Altered Urinary Amino Acids in Children With Autism Spectrum Disorders

Abstract

Autism spectrum disorders (ASD) affect 1% of children. Although there is no cure, early diagnosis and behavioral intervention can relieve the symptoms. The clinical heterogeneity of ASD has created a need for improved sensitive and specific laboratory diagnostic methods. Liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based analysis of the metabolome has shown great potential to uncover biomarkers for complex diseases such as ASD. Here, we used a two-step discovery–validation approach to identify potential novel metabolic biomarkers for ASD. Urine samples from 57 children with ASD and 81 matched children with typical development (TD) were analyzed by LS-MS/MS to assess differences in urinary amino acids and their metabolites (referred to as UAA indicators). A total of 63 UAA indicators were identified, of which 21 were present at significantly different levels in the urine of ASD children compared with TD children. Of these 21, the concentrations of 19 and 10 were higher and lower, respectively, in the urine of ASD children compared with TD children. Using support vector machine modeling and receiver operating characteristic curve analysis, we identified a panel of 7 UAA indicators that discriminated between the samples from ASD and TD children (lysine, 2-aminoisobutyric acid, 5-hydroxytryptamine, proline, aspartate, arginine/ornithine, and 4-hydroxyproline). Among the significantly changed pathways in ASD children were the ornithine/urea cycle (decreased levels of the excitatory amino acid aspartate [p = 2.15 × 10-10] and increased arginine/ornithine [p = 5.21 × 10-9]), tryptophan metabolism (increased levels of inhibitory 5-hydroxytryptamine p = 3.62 × 10-9), the methionine cycle (increased methionine sulfoxide [p = 1.46 × 10-10] and decreased homocysteine [p = 2.73 × 10-7]), and lysine metabolism (reduced lysine [p = 7.8 × 10-9], α-aminoadipic acid [p = 1.16 × 10-9], and 5-aminovaleric acid [p = 1.05 × 10-5]). Collectively, the data presented here identify a possible imbalance between excitatory and inhibitory amino acid metabolism in ASD children. The significantly altered UAA indicators could therefore be potential diagnostic biomarkers for ASD.

Differential Metabolites in Chinese Autistic Children: A Multi-Centre Study Based on Urinary 1H-NMR Metabolomics Analysis

“…S6). In accordance with previous observations, amino acid metabolism disorder plays an important role in the pathogenesis mechanism of ASD [33][34][35][36][37]. Creatine and creatinine, which show signi cant metabolism alterations in ASD, play an essential role in maintaining a high level of energy supply for the brain [38].…”

Plasma and Fecal Metabolite Profiles in Autism Spectrum Disorder

“…We also observe perturbations in the urea cycle, which processes the amino group of amino acids for excretion in urine ( Figure S4G-S4H). Abnormalities in this pathway can be indicative of altered amino acid degradation observed in ASD and can lead to neurotoxic accumulation of nitrogencontaining compounds in the blood (80). Together, these results corroborate and extend a growing body of research into altered mitochondrial metabolism and oxidative stress in ASD.…”

Composition of Gut Microbiota in Children with Autism Spectrum Disorder: A Systematic Review and Meta-Analysis

“…It is therefore expected that when the abundance of Trp-metabolizing bacteria such as Bacteroides and Clostridium increases, serotonin concentrations also increase as a result of their metabolic activity [64,65]. Meanwhile, lower levels of glutathione, homocysteine, methionine, and S-adenosylmethionine have been observed more in ASD children than in neurotypical children [66,67]. Some of these are involved in the metabolism of sulfur and methylation, which contribute to the reduction of oxidative stress, cell detoxification, and excretion of heavy metals [45].…”