Decreased tryptophan metabolism in patients with Autism Spectrum Disorders

Background: Autism spectrum disorders (ASDs) are relatively common neurodevelopmental conditions whose
biological basis has been incompletely determined. Several biochemical markers have been associated with ASDs,
but there is still no laboratory test for these conditions.
Methods: We analyzed the metabolic profile of lymphoblastoid cell lines from 137 patients with
neurodevelopmental disorders with or without ASDs and 78 normal individuals, using Biolog Phenotype
MicroArrays.
Results: Metabolic profiling of lymphoblastoid cells revealed that the 87 patients with ASD as a clinical feature, as
compared to the 78 controls, exhibited on average reduced generation of NADH when tryptophan was the sole
energy source. The results correlated with the behavioral traits associated with either syndromal or non-syndromal
autism, independent of the genetic background of the individual. The low level of NADH generation in the
presence of tryptophan was not observed in cell lines from non-ASD patients with intellectual disability,
schizophrenia or conditions exhibiting several similarities with syndromal autism except for the behavioral traits.
Analysis of a previous small gene expression study found abnormal levels for some genes involved in tryptophan
metabolic pathways in 10 patients.
Conclusions: Tryptophan is a precursor of important compounds, such as serotonin, quinolinic acid, and kynurenic
acid, which are involved in neurodevelopment and synaptogenesis. In addition, quinolinic acid is the structural
precursor of NAD+, a critical energy carrier in mitochondria. Also, the serotonin branch of the tryptophan metabolic
pathway generates NADH. Lastly, the levels of quinolinic and kynurenic acid are strongly influenced by the activity
of the immune system. Therefore, decreased tryptophan metabolism may alter brain development, neuroimmune
activity and mitochondrial function. Our finding of decreased tryptophan metabolism appears to provide a unifying
biochemical basis for ASDs and perhaps an initial step in the development of a diagnostic assay for ASDs.
Keywords: Autism, Biomarker, Tryptophan, Metabolism, Screening