Central Nervous System Metabolism in Autism, Epilepsy and Developmental Delays: A Cerebrospinal Fluid Analysis

Abstract

Neurodevelopmental disorders are associated with metabolic pathway imbalances; however, most metabolic measurements are made peripherally, leaving central metabolic disturbances under-investigated. Cerebrospinal fluid obtained intraoperatively from children with autism spectrum disorder (ASD, n = 34), developmental delays (DD, n = 20), and those without known DD/ASD (n = 34) was analyzed using large-scale targeted mass spectrometry. Eighteen also had epilepsy (EPI). Metabolites significantly related to ASD, DD and EPI were identified by linear models and entered into metabolite–metabolite network pathway analysis. Common disrupted pathways were analyzed for each group of interest. Central metabolites most involved in metabolic pathways were L-cysteine, adenine, and dodecanoic acid for ASD; nicotinamide adenine dinucleotide phosphate, L-aspartic acid, and glycine for EPI; and adenosine triphosphate, L-glutamine, ornithine, L-arginine, L-lysine, citrulline, and L-homoserine for DD. Amino acid and energy metabolism pathways were most disrupted in all disorders, but the source of the disruption was different for each disorder. Disruption in vitamin and one-carbon metabolism was associated with DD and EPI, lipid pathway disruption was associated with EPI and redox metabolism disruption was related to ASD. Two microbiome metabolites were also detected in the CSF: shikimic and cis-cis-muconic acid. Overall, this study provides increased insight into unique metabolic disruptions in distinct but overlapping neurodevelopmental disorders.

Metabolomic Signatures of Autism Spectrum Disorder

“…The repeated association of energy metabolism with many aspects of ASD is not surprising given the high rate of mitochondrial dysfunction associated with ASD [ 10 , 11 ]. Furthermore, the link to neurodevelopment and language is not surprising as previous studies have linked developmental delays to abnormal CAC and energy pathway biomarkers in urine [ 54 ], plasma [ 55 , 56 ], and CSF [ 34 ]. Children with ASD and mitochondrial disease appear to have two developmental profiles, those with developmental delays, including motor delay, and those that manifest NDR [ 10 ].…”

“…Procedures of metabolomic analysis have been outlined previously [ 34 ] but the procedures are outlined here for completeness.…”

“…One complication of metabolic biomarker studies is the large number of metabolites considered in the analysis, making any one metabolite often non-specific. Thus, for such analysis, pathway analysis is often helpful to better understand the complex data [ 34 ]. In this study, we use pathway analysis and analysis of metabolic-metabolic interactions to better understand metabolic signatures associated with ASD.…”

Modern Biomarkers for Autism Spectrum Disorder: Future Directions

“…Unfortunately, these measures do require cooperation of the infant and specialized centers. Other technologies such as untargeted metabolomics [138] and proteomics [139] are emerging but are still inconsistent in their findings.…”

Knowledge Atlas of the Co-Occurrence of Epilepsy and Autism: A Bibliometric Analysis and Visualization Using VOSviewer and CiteSpace

“…The author with the highest number of publications is Frye, R. E., who published recent articles discussing the pathogenesis of epilepsy and autism with topics such as metabolism, mitochondrial diseases, central nervous system metabolism, etc. [25][26][27] The author with the highest average number of citations per publication is Tuchman, R., who mainly discusses the relationship between epilepsy and ASD. [28][29][30] Although the number of authors of the 473 articles is as high as 2584, the author cooperation network map indicates that only a small number of authors cooperate closely and that most authors do not have cooperative relationships.…”