Metabolomic Signatures of Autism Spectrum Disorder

Abstract

Autism Spectrum Disorder (ASD) is associated with many variations in metabolism, but the ex-act correlates of these metabolic disturbances with behavior and development and their links to other core metabolic disruptions are understudied. In this study, large-scale targeted LC-MS/MS metabolomic analysis was conducted on fasting morning plasma samples from 57 children with ASD (29 with neurodevelopmental regression, NDR) and 37 healthy controls of similar age and gender. Linear model determined the metabolic signatures of ASD with and without NDR, measures of behavior and neurodevelopment, as well as markers of oxidative stress, inflammation, redox, methylation, and mitochondrial metabolism. MetaboAnalyst ver 5.0 (the Wishart Research Group at the University of Alberta, Edmonton, Canada) identified the pathways associated with altered metabolic signatures. Differences in histidine and glutathione metabolism as well as aromatic amino acid (AAA) biosynthesis differentiated ASD from controls. NDR was associated with disruption in nicotinamide and energy metabolism. Sleep and neurodevelopment were associated with energy metabolism while neurodevelopment was also associated with purine metabolism and aminoacyl-tRNA biosynthesis. While behavior was as-sociated with some of the same pathways as neurodevelopment, it was also associated with alternations in neurotransmitter metabolism. Alterations in methylation was associated with aminoacyl-tRNA biosynthesis and branched chain amino acid (BCAA) and nicotinamide metabolism. Alterations in glutathione metabolism was associated with changes in glycine, serine and threonine, BCAA and AAA metabolism. Markers of oxidative stress and inflammation were as-sociated with energy metabolism and aminoacyl-tRNA biosynthesis. Alterations in mitochondrial metabolism was associated with alterations in energy metabolism and L-glutamine. Using behavioral and biochemical markers, this study finds convergent disturbances in specific metabolic pathways with ASD, particularly changes in energy, nicotinamide, neurotransmitters, and BCAA, as well as aminoacyl-tRNA biosynthesis.

Metabolomics: Perspectives on Clinical Employment in Autism Spectrum Disorder

“…Furthermore, a correlation between clinical profile severity and the fecal metabolome emerged in a recent study on preschooler individuals with autism [24], showing higher levels of amino acids in children with a mild autism profile and higher levels of N-Methylhydantoin, 1,3-Dihydroxyacetone and fucose in children with greater clinical impairment. Finally, amino acid metabolism, monoamine neurotransmitters, γ-Aminobutyric acid (GABA), ornithine and choline have recently been related to core symptoms and aberrant behavior in ASD [48][49][50][51]. In particular, the negative correlation between the GABA (decreased level of inhibitory neurotransmitters) and autism's core symptoms [41,48,49] supports the theory of an excitatory-inhibitory imbalance in ASD [40,80].…”

“…Overall, the selected studies included a total of 2.079 individuals diagnosed with ASD (1.625 males, 394 females; mean age of 10,9 years), 51 individuals with other psychiatric comorbidities (developmental delays), 182 at-risk individuals (siblings, those with genetic conditions) and 1.530 healthy controls (TD). Sixteen of these studies were carried out in Europe [21,22,24,25,[29][30][31]35,37,39,41,44,45,47,52,56], twelve in Asia [23,28,33,34,36,40,42,43,46,50,54,55,58], eight in the USA [27,32,38,48,49,51,53,57] and one in Australia [58].…”

Autism spectrum disorder: pathogenesis, biomarker, and intervention therapy

“…At present, targeted detection of metabolites altered in blood include amino acids (tyrosine, tryptophan, arginine, proline, methionine, cysteine, and taurine), lipids (phospholipids, sphingolipids, and fatty acids), and metabolites in the urea cycle and xenobiotics metabolism. 142,235 The metabolites associated with branched-chain amino acid (BCAA) metabolism, 236 fatty acid metabolism (free carnitine, short-and long-chain acylcarnitine), 227 tricarboxylic acid (TCA) cycle, fatty acids, oxidative phosphorylation, mitochondrial dysfunction, gut microbiome metabolism, 142,237 and neurotransmitter metabolism 238 in the plasma of ASD are also involved.…”

NAD+ Precursors and Intestinal Inflammation: Therapeutic Insights Involving Gut Microbiota

“…Oxidative stress, mitochondrial dysfunction, and impaired energy metabolism involving NAD+, NADH, ATP, pyruvate, and lactate have been proposed as potential underlying mechanisms of ASD [115]. In children diagnosed with ASD, abnormal NAM-related biomarkers have been detected in both urine and stool samples, suggesting increased NAM breakdown [116]. Furthermore, compared to non-ASD individuals, children with ASD exhibited significantly lower levels of NADH oxidase activity (normalized to citrate synthase activity) in their lymphocyte mitochondria [117].…”