From Discovery to Innovative Translational Approaches in 80 Years of Fragile X Syndrome Research

Abstract

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and a major genetic contributor to autism spectrum disorder. It is caused by a CGG trinucleotide repeat expansion in the FMR1 gene, resulting in gene silencing and the loss of FMRP, an RNA-binding protein essential for synaptic plasticity. This review covers over 80 years of FXS research, highlighting key milestones, clinical features, genetic and molecular mechanisms, the FXS mouse model, disrupted molecular pathways, and current therapeutic strategies. Additionally, we discuss recent advances including AI-driven combination therapies, CRISPR-based gene editing, and antisense oligonucleotides (ASOs) therapies. Despite these scientific breakthroughs, translating preclinical findings into effective clinical treatments remains challenging. Clinical trials have faced several difficulties, including patient heterogeneity, inconsistent outcome measures, and variable therapeutic responses. Standardized preclinical testing protocols and refined clinical trial designs are required to overcome these challenges. The development of FXS-specific biomarkers could also improve the precision of treatment assessments. Ultimately, future therapies will need to combine pharmacological and behavioral interventions tailored to individual needs. While significant challenges remain, ongoing research continues to offer hope for transformative breakthroughs that could significantly improve the quality of life for individuals with FXS and their families.

Keywords: fragile X messenger ribonucleoprotein (FMRP); fragile X messenger ribonucleoprotein 1 (FMR1); fragile X syndrome (FXS); trinucleotide repeat expansion (CGG repeat).

Figure 2

CGG repeats and the structure of the FMR1 gene and FMRP protein. Most individuals have fewer than 45 CGG repeats in their FMR1 gene, which is considered normal and results in typical FMR1 mRNA levels and FMRP production. Individuals with 55–200 CGG repeats carry the premutation, which is associated with elevated FMR1 mRNA levels and a moderate reduction in FMRP production. Those with more than 200 CGG repeats have the full mutation, where FMR1 transcription is silenced due to promoter hypermethylation, leading to the absence of FMRP production. At the bottom is a schematic overview of the human FMR1 gene, highlighting its potential alternative splicing sites, along with the human FMRP protein and its functional domains. These domains include a Tudor methyl-lysine- and methyl-arginine-binding domain, a nuclear localization signal (NLS), three K homology (KH) domains, a nuclear export signal (NES), and an arginine-glycine-rich (RGG) domain. The figure is partially adapted from [75] and created with BioRender.com.

Figure 1

FXS over the past 80 years. FXS timeline with milestones, breakthroughs, and key events that have shaped the evolving understanding of the disorder over the past 80 years.