Pharmacological management of fragile X syndrome: a systematic review and narrative summary of the current evidence

ABSTRACT

Introduction

Fragile X syndrome (FXS) is the most common inherited cause of Intellectual Disability. There is a broad phenotype that includes deficits in cognition and behavioral changes, alongside physical characteristics. Phenotype depends upon the level of mutation in the FMR1 (fragile X messenger ribonucleoprotein 1) gene. The molecular understanding of the impact of the FMR1 gene mutation provides an opportunity to target treatment not only at symptoms but also on a molecular level.

Methods

We conducted a systematic review to provide an up-to-date narrative summary of the current evidence for pharmacological treatment in FXS. The review was restricted to randomized, blinded, placebo-controlled trials.

Results

The outcomes from these studies are discussed and the level of evidence assessed against validated criteria. The initial search identified 2377 articles, of which 16 were included in the final analysis.

Conclusion

Based on this review to date there is limited data to support any specific pharmacological treatments, although the data for cannabinoids are encouraging in those with FXS and in future developments in gene therapy may provide the answer to the search for precision medicine. Treatment must be person-centered and consider the combination of medical, genetic, cognitive, and emotional challenges.

KEYWORDS:

• Autism spectrum disorder
• CGG
• co-morbidities
• holistic
• FMR1
• FMRP

Article highlights

• Mutation of the FMR1 (Fragile X Messenger Ribonucleoprotein 1) gene leading to Fragile X Syndrome (FXS) provides an opportunity to consider pharmacological interventions on a molecular level.

• This systematic review of Randomised Controlled Trials identified 16 studies including 15 treatments specifically focused on FXS including specific symptoms and co-morbidities associated with the broad phenotype.

• Many of the treatments still being developed show positive findings, but results are not always translated to a significant clinical benefit.

• Further research will focus on instruments that measure outcomes specific to FXS, and require collaboration between research centres for larger cohorts.

• There is promise in a number of the pharmacological treatments identified including Cannabidiol based products and the versatile drug Metformin.

• FXS pharmacological research is leading the way in precision-based medicine, developments in gene therapy will likely be the future.

Declaration of interest

R Shankar has received institutional and research support from LivaNova, UCB, Eisai, Veriton Pharma, Bial, Angelini, UnEEG, and Jazz/GW pharma outside the submitted work. He holds grants from NIHR AI, SBRI, and other funding bodies all outside this work.

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Author contributions

All authors satisfy the ICMJE guidance by substantially contributing to the design, analysis and interpretation of the work, drafting of the manuscript, final approval of the manuscript, and all agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Data statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.