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The inclusion of urea cycle disorders (UCD) detection into newborn screening (NBS) is highly desirable; however, it is hampered by the lack of a specific marker for most of these disorders (exceptions to this are citrulline and argininosuccinate for detection of citrullinemia and argininosuccinic aciduria, respectively). Thus far, the common feature of all (proximal- and distal-) UCDs, hyperammonemia, is not directly detectable in dried blood spots (DBS). The quantification of secondary elevations of glutamine seemed, thus far, not feasible, based on the assumption of the instability of glutamine in DBS. We describe here a reliable method for the simultaneous detection of lysine and glutamine from DBS in multiple reaction monitoring (MRM) with a second-tier UPLC-method for the separation and specific quantification of glutamine. We combined this newly developed method with the measurement of all specific amino acids (arginine, argininosuccinic acid, citrulline, ornithine, and proline), N-acetyl-glutamate, and orotic acid. This combination proofed to be a reliable and sensitive method for the detection of all UCDs using tandem-mass spectrometry NBS. The next step will be a prospective study with dried blood samples from patients with hyperammonemia, allowing further testing and evaluation of the method in practice.Download