Alterations in intracellular amino acid kinetics in high-functioning young adults with Autism Spectrum Disorder: A stable isotope study

Abstract Metabolic disturbances play a role in the pathophysiology of Autism Spectrum Disorder (ASD). Changes in plasma amino acid levels are reported in ASD, particularly the branched-chain and aromatic amino acids, however findings vary across studies. To understand the underlying intracellular metabolic kinetic changes in ASD, stable isotope tracer methods and compartmental modeling was used in young adults with high-functioning ASD (n=19, age 24.4yr) and controls (n=16, age 23.5yr). Postabsorptive amino acid kinetics (intracellular production (ICP) and pool sizes) and concentrations of 18 amino acids were measured by pulse isotope administration and 2 hour blood sampling. Tracer enrichments were analyzed by LC-MS/MS and intracellular kinetics by compartmental analysis. Besides reduced executive function and increased depression and anxiety, the ASD group had higher ICP of phenylalanine (PHE) (p<0.001), tyrosine (TYR) (p=0.01), PHE to TYR conversion (p=0.001), leucine (p=0.002), valine (p=0.028), and methionine (p=0.033) despite comparable plasma concentrations. Although the concentrations of the keto acids of leucine and valine (KIC, KMV) were lower by ~18% in ASD (p<0.05), the ICPs and pool sizes were lower by ~13% for KIC and higher by ~52% for KMV. Therefore, upregulation of intracellular metabolism of several amino acids (i.e., aromatic) is already present in high-functioning young adults with ASD but cannot be explained by dietary intake or body composition. The increased leucine production was unable to prevent reduction of its keto acid concentration indicating enhanced leucine transamination. Clinical trial registration: ClinicalTrials.gov NCT02733120