Abstract：
BACKGROUND: Glutaric aciduria type-1 (GA-1) is a rare metabolic disorder due to glutaryl coenzyme A dehydrogenase deficiency, causing elevated levels of glutaryl-CoA and its derivatives. GA-1 exhibits symptoms like macrocephaly, developmental delays, and movement disorders. Timely diagnosis through genetic testing and newborn screening is crucial. However, in some cases, transiently elevated level of glutarylcarnitine (C5DC) challenges accurate diagnosis, highlighting the need for alternative diagnostic methods, like mass spectrometry-based untargeted metabolomics, to identify additional biomarkers for distinguishing falsely suspected GA-1 from healthy newborns.
METHODS: DBS samples from falsely suspected GA-1 newborns (n = 47) and matched control were collected through the NBS program. Untargeted metabolomics using liquid chromatography-high-resolution mass spectrometry (LC-HRMS) was performed to enable biomarker and pathway investigations for significantly altered metabolites.
RESULTS: 582 and 546 were up- and down-regulated metabolites in transient GA-1. 155 endogenous metabolites displayed significant variations compared to the control group. Furthermore, our data identified novel altered metabolic biomarkers, such as N-palmitoylcysteine, heptacarboxyporphyrin, 3-hydroxylinoleoylcarnitine, and monoacylglyceride (MG) (0:0/20:1/0:0), along with perturbed metabolic pathways like sphingolipid and thiamine metabolism associated with the transient elevated C5DC levels in DBS samples.
CONCLUSIONS: A distinct metabolic pattern linked to the transient C5DC elevation in newborns was reported to enhance the prediction of the falsely positive cases, which could help avoiding unnecessary medical treatments and minimizing the financial burdens in the health sector.
METHODS: DBS samples from falsely suspected GA-1 newborns (n = 47) and matched control were collected through the NBS program. Untargeted metabolomics using liquid chromatography-high-resolution mass spectrometry (LC-HRMS) was performed to enable biomarker and pathway investigations for significantly altered metabolites.
RESULTS: 582 and 546 were up- and down-regulated metabolites in transient GA-1. 155 endogenous metabolites displayed significant variations compared to the control group. Furthermore, our data identified novel altered metabolic biomarkers, such as N-palmitoylcysteine, heptacarboxyporphyrin, 3-hydroxylinoleoylcarnitine, and monoacylglyceride (MG) (0:0/20:1/0:0), along with perturbed metabolic pathways like sphingolipid and thiamine metabolism associated with the transient elevated C5DC levels in DBS samples.
CONCLUSIONS: A distinct metabolic pattern linked to the transient C5DC elevation in newborns was reported to enhance the prediction of the falsely positive cases, which could help avoiding unnecessary medical treatments and minimizing the financial burdens in the health sector.
摘要：
背景：戊二酸尿症1型（GA-1）是由于戊二酰辅酶A脱氢酶缺乏引起的罕见代谢紊乱，导致戊二酰辅酶A及其衍生物水平升高。GA-1表现出诸如大头畸形的症状，发育迟缓,和运动障碍。通过基因检测和新生儿筛查及时诊断至关重要。然而,在某些情况下,短暂升高的戊二酰肉碱（C5DC）挑战准确的诊断，强调需要替代诊断方法，比如基于质谱的非靶向代谢组学，鉴定用于区分错误怀疑的GA-1与健康新生儿的其他生物标志物。
方法：通过NBS程序收集来自错误怀疑的GA-1新生儿（n=47）和匹配的对照的DBS样本。使用液相色谱-高分辨率质谱（LC-HRMS）进行非靶向代谢组学，以使生物标志物和途径研究显着改变的代谢物。
结果：582和546是瞬时GA-1中上调和下调的代谢物。与对照组相比，155种内源性代谢物显示出明显的变化。此外，我们的数据确定了新的改变的代谢生物标志物，如N-棕榈酰半胱氨酸，七羧基卟啉，3-羟基亚油酰基肉碱,和单酰基甘油酯（MG）（0：0/20：1/0：0），以及与DBS样品中短暂升高的C5DC水平相关的鞘脂和硫胺素代谢等紊乱的代谢途径。
结论：据报道，与新生儿瞬时C5DC升高有关的独特代谢模式增强了对假阳性病例的预测，这有助于避免不必要的医疗，并最大限度地减少卫生部门的财政负担。
方法：通过NBS程序收集来自错误怀疑的GA-1新生儿（n=47）和匹配的对照的DBS样本。使用液相色谱-高分辨率质谱（LC-HRMS）进行非靶向代谢组学，以使生物标志物和途径研究显着改变的代谢物。
结果：582和546是瞬时GA-1中上调和下调的代谢物。与对照组相比，155种内源性代谢物显示出明显的变化。此外，我们的数据确定了新的改变的代谢生物标志物，如N-棕榈酰半胱氨酸，七羧基卟啉，3-羟基亚油酰基肉碱,和单酰基甘油酯（MG）（0：0/20：1/0：0），以及与DBS样品中短暂升高的C5DC水平相关的鞘脂和硫胺素代谢等紊乱的代谢途径。
结论：据报道，与新生儿瞬时C5DC升高有关的独特代谢模式增强了对假阳性病例的预测，这有助于避免不必要的医疗，并最大限度地减少卫生部门的财政负担。
