Integration of Proteomics and Metabolomics in Exploring Genetic and Rare Metabolic Diseases

Background: 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. Summary: 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. Key Message: Mass spectrometry-based "omics" approaches most frequently used to study the molecular mechanisms underlying inherited metabolic disorders pathophysiology are described. (c) 2017 S. Karger AG, Basel