Background

Autism spectrum disorder (ASD) is behaviorally and biologically heterogeneous and likely represents a series of conditions arising from different underlying genetic, metabolic, and environmental factors. There are currently no reliable diagnostic biomarkers for ASD. Based on evidence that dysregulation of branched-chain amino acids (BCAAs) may contribute to the behavioral characteristics of ASD, we tested whether dysregulation of amino acids (AAs) was a pervasive phenomenon in individuals with ASD. This is the first article to report results from the Children's Autism Metabolome Project (CAMP), a large-scale effort to define autism biomarkers based on metabolomic analyses of blood samples from young children.

Methods

Dysregulation of AA metabolism was identified by comparing plasma metabolites from 516 children with ASD with those from 164 age-matched typically developing children recruited into the CAMP. ASD subjects were stratified into subpopulations based on shared metabolic phenotypes associated with BCAA dysregulation.

Results

We identified groups of AAs with positive correlations that were, as a group, negatively correlated with BCAA levels in ASD. Imbalances between these two groups of AAs identified three ASD-associated amino acid dysregulation metabotypes. The combination of glutamine, glycine, and ornithine amino acid dysregulation metabotypes identified a dysregulation in AA/BCAA metabolism that is present in 16.7% of the CAMP subjects with ASD and is detectable with a specificity of 96.3% and a positive predictive value of 93.5% within the ASD subject cohort.

Conclusions

Identification and utilization of metabotypes of ASD can lead to actionable metabolic tests that support early diagnosis and stratification for targeted therapeutic interventions.