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Fragile X syndrome

Nature Reviews Disease Primers volume 3, Article number: 17065 (2017) Cite this article

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Abstract

Fragile X syndrome (FXS) is the leading inherited form of intellectual disability and autism spectrum disorder, and patients can present with severe behavioural alterations, including hyperactivity, impulsivity and anxiety, in addition to poor language development and seizures. FXS is a trinucleotide repeat disorder, in which >200 repeats of the CGG motif in FMR1 leads to silencing of the gene and the consequent loss of its product, fragile X mental retardation 1 protein (FMRP). FMRP has a central role in gene expression and regulates the translation of potentially hundreds of mRNAs, many of which are involved in the development and maintenance of neuronal synaptic connections. Indeed, disturbances in neuroplasticity is a key finding in FXS animal models, and an imbalance in inhibitory and excitatory neuronal circuits is believed to underlie many of the clinical manifestations of this disorder. Our knowledge of the proteins that are regulated by FMRP is rapidly growing, and this has led to the identification of multiple targets for therapeutic intervention, some of which have already moved into clinical trials or clinical practice.

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Figure 1: Clinical features of FXS.
Figure 2: Physical features of FXS.
Figure 3: Glutamatergic signalling and DGKκ deregulation in FXS.
Figure 4: Altered GABAergic signalling in Fmr1-knockout mice.
Figure 5: The effect of FMRP loss on the BMPR–LIMK–cofilin pathway.
Figure 6: Caudate volume in individuals with fragile X syndrome.

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Acknowledgements

This work was supported by the following grants. R.J.H., P.J.H. and F.T. were funded by US Health Resources and Services Administration (HRSA) grant R40MC27701, National Institute of Child Health and Human Development grant R01HD036071, HRSA grant R40MC22641, Department of Defense grant PR101054, MIND Institute Intellectual and Developmental Disability Research Center U54HD07912. H.M. and L.M. are funded by Agence Nationale de la Recherche (ANR-12-BSV8-0022), Fondation Jérôme Lejeune funding, FRAXA Research Foundation and grant ANR-10-LABX-0030-INRT, a French State fund managed by the Agence Nationale de la Recherche under the frame programme Investissements d’Avenir ANR-10-IDEX-0002-02 to H.M. and J.L.M. R.F.K. is funded by grants from the Research Foundation Flanders, FRAXA Research Foundation and the Fondation Jérôme Lejeune. H.C.H. was funded by NICHD R01HD059854. The authors thank L. Makhoul for help with preparation of this manuscript.

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Authors and Affiliations

  1. MIND Institute, UC Davis Health, University of California, Davis, 2826 50th Street, Sacramento, 95817, California, USA

    Randi J. Hagerman, Flora Tassone & Paul J. Hagerman

  2. Department of Pediatrics, School of Medicine, University of California, Davis, Sacramento, California, USA

    Randi J. Hagerman

  3. Department of Pediatrics, Neurological Sciences, Biochemistry, Rush University Medical Center, Chicago, Illinois, USA

    Elizabeth Berry-Kravis

  4. Carolina Institute for Developmental Disabilities and Department of Psychiatry, University of North Carolina, Chapel Hill, North Carolina, USA

    Heather Cody Hazlett

  5. RTI International, Research Triangle Park, North Carolina, USA

    Donald B. Bailey Jr

  6. Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France

    Herve Moine & Jean Louis Mandel

  7. Centre National de la Recherche Scientifique, Illkirch, France

    Herve Moine & Jean Louis Mandel

  8. Institut National de la Santé et de la Recherche Médicale, Illkirch, France

    Herve Moine & Jean Louis Mandel

  9. Université de Strasbourg, Strasbourg, France

    Herve Moine & Jean Louis Mandel

  10. Department of Medical Genetics, University of Antwerp, Antwerp, Belgium

    R. Frank Kooy

  11. Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, California, USA

    Flora Tassone & Paul J. Hagerman

  12. Department of Biochemistry, McGill University, Montréal, Québec, Canada

    Ilse Gantois & Nahum Sonenberg

  13. Rosalind and Morris Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada

    Ilse Gantois & Nahum Sonenberg

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  1. Randi J. Hagerman
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Contributions

Introduction (R.J.H. and P.J.H.); Epidemiology (F.T.); Mechanisms/pathophysiology (J.L.M., H.M., R.F.K., N.S., H.C.H. and P.J.H.); Diagnosis, screening and prevention (R.J.H. and F.T.); Management (E.B.-K. and R.J.H.); Quality of life (D.B.B.); Outlook (R.J.H., E.B.-K. and P.J.H); Overview of Primer (R.J.H. and P.J.H.).

Corresponding author

Correspondence to Randi J. Hagerman.

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Competing interests

R.J.H. has received funding from Novartis, Roche, Alcobra, Neuren and Marinus for clinical trials in FXS and has consulted with Zynerba for clinical trials in FXS. E.B.-K. has received funding from Novartis, Roche, Alcobra, Neuren, Cydan, Fulcrum, GW, Marinus, Edison and Neurotrope Pharmaceuticals to consult on trial design and development strategies and/or conduct clinical trials in FXS, and from Asuragen Inc. to develop testing standards for FMR1 testing. D.B.B. received funding from The John Merck Fund to plan a fragile X newborn screening study. R.F.K. has received logistic support and ganaxolone treatment funding from Marinus Pharmaceuticals to conduct a clinical trial in FXS. F.T. has received funding for molecular studies in FXS from Asuragen. All other authors declare no competing interests.

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Hagerman, R., Berry-Kravis, E., Hazlett, H. et al. Fragile X syndrome. Nat Rev Dis Primers 3, 17065 (2017). https://doi.org/10.1038/nrdp.2017.65

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