Abstract
BackgroundAutism 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.MethodsWe 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.ResultsMetabolic 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.ConclusionsTryptophan 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.
Highlights
Autism spectrum disorders (ASDs) are relatively common neurodevelopmental conditions whose biological basis has been incompletely determined
Identification of reduced tryptophan metabolism in the ASD cells We initiated an investigation of the metabolic profile of lymphoblastoid cell lines from patients with different neurobehavioral disorders and normal individuals, utilizing Biolog Phenotype MicroArray plates to see if patients with specific disorders had a characteristic profile
The remaining seven cell lines were from patients with syndromal autism: four cases had Fragile X syndrome, autistic features and full methylation at the FRAXA locus; two cases had Rett syndrome and MECP2 mutations; one case had a ZNF711 mutation, X-linked intellectual disability and clinical findings consistent with ASDs
Summary
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. Autism spectrum disorders (ASDs) constitute a heterogeneous group of neurodevelopmental conditions characterized by three core signs: impairment of social interactions, communication issues, and repetitive behaviors. The investigation for the molecular bases of these disorders has highlighted numerous metabolic abnormalities in ASD patients and several biochemical markers have been associated with autistic traits (hyperserotoninemia [6], urinary catabolites of sulfur and amino acid metabolism [7], and oxidative metabolism biomarkers [8]). There are still no laboratory tests that offer a reliable confirmation for the clinical diagnosis, or provide for efficient screening of individuals presenting with behavioral features suggestive of ASDs
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