Background: Neurodevelopmental disorders, including autism spectrum disorder (ASD), are characterised by alterations in genetic, neural, and cognitive development. The methylenetetrahydrofolate reductase (MTHFR) gene, particularly C677T and A1298C polymorphisms, influences methylation cycles and neurotransmitter synthesis pathways. Despite its clinical relevance, little is known about how MTHFR polymorphisms impact neurophysiology. Electroencephalography (EEG), a non-invasive measure of brain activity, may offer insight into genotype-related functional alterations and serve as potential biomarkers linking MTHFR variants to altered brain function in ASD. Aim: This systematic review aimed to evaluate published evidence linking MTHFR polymorphisms with EEG characteristics, and to explore whether EEG could be a potential screening or diagnostic tool for neurodevelopmental disorders, particularly ASD.
Methods: A systematic search was conducted across Scopus, PubMed, Web of Science, and Google Scholar using PRISMA guidelines and a PROSPERO-registered protocol. Two thematic streams were reviewed: (1) EEG features associated with MTHFR variants, and (2) MTHFR associations with neurodevelopmental disorders, particularly ASD. Inclusion criteria were original human studies involving MTHFR C677T and/or A1298C variants and EEG or ASD outcomes. Data were extracted using a standardised template and quality was reviewed using the CASP checklist.
Results: A limited number of studies directly linked EEG to MTHFR genotype, with only one reporting a distinct bilateral 4.5 Hz parieto-temporal rhythm in children with ASD, which was strongly associated with MTHFR variants. No study has yet validated EEG as a formal screening tool for genotype, however, theoretical evidence supports an association between MTHFR polymorphisms and ASD.
Implications: EEG may hold promise as a non-invasive screening method for identifying gene-associated neurodevelopmental risk profiles. Further research is needed to standardise EEG protocols and validate biomarkers. 49
Relevance: Early detection of genetic vulnerabilities using EEG could improve diagnostic and health outcomes for neurodiverse populations, which aligns directly with the conference’s theme of social and environmental justice.