5-mC DNA methylation in neurodevelopment: from molecular mechanisms to therapeutic implications.

5-mC DNA methylation is a fundamental epigenetic modification that plays a crucial role in neurodevelopment and neurological disorders. This review synthesizes the current understanding of 5-mC DNA methylation in neural system development and its implications in neurodevelopmental disorders. During normal neural development, 5-mC methylation precisely regulates neural stem cell differentiation and neuronal maturation through DNA methyltransferases (DNMTs) and methyl-CpG-binding domain (MBD) proteins. Disruption of these methylation patterns contributes to various neurodevelopmental disorders. In autism spectrum disorder (ASD), altered methylation patterns in specific genes like SHANK family and genome-wide methylation changes have been identified as potential diagnostic biomarkers. In fragile X syndrome, CGG trinucleotide repeat expansion increases methylation of the FMR1 gene promoter, leading to FMRP protein deficiency. Rett syndrome, primarily caused by MECP2 mutations, involves disrupted methylation-dependent transcriptional regulation. In epilepsy, DNA methylation abnormalities affect multiple epilepsy-related genes and may influence treatment responses to ketogenic diets. Despite these advances, the field faces significant challenges including tissue specificity issues, technical limitations in methylation detection, and therapeutic targeting difficulties. This review also discusses future perspectives, emphasizing the potential of DNA methylation as a therapeutic target and biomarker for neurodevelopmental disorders. Understanding these methylation mechanisms could lead to novel diagnostic tools and therapeutic strategies for various neurological conditions.