UC Davis

Key PointsFragile X syndrome is a monogenic neurodevelopmental disorder associated with intellectual disability and autism spectrum disorders.Animal models have provided insights into the neurobiological mechanisms and enabled the identification of novel drug targets.Promising targets include metabotropic glutamate receptor 5 (mGluR5), GABA receptors and proteins that are regulated or regulate fragile X mental retardation protein 1 (FMRP).Many compounds have been extensively investigated in preclinical studies and are able to rescue altered levels of protein synthesis, synaptic plasticity and behaviour. Behavioural phenotypes in Fmr1-knockout mice are difficult to measure, and the rescue of these deficits has been inconsistent across these different drugs.Subsequent clinical trials in humans were unable to demonstrate any improvement using behavioural measures as primary end points.Objective measures of core phenotypes such as direct assessments of cognition and language rather than secondary behaviours need to be implemented in future trials.Very young patients have not yet been included in clinical trials, and this may be the only group in which effects of a disease-modifying agent targeting cognition and development can be seen. Efforts may need to be redirected towards the implementation of longer trials in younger children accompanied by learning interventions measuring cognitive and developmental outcomes.