Randi Hagerman resized Speaker 

Randi Hagerman

MD, University of California at Davis Medical Center and MIND Institute


From molecular studies to targeted treatments in Fragile X syndrome 

Studies of animal models of fragile X syndrome (FXS) and the molecular pathways that are dysregulated in the absence of FMRP have led to new targeted treatments of children and adults with FXS. FMRP controls the translation of hundreds of messages important for other disorders including schizophrenia and autism spectrum disorder (ASD). We know that the mGluR5 pathway is upregulated in FXS and the GABA pathways are downregulated. The initial trials of mGluR5 antagonists did not show efficacy in adolescents and adults with FXS in the behavioral outcome measures that were chosen. However, there is evidence that younger patients may do better and the outcome measures should include cognitive measures in addition to electrophysiological studies, measures of habituation to sensory stimuli, eye tracking studies, and behavioral measures.  We have found that the event related potentials (ERPs) particularly habituation paradigms that target brain processing abnormalities with deficient GABA inhibitory input were particularly helpful in our controlled trial of minocycline in young children with FXS. Other new measures include  expressive language sampling measures developed by Dr Len Abbeduto and colleagues and the use of the NIH toolbox adapted by Dr David Hessl for children with FXS  to assess improvements in cognitive processes and attention.  

We have also learned that early intervention with targeted treatments can significantly improve developmental testing in young children with FXS as seen by the controlled trial of low dose sertraline in those ages 2 to 6yo. This controlled trial of 2.5 to 5.0 mg of sertraline over a 6 month period demonstrated significant improvements in the Visual Perception and Fine Motor subtests and in the overall Composite T score in the Mullen Scales of Early Learning (MSEL) in those on sertraline vs placebo. Those with FXS plus ASD also demonstrated significant improvement in the Expressive Language subtest of the MSEL on sertraline vs placebo. Early intervention is also studied now with the mGluR5 antagonist, AFQ056, combined with intensive language intervention provided by videoconferencing to the family in their home for young children with FXS ages 3 to 6yo in a multicenter trial funded by NIH. Mouse and Drosophila models of FXS have demonstrated the benefit of metformin as a targeted treatment and encouraging results are seen in open label studies with a controlled trial in process. Other medications that have shown efficacy in FXS include minocycline, arbaclofen and trofinetide and these studies will be reviewed. Since many pathways are dysregulated in FXS it may take more than one treatment to make overall cognitive and behavioral improvements in FXS. The addition to novel learning paradigms for FXS are also expanding and such paradigms can be combined with a targeted treatment. We have shown efficacy in language improvements with a Parent Implemented Language Intervention (PILI) that is guided by a speech and language pathologist combined with a BCBA and the intervention is given through skype twice a week in the home. The PILI intervention has also been combined with a controlled trial of lovastatin, another targeted treatment for FXS in an ongoing trial. The future looks bright for new targeted treatments that will benefit not only FXS but other neurodevelopmental disorders including ASD that have common aspects of molecular dysregulation.