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It has been more than 25 years since the identification of the FMR1 gene and the demonstration of the causative role of CGG-repeat expansion in the disease pathology of fragile X syndrome (FXS), but the underlying mechanisms involved in the expansion mutation and the resulting gene silencing still remain elusive. Our understanding of the pathways impacted by the loss of FMRP function has grown tremendously, and has opened new avenues for targeted treatments for FXS. However, the failure of recent clinical trials that were based on successful preclinical studies using the Fmr1 knockout mouse model has forced the scientific community to revisit clinical trial design and identify objective outcome measures. There has also been a renewed interest in restoring FMR1 gene expression as a possible treatment approach for FXS. This special issue of Brain Sciences highlights the progress that has been made towards understanding the disease mechanisms and how this has informed the development of treatment strategies that are being explored for FXS.

n/a --- lymphoblast --- pluripotent stem cells --- FMR1 --- Gene editing --- X chromosome --- Fmr1 --- epigenetic gene silencing --- FMR1 gene --- Fragile X syndrome 1 --- repeat instability --- characteristics that have the greatest impact --- DNA instability --- working memory --- language development --- mosaicism --- CRISPR 3 --- clinical trials --- autism spectrum disorders --- Fmr1 KO mouse --- automated vocal analysis --- base excision repair (BER) --- inhibitory control --- cerebral spinal fluid --- iPSC --- drug development --- targeted treatments --- molecular biomarkers --- viral vector --- avoidance --- biomarker --- set-shifting --- early identification --- expansion --- anxiety --- planning --- voice of the person --- mismatch repair (MMR) --- gene reactivation --- double-strand break repair (DSBR) --- newborn screening --- intellectual disability --- processing speed --- voice of the patient --- fragile X syndrome --- adeno-associated virus --- neurodevelopmental disorders --- histone methylation --- Non-homologous end-joining (NHEJ) --- ASD --- Fxr2 --- Fragile X-associated Tremor/Ataxia Syndrome 2 --- Trinucleotide Repeat 4 --- CGG Repeat Expansion Disease --- DNA methylation --- contraction --- fragile X mental retardation protein --- RNA:DNA hybrid --- behavior --- developmental disorders --- cognition --- females --- FMRP --- Fragile X Syndrome --- unstable repeat diseases --- protein synthesis --- brain --- cognitive flexibility --- treatment development --- fibroblast --- PRC2 --- transcription coupled repair (TCR) --- best practices --- attention --- Fragile X --- executive function