From Repeat Expansion to Circuit Disruption: 35 Years of Fragile X Pathophysiology

Fragile X syndrome (FXS) is caused by CGG repeat expansion in FMR1, leading to gene silencing and loss of fragile X messenger ribonucleoprotein (FMRP). As the most common inherited cause of intellectual disability and a leading monogenic cause of autism spectrum disorder, FXS has provided an unusually tractable framework for linking a single-gene defect to abnormalities in RNA regulation, synaptic development, circuit function, and behavior. In this review, we synthesize current understanding of FMRP function, dysregulated signaling pathways, synaptic and network phenotypes, and emerging contributions from glial and human organoid models. We also evaluate therapeutic efforts, emphasizing lessons from failed targeted trials, the constraints imposed by critical developmental periods, and newer strategies aimed at restoring FMR1 itself. We argue that future progress will depend on earlier intervention, biologically informed patient stratification, and objective measures of target engagement and circuit response.