Role of Folate-Dependent One-Carbon Metabolism and Transulfuration Pathways in Autism Spectrum Disorder
- Conference: Translational Medicine and Bioengineering Conference
- Year: 2017
- Proceeding: 2nd Bioengineering & Translational Medicine Conference
- Group: General Submissions
- Time: Sunday, October 29, 2017 - 9:30am-10:00am
Stepping towards this goal of incorporating biochemical data into ASD diagnosis, we analyzed measurements of metabolite concentrations of the folate-dependent one-carbon metabolism and transulfuration pathways taken from blood samples of 83 participants with ASD and 76 age-matched neurotypical peers. Fisher Discriminant Analysis enabled multivariate classification of the participants as on the spectrum or neurotypical which results in 96.1% of all neurotypical participants being correctly identified as such while still correctly identifying 97.6% of the ASD cohort. Furthermore, kernel partial least squares was used to predict adaptive behavior, as measured by the Vineland Adaptive Behavior Composite score, where measurement of five metabolites of the pathways was sufficient to predict the Vineland score with an R2 of 0.45 after cross-validation. This level of accuracy for classification as well as adaptive behavior prediction far exceeds any other approach in this field.
In addition to classification and adaptive behavior prediction, we have developed a steady state model of the metabolic pathways. We estimated flux parameters for every participant of the study and derived a probability density function for each parameter for the neurotypical participants and, separately, for participants with an ASD diagnosis. Comparison of the parameter distributions between neurotypical study participants and those on the autism spectrum revealed significant differences for four model parameters. Sensitivity analysis identified the parameter describing the rate of glutamylcysteine synthesis, the rate-limiting step in glutathione production, to be particularly important in determining steady-state metabolite concentrations.
These computational studies enhance the analysis obtained from traditional population-level statistics and suggest that folate-dependent one carbon metabolism and transsulfuration may play an integral role in ASD pathophysiology. Although these results need to be replicated in independent studies, these analyses suggest combinations of metabolites in these pathways as potential biomarkers for ASD.