Metabolic network analysis of pre-ASD newborns and 5-year-old children with autism spectrum disorder
Sai Sachin Lingampelly1,2, Jane C Naviaux1,3, Luke S Heuer4
1The Mitochondrial and Metabolic Disease Center, University of California, San Diego School of Medicine, San Diego, CA, 92103-8467, USA.
Insights
Autism spectrum disorder (ASD) shows distinct metabolic changes, including reduced antioxidant defenses and altered purine metabolism networks. These findings highlight new metabolic phenotypes and the role of mitochondrial function in ASD development.
Area of Science:
- Biochemistry
- Metabolomics
- Developmental Biology
Background:
- Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with poorly understood metabolic underpinnings.
- Previous research has suggested metabolic alterations in ASD, but comprehensive developmental analyses are limited.
Purpose of the Study:
- To investigate developmental metabolic features in autism spectrum disorder (ASD) using classical metabolomics and novel metabolic network analysis.
- To identify specific biochemical pathways and network alterations associated with ASD development from infancy to early childhood.
Main Methods:
- Employed classical metabolomic profiling and advanced metabolic network analysis on samples from newborns and 5-year-old children.
- Utilized CIRCOS plots and a novel parameter ( net) to assess metabolic network connectivity and identify key pathway hubs.
- Examined 50 biochemical pathways and 450 polar and lipid metabolites.
Main Results:
- Eighty percent of the metabolic impact in ASD was attributed to 14 shared biochemical pathways, characterized by decreased anti-inflammatory/antioxidant defenses and increased stress molecules (lactate, glycerol, cholesterol, ceramides).
- Significant differences in metabolic network connectivity were observed between typically developing children and those with ASD.
- The purine metabolic network exhibited the most substantial developmental dysregulation in ASD, notably lacking a 17-fold reversal seen in typically developing children.
Conclusions:
- Identified novel metabolic phenotypes and developmental states of metabolic correlation networks in ASD.
- Highlighted the critical role of mitochondrial dysfunction, purine metabolism, and purinergic signaling in the pathophysiology of autism spectrum disorder.
- Findings provide a foundation for understanding ASD's metabolic basis and potential therapeutic targets.
Abstract:
Classical metabolomic and new metabolic network methods were used to study the developmental features of autism spectrum disorder (ASD) in newborns (n = 205) and 5-year-old children (n = 53). Eighty percent of the metabolic impact in ASD was caused by 14 shared biochemical pathways that led to decreased anti-inflammatory and antioxidant defenses, and to increased physiologic stress molecules like lactate, glycerol, cholesterol, and ceramides. CIRCOS plots and a new metabolic network parameter, net, revealed differences in both the kind and degree of network connectivity. Of 50 biochemical pathways and 450 polar and lipid metabolites examined, the developmental regulation of the purine network was most changed. Purine network hub analysis revealed a 17-fold reversal in typically developing children. This purine network reversal did not occur in ASD. These results revealed previously unknown metabolic phenotypes, identified new developmental states of the metabolic correlation network, and underscored the role of mitochondrial functional changes, purine metabolism, and purinergic signaling in autism spectrum disorder.
