Transcranial Photobiomodulation in Rett Syndrome: A Mechanistic Review and Therapeutic Hypothesis

Objective: To propose a mechanistic framework for the use of transcranial photobiomodulation (tPBM) as an adjunctive treatment in Rett syndrome (RTT). Background Data: RTT is a severe X-linked neurodevelopmental disorder caused mainly by MECP2 variants, with limited disease-modifying therapies. tPBM delivers red-to-near-infrared light to the brain and shows promising effects in several neurocognitive and neuropsychiatric conditions. Methods: We reviewed key cellular mechanisms of RTT, namely mitochondrial dysfunction, oxidative stress, neuroinflammation, and impaired synaptic plasticity, and summarized established bioenergetic, redox, anti-inflammatory, and neurotrophic actions of tPBM. Results: The convergence between these pathways suggests that tPBM could partially compensate for bioenergetic and signaling abnormalities in RTT, acting as a multi-target, pathophysiology-informed neuromodulation strategy. Conclusions: Although speculative, this mechanistic convergence supports prioritizing preclinical studies in Mecp2-deficient models and early-phase feasibility trials of tPBM in individuals with RTT.