The current diagnostic work-up of inborn errors of metabolism (IEM) is rapidly moving toward integrative analytical approaches. We aimed to develop an innovative, targeted urine metabolomics (TUM) screening procedure to accelerate the diagnosis of patients with IEM. Urinary samples, spiked with three stable isotope-labeled internal standards, were analyzed for 258 diagnostic metabolites with an ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS) configuration run in positive and negative ESI modes. The software automatically annotated peaks, corrected for peak overloading, and reported peak quality and shifting. Robustness and reproducibility were satisfactory for most metabolites. Z-scores were calculated against four age-group-matched control cohorts. Disease phenotypes were scored based on database metabolite matching. Graphical reports comprised a needle plot, annotating abnormal metabolites, and a heatmap showing the prioritized disease phenotypes. In the clinical validation, we analyzed samples of 289 patients covering 78 OMIM phenotypes from 12 of the 15 society for the study of inborn errors of metabolism (SSIEM) disease groups. The disease groups include disorders in the metabolism of amino acids, fatty acids, ketones, purines and pyrimidines, carbohydrates, porphyrias, neurotransmitters, vitamins, cofactors, and creatine. The reporting tool easily and correctly diagnosed most samples. Even subtle aberrant metabolite patterns as seen in mild multiple acyl-CoA dehydrogenase deficiency (GAII) and maple syrup urine disease (MSUD) were correctly called without difficulty. Others, like creatine transporter deficiency, are illustrative of IEM that remain difficult to diagnose. We present TUM as a powerful diagnostic screening tool that merges most urinary diagnostic assays expediting the diagnostics for patients suspected of an IEM.

中文翻译：

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具有图形报告工具的靶向尿液代谢组学用于快速诊断先天性代谢错误

目前对先天性代谢错误 (IEM) 的诊断工作正在迅速转向综合分析方法。我们旨在开发一种创新的靶向尿液代谢组学 (TUM) 筛查程序，以加速 IEM 患者的诊断。采用超高效液相色谱-四极杆飞行时间质谱 (UHPLC-QTOF-MS) 配置，在正负 ESI 下运行，对掺入三种稳定同位素标记的内标的尿液样本进行了 258 种诊断代谢物分析模式。该软件自动注释峰，校正峰过载，并报告峰质量和偏移。大多数代谢物的稳定性和重现性都令人满意。Z 分数是针对四个年龄组匹配的对照组计算的。基于数据库代谢物匹配对疾病表型进行评分。图形报告包括针状图、注释异常代谢物和显示优先疾病表型的热图。在临床验证中，我们分析了来自 15 个学会中的 12 个的 289 名患者的样本，涵盖 78 种 OMIM 表型，用于研究先天性代谢错误 (SSIEM) 疾病组。疾病组包括氨基酸、脂肪酸、酮、嘌呤和嘧啶、碳水化合物、卟啉、神经递质、维生素、辅因子和肌酸的代谢紊乱。该报告工具可轻松正确地诊断大多数样本。甚至在轻度多酰基辅酶A 脱氢酶缺乏症 (GAII) 和枫糖浆尿病 (MSUD) 中所见的细微异常代谢物模式也能毫无困难地正确识别。其他，像肌酸转运蛋白缺乏一样，说明 IEM 仍然难以诊断。我们将 TUM 介绍为一种强大的诊断筛查工具，它融合了大多数泌尿诊断分析，加快了疑似 IEM 患者的诊断。