Costanzo Michele, Zacchia Miriam, Bruno Giuliana, Crisci Daniela, Caterino Marianna, Ruoppolo Margherita
Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II," Naples, Italy.
Prima Divisione di Nefrologia, Dipartimento di Scienze Cardio-Toraciche e Respiratorie, Università degli studi della Campania "Luigi Vanvitelli," Scuola di Medicina, Naples, Italy.
Kidney Dis (Basel). 2017 Jul;3(2):66-77. doi: 10.1159/000477493. Epub 2017 Jun 30.
Inherited metabolic disorders or inborn errors of metabolism are caused by deficiency of enzymatic activities in the catabolism of amino acids, carbohydrates, or lipids. These disorders include aminoacidopathies, urea cycle defects, organic acidemias, defects of oxidation of fatty acids, and lysosomal storage diseases. Inborn errors of metabolism constitute a significant proportion of genetic diseases, particularly in children; however, they are individually rare. Clinical phenotypes are very variable, some of them remain asymptomatic, others manifest metabolic decompensation in neonatal age, and others encompass mental retardation at later age. The clinical manifestation of these disorders can involve different organs and/or systems. Some disorders are easily managed if promptly diagnosed and treated, whereas in other cases neither diet, vitamin therapy, nor transplantation appears to prevent multi-organ impairment.
Here, we discuss the principal challenges of metabolomics and proteomics in inherited metabolic disorders. We review the recent developments in mass spectrometry-based proteomic and metabolomic strategies. Mass spectrometry has become the most widely used platform in proteomics and metabolomics because of its ability to analyze a wide range of molecules, its optimal dynamic range, and great sensitivity. The fast measurement of a broad spectrum of metabolites in various body fluids, also collected in small samples like dried blood spots, have been facilitated by the use of mass spectrometry-based techniques. These approaches have enabled the timely diagnosis of inherited metabolic disorders, thereby facilitating early therapeutic intervention. Due to its analytical features, proteomics is suited for the basic investigation of inborn errors of metabolism. Modern approaches enable detailed functional characterization of the pathogenic biochemical processes, as achieved by quantification of proteins and identification of their regulatory chemical modifications.
Mass spectrometry-based "omics" approaches most frequently used to study the molecular mechanisms underlying inherited metabolic disorders pathophysiology are described.
遗传性代谢紊乱或先天性代谢缺陷是由氨基酸、碳水化合物或脂质分解代谢中酶活性缺乏引起的。这些疾病包括氨基酸病、尿素循环缺陷、有机酸血症、脂肪酸氧化缺陷和溶酶体贮积病。先天性代谢缺陷在遗传病中占很大比例，尤其是在儿童中；然而，它们个体发病率较低。临床表型差异很大，有些无症状，有些在新生儿期出现代谢失代偿，还有些在后期出现智力发育迟缓。这些疾病的临床表现可累及不同器官和/或系统。有些疾病如果能及时诊断和治疗很容易控制，而在其他情况下，饮食、维生素治疗或移植似乎都无法预防多器官损害。
在此，我们讨论代谢组学和蛋白质组学在遗传性代谢紊乱中的主要挑战。我们回顾了基于质谱的蛋白质组学和代谢组学策略的最新进展。由于能够分析广泛的分子、具有最佳的动态范围和高灵敏度，质谱已成为蛋白质组学和代谢组学中使用最广泛的平台。基于质谱的技术有助于快速测量各种体液中的多种代谢物，这些体液也可以从小样本如干血斑中采集。这些方法能够及时诊断遗传性代谢紊乱，从而促进早期治疗干预。由于其分析特性，蛋白质组学适用于先天性代谢缺陷的基础研究。现代方法能够对致病生化过程进行详细的功能表征，这可以通过蛋白质定量和鉴定其调节性化学修饰来实现。
描述了基于质谱的“组学”方法，这些方法最常用于研究遗传性代谢紊乱病理生理学的分子机制。
