Screening Urine from Newborns for Inborn Errors of Metabolism Using NMR

Selective screening of urine samples by the NMR technique involves targeted analysis of metabolites such as Inborn Error of Metabolism and other disease markers, and also non-targeted classification against healthy newborn models.

Non-targeted screening helps in detecting all NMR-visible deviations from normal references, be it known or unknown deviations. The detection of deviations from normality is shown in Figure 1.

Projection of the urine spectrum of an inborn error sample into the German normal model.

Figure 1. Projection of the urine spectrum of an inborn error sample into the German normal model. Image Credit: Bruker BioSpin -  NMR, EPR and Imaging.

The reference model includes all NMR spectra that are integrated into a so-called quantile plot, illustrated as a color band over the NMR spectrum. The new sample spectrum can be superimposed and analyzed for consistency with the model, that is, all resonances will be accommodated into the envelope defined by the model.

This testing can be automatically carried out in a univariate or multivariate manner. The spectrum of the sample constitutes a Canavan disease case. When the overall NMR spectrum is expanded, signals of N-Acetyl aspartic acid can be evidently seen.

N-Acetyl aspartic acid can be detected and measured automatically as part of the B.I.QUANT-UR panel. But statistics would also demonstrate the presence of previously unobserved deviations with the same certainty.

Influence of Metadata

Apart from using the normal models, the effect of metadata on the NMR spectra can also be investigated. The impact of the day of life after birth on the NMR spectra has been specifically analyzed, and the evolution of metabolic profile during the initial days of life can be demonstrated (refer to Figure 2).

trajectory of the first days of life as obtained from the NMR analysis of urine, containing 2 new samples projected onto the trajectory. The color of the stars represents the age group in which the babies should be.

Figure 2. The trajectory of the first days of life as obtained from the NMR analysis of urine, containing 2 new samples projected onto the trajectory. The color of the stars represents the age group in which the babies should be. Image Credit: Bruker BioSpin -  NMR, EPR and Imaging.

When projecting new samples onto this trajectory, it can be established whether the development of the infants follows the model pattern. Sample B clearly corresponds to a baby whose development has been more than usual. Sample A is fascinating because it falls into the group of days 1 and 2, despite coming from day 5.

This may indicate delayed development and therefore further testing is recommended. This is because the delay could point to the initial sign of an inborn error that is yet to be manifested by the normal biomarkers.

Support for Interpretation in the Context of IEM

Bruker IVDr Inborn Error of Metabolism Panel (B.I.IEM Panel)

The IVDr Inborn Errors of Metabolism Panel (B.I.IEM Panel) from Bruker has been developed for research use only (RUO). By using the database Metagene, the B.I.IEM Panel automatically provides valuable support for the diagnostic interpretation of B.I.QUANT-UR results.

The data can be used by healthcare professionals in the context of management and diagnosis of inborn errors of metabolism in adults, children, and newborns.

B.I.QUANT-UR’s NMR metabolic findings can be compared against a specialized Bruker version of Metagene’s current database. This database contains virtually 1000 diseases and differential diagnoses, offering clinicians a vast amount of data to support diagnoses.

Interactively, clinically relevant data can be added that can help grade possible diagnoses. This panel method supports diagnostics of inborn errors of metabolism, and also studies in the pediatrics field.