurement time per sample. The study successfully demonstrated the ability to quantify simultaneously 45 metabolites occurring in 49 different types of inborn errors of metabolism in neonates at clinically relevant metabolite concentrations. The novel screen also provides additional metabolic information on other health conditions, such as maturity problems, jaundice, or ketosis, from the same assay and without additional measurements or cost.

In the screening study in Turkey, the targeted method was optimized to deliver the automatic quantification of 65 relevant urinary metabolites, including 20 endogenous metabolites connected to general health state and 45 metabolites indicative for inborn errors of metabolism, allowing to screen for 49 inborn errors on newborns, as several markers appear in more than one disease, but with different co-biomarkers. The metabolic screening of urine by NMR has significant benefits over other methods, being non-invasive, including straightforward sample collection and preparation without derivatization, requiring only 12 minutes for one-dimensional and two-dimensional NMR measurements without the need for chromatography, and offering unbiased NMR quantitation with high dynamic range and without the need for spiking expensive isotopic standards.

The emerging NMR screening method also has potential limitations, including intrinsically lower metabolite sensitivity compared to mass spectrometry or immunoassays, as NMR is generally not suitable for trace analysis and requires moderate to high metabolite concentrations for correct identification and quantification. This screening assay also is not designed to detect any genetic, proteomic or peptide biomarkers. 

The majority of inborn errors of metabolism, however, can be quantified with NMR simultaneously and quickly, which promises to this screening cost-effective, as multiple conventional methods would be needed to get the same results.

This project was initially started under the German Government Central Innovation Program “ZIM.” Bruker (Billerica, Massachusetts) partnered on the development of this screening method for Turkish newborns with INFAI GmbH in Cologne, Germany, which coordinated the screening program in Turkey with the assistance of Professor Selda Bülbül from Kirikkale University (Kinkkale Province, Turkey). This screening study used the Bruker Avance IVDr, a novel high-throughput screening and in vitro diagnostics research NMR platform.