Table 2.

Abnormal metabolism associated with autism spectrum disorder from metabolomic studies in blood samples

Ref and Subjects	Age (years)	Method	Categories of Metabo- lites/ Involved metabolic pathways	Changes in metabolites compared to typical children		Interpretation
				Increase	Decrease
Kelly et al. 2019
403 children (365 categorized to “on schedule” and 38 categorized to “requiring further monitoring/evaluation” from ASQ)	3	Targeted approach using UPLC-MS/MS	Tyrosine metabolism		N-formylphenylalanine	There are abnormalities of amino acid (tyrosine, tryptophan, arginine, proline, methionine, cysteine, and taurine), lipid (phospholipid, sphingolipid, and fatty acid), urea cycle, and xenobiotics metabolism in children with poor ASQ communication skills, relative to children with typical communication development.
			Phospholipid metabolism	trimethylamine N-oxide
			Food Component/Plant	Cinnamoylglycine Erythritol	Pyrraline
			Endocannabinoid	Oleoyl ethanolamide Palmitoyl ethanolamide Linoleoyl ethanolamide
			Tryptophan metabolism	Serotonin	5-hydroxyindoleacetate N-formylanthranilic acid
			Sphingolipid metabolism		Sphingomyelin
			Fatty acid metabolism	Docosahexaenoylcarnitine
			Urea cycle	Prolylhydroxyproline
			Arginine and Proline metabolism	Prolylhydroxyproline
			Methionine, cysteine, and Taurine metabolism	Alpha-ketobutyrate
Smith et al. 2019
516 ASD compared with 164 typical children	1.5-4	Targeted approach using LC-MS	BCAA metabolism	Glutamine-to-isoleucine ratio Glutamine-to-leucine ratio Glutamine-to-valine ratio Glycine-to-isoleucine ratio Glycine-to-leucine ratio Glycine-to-valine ratio Ornithine-to-isoleucine Ornithine-to-leucine ratio Ornithine-to-valine ratio		There are abnormalities of BCAA metabolism in plasma of ASD.
Rangel-Huerta et al. 2019
30 ASD compared with 30 typical children	2-6	Untargeted approach using LC-MS	Neurotransmitter		Glutamate	There are abnormalities of neurotransmitter, reactive oxidative stress, BCAA, NAD, phospholipid metabolism in plasma of ASD.
			Reactive oxidative stress	Arginine N-acetylarginine Homoarginine
			BCAA metabolism	3-methyl-2-oxobutyrate 3-methyl-2-oxovalerate 4-methyl-2-oxopentanoate Isovalerylcarnitine Isobutyrylcarnitine
			NAD+ metabolism	1-methylnicotinamide N-methyl-2-pyridone-5-carboxamide	Nicotinamide
			Phospholipid metabolism		1-palmitoyl-glycerol-phosphatidyl-etholamine 1-stearoyl-glycerol-phosphatidyl-etholamine
			Others	n-alpha-acetylornithine Tryptophan Kynurenine 5-bromotryptophan 3-indoxyl sulfate Indole lactate 6-hydroxyindole sulfate
Orozco et al. 2019
167 ASD 51 i-DD 31 DS 193 typical children	2-5	Untargeted approach using 1H-NMR	One carbon metabolism	Glycine Serine		There are abnormalities of one carbon metabolism, TCA cycle, urea cycle in plasma of ASD.
			TCA cycle	Cis-aconitate
			Urea cycle	Ornithine
Lv et al. 2018
60 ASD compared with 30 typical children	2-5	Targeted approach using MS/MS	Fatty acid metabolism		Free carnitine Glutaryl carnitine Octyl carnitine Twenty-four carbonyl carnitine Carnosyl carnitine	There are abnormalities of fatty acid metabolism (free carnitine, short and long chain acyl carnitines) in plasma of ASD.
Anwar et al. 2018
38 ASD compared with 31 typical children	5-12	Targeted approach using LC-MS	Protein glycation	Nε-carboxymethyllysine Nω-carboxymethyllysine	3-deoxyglucoosone-derived hydroimidazolone	There are abnormalities of protein glycation and protein oxidation metabolism in plasma of ASD.
			Protein oxidation	Dityrosine
Wang et al. 2016
173 ASD compared with 163 typical children	3-6	Untargeted approach using UPLC/Q-TOF MS/MS	Fatty acid metabolism		Docosahexaenoic acid Docosapentaenoic acid	There are abnormalities of fatty acid, sphingomyelin, lysophosphatide, and beta oxidation in plasma of ASD.
			Sphingomyelin metabolism		Sphingosine-1-phosphate
			Lysophosphatide metabolism		LPA LysoPE
			Fatty acid beta oxidation	Decanoylcarnitine	9,10-Epoxyoctadecenoic acid
			Others	Pregnanetriol	Adrenic acid Uric acid
West et al. 2014
52 ASD compared with 30 typical children	4-6	Targeted approach using GC-MS and untargeted approach using LC-HRMS	TCA cycle	Succinate	Citrate	There are abnormalities of TCA cycle, fatty acid, oxidative phosphorylation, mitochondrial dysfunction, and gut microbiome metabolism in plasma of ASD.
			Fatty acid metabolism and oxidative stress		Methylhexa-decanoic acid Hepta-decanoic acid
			Oxidative phosphorylation	Aspartate Glutamate
			Mitochondrial energy production	DHEA-S	Isoleucine
			Gut microbiome		4-hydroxyphenyllactate
			Others	Glutaric acid 3-aminoisobutyric acid	Creatinine Homocitrulline
Kuwabara et al. 2013
25 ASD compared with 28 typical children	25-40 male	Untargeted approach using CE-TOF-MS	Oxidative stress	Arginine Taurine	5-Oxoproline	There are abnormalities of oxidative stress and mitochondrial metabolism in plasma of ASD.
			Mitochondrial dysfunction		Lactic acid
Delaye et al. 2018
22 ASD 29 ID 30 typical children	> 18	Targeted approach using amino acid chromatography	Neurotransmitter		Glutamate Serine	There are abnormalities of neurotransmitter metabolism in plasma of ASD.
			Others		Proline Ornithine

ASD autism spectrum disorder, i-DD idiopathic-developmental delay, DS Down syndrome, ID intellectual disability, ASQ Ages and Stages Questionnaire, UPLC-MS/MS ultra-performance liquid chromatography-tandem mass spectrometer, LC–MS liquid chromatography–mass spectrometry, GC–MS gas chromatography-mass spectrometry, ¹H-NMR hydrogen-1 nuclear magnetic resonance, MS/MS tandem mass spectrometry, UPLC/Q-TOF–MS ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry, LC-HRMS liquid chromatography-high resolution mass spectrometry, CE-TOF–MS capillary-electrophoresis-time-of-flight-mass-spectrometer, NAD nicotinamide adenine dinucleotide, LPA lysophosphatidic acid, LysoPE lysophosphatidylethanolamine, BCAA branched-chain amino acids, TCA tricarboxylic acid cycle, DHEA-S dehydroepiandrosterone sulfate