PDF(Pubmed)
Abstract：
Very long-chain acylcarnitine dehydrogenase deficiency (VLCADD) is a rare inherited metabolic disorder associated with fatty acid β-oxidation and characterized by genetic mutations in the ACADVL gene and accumulations of acylcarnitines. VLCADD, developed in neonates or later adults, can be diagnosed using newborn bloodspot screening (NBS) or genetic sequencing. These techniques have limitations, such as a high false discovery rate and variants of uncertain significance (VUS). As a result, an extra diagnostic tool is needed to deliver improved performance and health outcomes. As VLCADD is linked with metabolic disturbance, we postulated that newborn patients with VLCADD could display a distinct metabolomics pattern compared to healthy newborns and other disorders. Herein, we applied an untargeted metabolomics approach using liquid chromatography-high resolution mass spectrometry (LC-HRMS) to measure the global metabolites in dried blood spot (DBS) cards collected from VLCADD newborns (n = 15) and healthy controls (n = 15). Two hundred and six significantly dysregulated endogenous metabolites were identified in VLCADD, in contrast to healthy newborns. Fifty-eight and one hundred and eight up- and down-regulated endogenous metabolites were involved in several pathways such as tryptophan biosynthesis, aminoacyl-tRNA biosynthesis, amino sugar and nucleotide sugar metabolism, pyrimidine metabolism and pantothenate, and CoA biosynthesis. Furthermore, biomarker analyses identified 3,4-Dihydroxytetradecanoylcarnitine (AUC = 1), PIP (20:1)/PGF1alpha) (AUC = 0.982), and PIP2 (16:0/22:3) (AUC = 0.978) as potential metabolic biomarkers for VLCADD diagnosis. Our findings showed that compared to healthy newborns, VLCAADD newborns exhibit a distinctive metabolic profile, and identified potential biomarkers that can be used for early diagnosis, which improves the identification of the affected patients earlier. This allows for the timely administration of proper treatments, leading to improved health. However, further studies with large independent cohorts of VLCADD patients with different ages and phenotypes need to be studied to validate our potential diagnostic biomarkers and their specificity and accuracy during early life.
摘要：
超长链酰基肉碱脱氢酶缺乏症（VLCADD）是一种罕见的遗传性代谢紊乱，与脂肪酸β-氧化相关，其特征是ACADVL基因的基因突变和酰基肉碱的积累。VLCADD,在新生儿或以后的成年人中发展，可以使用新生儿血斑筛查（NBS）或基因测序进行诊断。这些技术有局限性，例如高错误发现率和不确定意义的变体(VUS)。因此,需要额外的诊断工具来改善绩效和健康结果.由于VLCADD与代谢紊乱有关，我们推测,与健康新生儿和其他疾病相比,VLCADD新生儿患者可以显示出不同的代谢组学模式.在这里，我们采用液相色谱-高分辨率质谱(LC-HRMS)非靶向代谢组学方法,对从VLCADD新生儿(n=15)和健康对照(n=15)采集的干血斑(DBS)卡中的整体代谢物进行了测定.在VLCADD中鉴定出两百六个明显失调的内源性代谢物，与健康的新生儿相反。五十八和一百零八个上调和下调的内源性代谢物参与了几种途径，如色氨酸生物合成，氨酰基-tRNA生物合成，氨基糖和核苷酸糖代谢，嘧啶代谢和泛酸，和CoA生物合成。此外，生物标志物分析确定3,4-二羟基十四酰基肉碱（AUC=1），PIP（20：1）/PGF1α）（AUC=0.982），和PIP2(16:0/22:3)(AUC=0.978)作为VLCADD诊断的潜在代谢生物标志物。我们的研究结果表明，与健康的新生儿相比，VLCAADD新生儿表现出独特的代谢特征，并确定了可用于早期诊断的潜在生物标志物，这改善了受影响患者的早期识别。这允许及时给予适当的治疗，改善健康。然而,需要对不同年龄和表型的VLCADD患者的大型独立队列进行进一步研究,以验证我们潜在的诊断生物标志物及其在生命早期的特异性和准确性.
