Epigenetic Dysregulation in Rett Syndrome: Multisystem Pathophysiology, MECP2 Isoform-Specific Mechanisms, and Targeted Therapeutic Strategies

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Abstract
Rett syndrome (RTT), an X-linked neurodevelopmental disorder predominantly arising from de novo MECP2 mutations, manifests with psychomotor regression, stereotypic hand movements, gait apraxia, and expressive aphasia, driven by dosage-sensitive epigenetic dysregulation via MeCP2's methyl-CpG-binding domain (MBD) and transcriptional repression domain (TRD). Isoform-specific expression (MeCP2-E1 neuronal predominance) and X-chromosome inactivation mosaicism underpin phenotypic variability, with missense (R133C, T158M) and nonsense (R168X, R255X) variants correlating to severity gradients. Multisystem pathophysiology encompasses brainstem-mediated respiratory dysrhythmias, QTc prolongation via ion channel perturbations, enteric hypomotility, osteopenic fractures, and mitochondrial bioenergetic deficits, exacerbated by glial-neuronal crosstalk and oxidative stress. Preclinical platforms, including Mecp2-null rodents, patient-derived iPSCs, and cerebral organoids, elucidate synaptic hyperexcitability, dendritic arborization deficits, and reversibility upon Mecp2 reactivation. Therapeutic modalities span supportive multidisciplinary interventions, FDA-approved trofinetide (IGF-1 analog modulating neurotrophic cascades), AAV-mediated gene replacement (NGN-401, TSHA-102 with miRARE autoregulation), ASOs for dosage normalization, and emerging PPAR-γ agonists targeting metabolic homeostasis. Prioritized research agendas emphasize validated biomarkers (BDNF/IGF-1 axes, miRNA signatures), combinatorial regimens, and equitable global access to mitigate caregiver burden and phenotypic heterogeneity.

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