Abstract
Autism spectrum disorder (ASD) is a complex neurodevelopmental condition affecting behavior and communication, presenting with extremely different clinical phenotypes and features. ASD etiology is composite and multifaceted with several causes and risk factors responsible for different individual disease pathophysiological processes and clinical phenotypes. From a genetic and epigenetic side, several candidate genes have been reported as potentially linked to ASD, which can be detected in about 10–25% of patients. Folate gene polymorphisms have been previously associated with other psychiatric and neurodegenerative diseases, mainly focused on gene variants in the DHFR gene (5q14.1; rs70991108, 19bp ins/del), MTHFR gene (1p36.22; rs1801133, C677T and rs1801131, A1298C), and CBS gene (21q22.3; rs876657421, 844ins68). Of note, their roles have been scarcely investigated from a sex/gender viewpoint, though ASD is characterized by a strong sex gap in onset-risk and progression. The aim of the present review is to point out the molecular mechanisms related to intracellular folate recycling affecting in turn remethylation and transsulfuration pathways having potential effects on ASD. Brain epigenome during fetal life necessarily reflects the sex-dependent different imprint of the genome-environment interactions which effects are difficult to decrypt. We here will focus on the DHFR, MTHFR and CBS gene-triad by dissecting their roles in a sex-oriented view, primarily to bring new perspectives in ASD epigenetics.
Highlights
In 1943, Kanner was the first to systematically define autism as an innate inability to create normal, biologically determined, and emotional contact with others [1]
One-carbon metabolism is crucial in epigenetic regulation during embryo development and it is an integrated complex system composed of three main pathways: the folate cycle, the methionine cycle, and the transsulfuration pathway [38]
The role of methylenetetrahydrofolate reductase (MTHFR) in Autism spectrum disorder (ASD) has been less investigated compared with other mental illnesses, such as schizophrenia and depression, though several reports highlighted a potential role of C677T and A1298C variants in ASD risk establishment (Table 1)
Summary
In 1943, Kanner was the first to systematically define autism as an innate inability to create normal, biologically determined, and emotional contact with others [1]. Together with recognized gene-linked syndromes, several ASD patients show chromosomal rearrangements [14], with a crucial time point for damageonset identified during embryogenesis at the stage of neural tube closure [15] Of note, this event has been hypothesized to have sex-related differences due to the role of specific genes (i.e., SOX9) in affecting male phenotype development and skeletal growth [16,17]. Despite the several hypotheses, the precise role of genetic and environmental factors in determining the individual risk and disease phenotype still needs to be fully clarified Among those genes associated with modification of disease susceptibility, the ones belonging to the folate homeostasis and methionine-homocysteine recycling are gaining interest in the context of different neuropsychiatric/neurobehavioral disorders [34,35]. The gene-triad belonging to the remethylation and transsulfuration pathways are dihydrofolate reductase (DHFR), methylenetetrahydrofolate reductase (MTHFR), and cystathionine-β synthase (CBS) are potential candidates as modifier genes in ASD susceptibility
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