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

To propose a mechanistic framework for the use of transcranial photobiomodulation (tPBM) as an adjunctive treatment in Rett syndrome (RTT).

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.

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.

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.

Although speculative, this mechanistic convergence supports prioritizing preclinical studies in Mecp2-deficient models and early-phase feasibility trials of tPBM in individuals with RTT.