Epigenetic Hierarchies in Autism from Folate–SAM Metabolism to LSD1 and G9a

Autism spectrum disorder (ASD) is a diverse neurodevelopmental condition involving interactions among genetic, environmental, metabolic, immune, synaptic, and epigenetic factors. This review explores whether disruptions in folate-dependent one-carbon metabolism and S-adenosylmethionine (SAM) availability may increase epigenetic susceptibility in specific ASD subgroups based on biological criteria. This narrative, hypothesis-driven review synthesizes selected peer-reviewed literature encompassing human studies, animal models, cell systems, and biochemical research. Findings including decreased methylation capacity, altered DNA methylation, and abnormal histone methylation have been reported in ASD and related neurodevelopmental conditions. Nonetheless, evidence strength varies considerably depending on phenotype, tissue type, developmental stage, and experimental system. On this basis, a provisional SAM-dependent epigenetic hierarchy is proposed in which methyltransferases may differ in vulnerability to metabolic stress according to enzyme kinetics, subcellular context, developmental timing, and compensatory regulation. This model is conceptual rather than an established mechanism demonstrated uniformly across ASD. Clinical and translational findings are interpreted cautiously. Evidence for folinic acid is strongest in selected subgroups such as folate receptor alpha autoantibody-positive ASD and cerebral folate deficiency-related presentations, whereas LSD1/KDM1A and G9a/EHMT1/2 modulation remains largely preclinical. Overall, the review argues that folate–SAM-related epigenetic dysregulation may represent one contributory pathway in some ASD subgroups and provides a framework for future mechanistic and stratified therapeutic studies.