Mass Spectrometry-Based Metabolomic and Proteomic Strategies in Organic Acidemias.

Esther Imperlini,Margherita Ruoppolo,Marianna Caterino,Emanuela Scolamiero,Lucia Santorelli,Stefania Orrù

doi:10.1155/2016/9210408

Abstract

Organic acidemias (OAs) are inherited metabolic disorders caused by deficiency of enzymatic activities in the catabolism of amino acids, carbohydrates, or lipids. These disorders result in the accumulation of mono-, di-, or tricarboxylic acids, generally referred to as organic acids. The OA outcomes can involve different organs and/or systems. Some OA disorders are easily managed if promptly diagnosed and treated, whereas, in others cases, such as propionate metabolism-related OAs (propionic acidemia, PA; methylmalonic acidemia, MMA), neither diet, vitamin therapy, nor liver transplantation appears to prevent multiorgan impairment. Here, we review the recent developments in dissecting molecular bases of OAs by using integration of mass spectrometry- (MS-) based metabolomic and proteomic strategies. MS-based techniques have facilitated the rapid and economical evaluation of a broad spectrum of metabolites in various body fluids, also collected in small samples, like dried blood spots. This approach has enabled the timely diagnosis of OAs, thereby facilitating early therapeutic intervention. Besides providing an overview of MS-based approaches most frequently used to study the molecular mechanisms underlying OA pathophysiology, we discuss the principal challenges of metabolomic and proteomic applications to OAs.

Highlights

The term “inborn errors of metabolism” (IEMs) was coined by Garrod in 1908 to describe genetically determined conditions, such as alkaptonuria, albinism, pentosuria, and cystinuria [1]
Results reported consistent detection of key biomarkers across many specimens with clear segregation of disease-related analyte levels between unaffected versus affected individuals in most cases tested. Overall this analysis provided excellent coverage of the amino acids and acylcarnitines performed by targeted methods; a number a relevant plasma compounds like homocysteine and methylmalonic acid were not identified
Metabolomic strategies need to improve its analytical protocols; they lack a standard operating procedure to analyze biofluids and a proper validation of the obtained results that allow comparing the analytical data between different studies and/or laboratories

Summary

Introduction

The term “inborn errors of metabolism” (IEMs) was coined by Garrod in 1908 to describe genetically determined conditions, such as alkaptonuria, albinism, pentosuria, and cystinuria [1]. Organic acidemias or organic acidurias (OAs) are inherited metabolic disorders caused by deficiency of enzymatic activities in the catabolism of amino acids, carbohydrates, or lipids [4, 5] These disorders result in the accumulation of mono-, di-, or tricarboxylic acids, generally referred to as organic acids. The energetic functional impairment of other organs or systems in OAs may be related to a preferential accumulation of mitochondrial intermediates within this same organelle, before leaving the cell [9] This is true for OAs related to propionate metabolism such as MMA and PA, in which neither diet, vitamin therapy, nor liver transplantation appears to prevent neurologic complications such as leukoencephalopathy and basal ganglia atrophy [9]. This approach has enabled the timely diagnosis of OAs, thereby facilitating early institution of therapy

Metabolomic Strategies and Applications in Organic Acidemias

Proteomics Strategies and Applications in Organic Acidemias

Conclusions

C16: Hexadecanoyl-L-carnitine