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Abstract：
Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is the most common inherited mitochondrial metabolic disease of fatty acid β-oxidation, especially in newborns. MCADD is clinically diagnosed using Newborn Bloodspot Screening (NBS) and genetic testing. Still, these methods have limitations, such as false negatives or positives in NBS and the variants of uncertain significance in genetic testing. Thus, complementary diagnostic approaches for MCADD are needed. Recently, untargeted metabolomics has been proposed as a diagnostic approach for inherited metabolic diseases (IMDs) due to its ability to detect a wide range of metabolic alterations. We performed an untargeted metabolic profiling of dried blood spots (DBS) from MCADD newborns (n = 14) and healthy controls (n = 14) to discover potential metabolic biomarkers/pathways associated with MCADD. Extracted metabolites from DBS samples were analyzed using UPLC-QToF-MS for untargeted metabolomics analyses. Multivariate and univariate analyses were used to analyze the metabolomics data, and pathway and biomarker analyses were also performed on the significantly identified endogenous metabolites. The MCADD newborns had 1034 significantly dysregulated metabolites compared to healthy newborns (moderated t-test, no correction, p-value ≤ 0.05, FC 1.5). A total of 23 endogenous metabolites were up-regulated, while 84 endogenous metabolites were down-regulated. Pathway analyses showed phenylalanine, tyrosine, and tryptophan biosynthesis as the most affected pathways. Potential metabolic biomarkers for MCADD were PGP (a21:0/PG/F1alpha) and glutathione, with an area under the curve (AUC) of 0.949 and 0.898, respectively. PGP (a21:0/PG/F1alpha) was the first oxidized lipid in the top 15 biomarker list affected by MCADD. Additionally, glutathione was chosen to indicate oxidative stress events that could happen during fatty acid oxidation defects. Our findings suggest that MCADD newborns may have oxidative stress events as signs of the disease. However, further validations of these biomarkers are needed in future studies to ensure their accuracy and reliability as complementary markers with established MCADD markers for clinical diagnosis.
摘要：
中链酰基辅酶A脱氢酶缺乏症（MCADD）是最常见的遗传性线粒体脂肪酸β-氧化代谢疾病，尤其是新生儿。MCADD使用新生儿血斑筛查（NBS）和基因检测进行临床诊断。尽管如此，这些方法有局限性，如NBS的假阴性或阳性，以及基因检测中意义不确定的变异。因此，MCADD的补充诊断方法是必要的。最近,由于非靶向代谢组学能够检测广泛的代谢改变，因此已被提出作为遗传代谢疾病（IMD）的诊断方法。我们对MCADD新生儿（n=14）和健康对照（n=14）的干血斑（DBS）进行了非靶向代谢分析，以发现与MCADD相关的潜在代谢生物标志物/途径。使用UPLC-QToF-MS分析来自DBS样品的提取代谢物,用于非靶向代谢组学分析。多变量和单变量分析用于分析代谢组学数据，还对显著鉴定的内源性代谢物进行了通路和生物标志物分析。与健康新生儿相比，MCADD新生儿有1034个显著失调的代谢物(适度t检验，没有更正,p值≤0.05,FC1.5)。共有23种内源性代谢物上调，而84个内源性代谢物下调。通路分析显示苯丙氨酸,酪氨酸,色氨酸生物合成是受影响最大的途径。MCADD的潜在代谢生物标志物是PGP(a21:0/PG/F1α)和谷胱甘肽,曲线下面积（AUC）分别为0.949和0.898。PGP(a21:0/PG/F1α)是受MCADD影响的前15个生物标志物列表中的第一个氧化脂质。此外,选择谷胱甘肽来指示在脂肪酸氧化缺陷期间可能发生的氧化应激事件。我们的发现表明，MCADD新生儿可能有氧化应激事件作为疾病的征兆。然而,在未来的研究中需要对这些生物标志物进行进一步验证,以确保其作为临床诊断中已建立的MCADD标志物的互补标志物的准确性和可靠性.
