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. 2022 Apr 20;12(5):371.
doi: 10.3390/metabo12050371.

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

Danielle Brister  1 , Brianna A Werner  2   3 , Geoffrey Gideon  4 , Patrick J McCarty  2   3 , Alison Lane  2   3 , Brian T Burrows  5 , Sallie McLees  2   3 , P David Adelson  5 , Jorge I Arango  5 , William Marsh  6 , Angelea Flores  7 , Matthew T Pankratz  7 , Ngoc Han Ly  5 , Madison Flood  2   3 , Danni Brown  5 , David Carpentieri  7 , Yan Jin  8 , Haiwei Gu  8 , Richard E Frye  2   3
Affiliations

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

Danielle Brister et al. Metabolites. .

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.

Keywords: amino acid metabolism; autism spectrum disorder; cerebrospinal fluid; cis-cis-muconic acid; developmental delay; energy metabolism; epilepsy; mass spectrometry; metabolomics; redox metabolism; shikimic acid; vitamins.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Heatmaps for Metabolites Found to Be Significantly (p ≤ 0.05) Related to Specific Clinical Groups. Each map is sorted by clinical group with color key for group membership on top of heatmap. Heatmap color represents (A) ASD (28 significant features); (B) epilepsy (28 significant features); (C) DD (19 significant features).
Figure 2
Figure 2
Major Nodes for Metabolite–Metabolite Interaction Networks for (A) Autism Spectrum Disorder (ASD), (B) epilepsy (EPI) and (C) Developmental Delay (DD) as well as (D) Categories for Pathways Identified for each Disorder.
Figure 2
Figure 2
Major Nodes for Metabolite–Metabolite Interaction Networks for (A) Autism Spectrum Disorder (ASD), (B) epilepsy (EPI) and (C) Developmental Delay (DD) as well as (D) Categories for Pathways Identified for each Disorder.
Figure 3
Figure 3
Metabolite–Metabolite Network Pathway Overlap by Clinical Group. Color code represents pathway category. Metabolites in black belong to multiple pathways which are specified by colored numbers in parenthesis following the metabolite name.
Figure 4
Figure 4
Major Nodes for Metabolite–Metabolite Interaction Networks for (A) ASD, (B) epilepsy (EPI) and (C) DD.
Figure 5
Figure 5
Metabolite–Metabolite Interaction Networks for Energy and Amino Acid Pathways in ASD (A,B), epilepsy (EPI) (C,D) and DD (E,F) Groups.
Figure 5
Figure 5
Metabolite–Metabolite Interaction Networks for Energy and Amino Acid Pathways in ASD (A,B), epilepsy (EPI) (C,D) and DD (E,F) Groups.
See this image and copyright information in PMC

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