Identification of likely associations between cerebral folate deficiency and complex genetic‐ and metabolic pathogenesis of autism spectrum disorders by utilization of a pilot interaction modeling approach

Abstract

Recently, cerebral folate deficiency (CFD) was suggested to be involved in the pathogenesis of autism spectrum disorders (ASD). However, the exact role of folate metabolism in the pathogenesis of ASD, identification of underlying pathogenic mechanisms and impaired metabolic pathways remain unexplained. The aim of our study was to develop and test a novel, unbiased, bioinformatics approach in order to identify links between ASD and disturbed cerebral metabolism by focusing on abnormal folate metabolism, which could foster patient stratification and novel therapeutic interventions. An unbiased, automatable, computational workflow interaction model was developed using available data from public databases. The interaction network model of ASD-associated genes with known cerebral expression and function (SFARI) and metabolic networks (MetScape), including connections to known metabolic substrates, metabolites and cofactors involving folates, was established. Intersection of bioinformatically created networks resulted in a limited amount of interaction modules pointing to common disturbed metabolic pathways, linking ASD to CFD. Two independent interaction modules (comprising three pathways) covering enzymes encoded by ASD-related genes and folate cofactors utilizing enzymes were generated. Module 1 suggested possible interference of CFD with serine and lysine metabolism, while module 2 identified correlations with purine metabolism and inosine monophosphate production. Since our approach was primarily conceived as a proof of principle, further amendments of the presented initial model are necessary to obtain additional actionable outcomes. Our modelling strategy identified not only previously known interactions supported by evidence-based analyses, but also novel plausible interactions, which could be validated in subsequent functional and/or clinical studies. Autism Res 2017, 10: 1424-1435. © 2017 International Society for Autism Research, Wiley Periodicals, Inc.

Folate Metabolism Abnormalities in Autism: Potential Biomarkers

“…Folate is essential for mitochondrial function [25,65], raising the possibility that insufficiency of folate could account for mitochondrial abnormalities. Others have recently suggested that folate abnormalities and ASD may be connected through other metabolic pathways that are commonly abnormal to both such as serine, lysine and/or purine metabolism [66]. We have recently demonstrated that FRAAs during gestation may play a role in thyroid abnormalities present in children with ASD [67].…”

Nutritional Status and Symptoms in Preschool Children With Autism Spectrum Disorder: A Two-Center Comparative Study in Chongqing and Hainan Province, China

“…As a one-carbon donor, folate is essential for numerous metabolic biochemical processes. Many studies showed the association between genetic and abnormalities of folic acid and the pathogenesis of ASD ( 51 – 56 ). In addition, in our study, there was a negative association between folate and severity of ASD symptom.…”

<p>Bridging the Gap Between Physical Health and Autism Spectrum Disorder</p>

“…184 Cerebral folate deficiency, together with folate receptors autoantibodies, have also been reported to play a pathological role in cases of ASD. 185 Healthcare professionals should have awareness of and screen for metabolic and/or mitochondrial dysfunction as these physical comorbidities can potentially contribute to ASD severity.…”