Sebaa Rajaa, AlMalki Reem H, Alseraty Wafaa, Abdel Rahman Anas M
Department of Medical Laboratories, College of Applied Medical Sciences, Shaqra University, Al-Dawadmi 17472, Saudi Arabia.
Metabolomics Section, Department of Clinical Genomics, Center for Genomics Medicine, King Faisal Specialist Hospital and Research Centre (KFSHRC), Riyadh 11211, Saudi Arabia.
Metabolites. 2023 Jun 5;13(6):725. doi: 10.3390/metabo13060725.
Very long-chain acylcarnitine dehydrogenase deficiency (VLCADD) is a rare inherited metabolic disorder associated with fatty acid -oxidation and characterized by genetic mutations in the 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 ( = 15) and healthy controls ( = 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.
极长链酰基辅酶A脱氢酶缺乏症（VLCADD）是一种罕见的遗传性代谢紊乱疾病，与脂肪酸氧化相关，其特征是该基因发生基因突变以及酰基肉碱蓄积。VLCADD可在新生儿期或成年后期发病，可通过新生儿血斑筛查（NBS）或基因测序进行诊断。这些技术存在局限性，如假发现率高和意义不明确的变异（VUS）。因此，需要一种额外的诊断工具来提高诊断性能和改善健康结局。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，患有VLCADD的新生儿可能表现出独特的代谢组学模式。在此，我们应用非靶向代谢组学方法，使用液相色谱-高分辨率质谱（LC-HRMS）来测量从VLCADD新生儿（n = 15）和健康对照（n = 15）收集的干血斑（DBS）卡片中的整体代谢物。与健康新生儿相比，在VLCADD中鉴定出206种显著失调的内源性代谢物。58种上调和108种下调的内源性代谢物参与了多种途径，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、嘧啶代谢以及泛酸和辅酶A生物合成。此外，生物标志物分析确定3,4-二羟基十四烷酰肉碱（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，与健康新生儿相比，VLCADD新生儿表现出独特的代谢谱，并鉴定出可用于早期诊断的潜在生物标志物，这有助于更早地识别受影响的患者。这使得能够及时给予适当的治疗，从而改善健康状况。然而，需要对不同年龄和表型的大量独立VLCADD患者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。
