Abstract
The utility of low-resolution 1H-NMR analysis for the identification of biomarkers provided evidence for rapid biochemical diagnoses of organic acidemia and aminoacidopathy. 1H-NMR, with a sensitivity expected for a field strength of 400 MHz at 64 scans was used to establish the metabolomic urine sample profiles of an infant population diagnosed with small molecule Inborn Errors of Metabolism (smIEM) compared to unaffected individuals. A qualitative differentiation of the 1H-NMR spectral profiles of urine samples obtained from individuals affected by different organic acidemias and aminoacidopathies was achieved in combination with GC–MS. The smIEM disorders investigated in this study included phenylalanine metabolism; isovaleric, propionic, 3-methylglutaconicm and glutaric type I acidemia; and deficiencies in medium chain acyl-coenzyme and holocarboxylase synthase. The observed metabolites were comparable and similar to those reported in the literature, as well as to those detected with higher-resolution NMR. In this study, diagnostic marker metabolites were identified for the smIEM disorders. In some cases, changes in metabolite profiles differentiated post-treatments and follow-ups while allowing for the establishment of different clinical states of a biochemical disorder. In addition, for the first time, a 1H-NMR-based biomarker profile was established for holocarboxylase synthase deficiency spectrum.
Highlights
IntroductionInborn Errors of Metabolism (IEM) are monogenic diseases that affect the normal functioning of the human metabolism due to mutations in enzymes, transporters, and co-enzymes, among other proteins directly or indirectly involved in a metabolic pathway
Inborn Errors of Metabolism (IEM) are monogenic diseases that affect the normal functioning of the human metabolism due to mutations in enzymes, transporters, and co-enzymes, among other proteins directly or indirectly involved in a metabolic pathway.IEM classification could be based on either the involved metabolic pathways of amino acids, fatty acids, carbohydrates, etc., or affected organelles, as in the case of lysosomal storage diseases and peroxisome alterations [1,2,3]
The combination of gas chromatography coupled to mass spectrometry (GC–MS) and 1 H-NMR as metabolomic approach used in this study allows one to obtain a more holistic view of small molecule Inborn Errors of Metabolism (smIEM) disorders such as phenylalanine metabolism; isovaleric, propionic, 3-methylglutaconic, and glutaric type I acidemia; and deficiencies in medium chain acyl-coenzyme and holocarboxylase synthase
Summary
Inborn Errors of Metabolism (IEM) are monogenic diseases that affect the normal functioning of the human metabolism due to mutations in enzymes, transporters, and co-enzymes, among other proteins directly or indirectly involved in a metabolic pathway. IEM classification could be based on either the involved metabolic pathways of amino acids, fatty acids, carbohydrates, etc., or affected organelles, as in the case of lysosomal storage diseases and peroxisome alterations [1,2,3]. Errors of Metabolism (smIEM) are disorders in the metabolism of carbohydrates, purines, pyrimidines, creatine, and vitamins, as well as organic acidemias and aminoacidopathies. These groups of IEMs are characterized by clinical indications of intoxication, mainly caused by the abnormal production (usually a result of alternating pathways) of toxic metabolites. It is important to consider that effective treatments are available for many smIEM including nutritional intervention, pharmacotherapy, supplements, life style changes and transplants, among others [3,4,5]
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