Methyl-CpG-binding protein 2 (MeCP2) is an epigenetic regulator essential for synaptic development, plasticity, and neuronal maturation. Altered MeCP2 dosage, such as its decrease in Rett syndrome (RTT) or increase in MECP2 duplication syndrome (MDS), has been associated with altered pain sensitivity and progression. This systematic review integrates preclinical and clinical studies to synthesise evidence on MeCP2’s role in pain and identify mechanistic and translational limitations. We followed PRISMA to systematically search three major databases (PubMed, Web of Science, and Scopus) followed by quality appraisal. We extracted models, modalities, tissues, MeCP2 manipulations and molecular readouts, and performed an exploratory Gene Ontology (GO) enrichment analysis. Preclinical models report context-dependent MeCP2-associated transcriptional changes including activity-dependent phosphorylation in dorsal horn neurons and peripheral nociceptors, and alterations in neurotransmission, and signalling programmes (including opioid-related genes), alongside selective chromatin-associated changes. Loss-of-function studies report modality- and circuit-specific deficits from peripheral afferents to cortex, whereas overexpression models report nociception and neuropathic hypersensitivity. Clinically, proxy-based studies often report apparent hyposensitivity in RTT and MDS, particularly to external pain. However, pain may still be under-recognised, as caregivers also report that pain is common and frequently related to internal/visceral comorbidities. MeCP2 dysregulation is associated with altered nociceptive processing, but conclusions are tempered by heterogeneity and a predominance of proxy-based and often correlative evidence. Future work should combine objective biomarkers with harmonised preclinical and clinical designs to strengthen mechanistic inference. • Evidence supports a role for MeCP2-associated mechanisms in pain-related plasticity • Altered MeCP2 dosage is linked to atypical nociceptive phenotypes • RTT and MDS suggest atypical pain sensitivity and under-recognised pain • Much of the current evidence on MeCP2-pain remains correlative rather than causal • Exploratory GO enrichment suggests synaptic and signalling-related themes
Abellán-Álvaro et al. (Wed,) studied this question.