Narrowing margins: exploring how MeCP2 deficiency degrades precision, timing, and adaptability in motor circuits

The X-linked gene methyl-CpG-binding protein 2 (MECP2) is a critical epigenetic regulator with important roles in neuronal gene regulation and neuronal plasticity during sensitive periods of development and beyond. Mutations in MECP2 result in Rett syndrome (RTT), a neurodevelopmental disorder predominantly affecting females. Motor dysfunction is among the most consistently disrupted domains in RTT. The literature on this domain is under-synthesized and a cohesive framework to explain the neurobiological underpinnings of the varied motor phenotypes by sex, allele and age is lacking. In this review, we focus on the literature on motor dysfunction in RTT and propose a convergent-constraint model, in which MeCP2 loss compromises mitochondrial capacity, GPCR signaling, and calcium handling in high-energy-demand neuronal populations, with perineuronal nets acting as a structural node that reinforces this constraint. This model accounts for a recurring pattern across the intervention literature: genetic, viral, pharmacological, and behavioral approaches consistently produce partial, overlapping rescue rather than full correction, consistent with circuits operating below capacity rather than missing a single essential component. We identify testable hypotheses and gaps in the field, including the temporal sequence of these constraints and the absence of motor-specific mechanistic data for current and emerging therapies, that offer potential avenues for combinatorial therapeutic targets for RTT.