Brain network alterations in fragile X syndrome

Abstract

Fragile X syndrome (FXS), caused by FMR1 gene mutations, leads to widespread brain alterations significantly impacting cognition and behaviour. Recent advances have provided a deeper understanding of the neural substrates of FXS. This review provides a comprehensive overview of the current knowledge of neuronal network alterations in FXS. We highlight imaging studies that demonstrate network-level disruptions within resting-state networks, including the default mode network, frontoparietal network, salience network, and basal ganglia network, linked to cognitive, emotional and motor deficits in FXS. Next, we link dysregulated network activity in FXS to molecular studies showing neurometabolic imbalances, particularly in GABAergic and glutamatergic systems. Additionally, gene-brain-behavior correlations are explored with gene expression maps to illustrate regional FMR1 expression patterns tied to clinical symptoms. A graph analysis and meta-analytic mapping further link these dysfunctional networks to the specific symptoms of FXS. We conclude by highlighting gaps in the literature, including the need for greater global collaboration, inclusion of underrepresented populations, and consideration of transdiagnostic effects in future research to advance neuroimaging and therapeutic approaches for FXS.