Elsevier

Neuropharmacology

Volume 68, May 2013, Pages 83-96
Neuropharmacology

Invited review
Fragile X syndrome: From targets to treatments

https://doi.org/10.1016/j.neuropharm.2012.11.028Get rights and content

Abstract

Fragile X syndrome (FXS) is one of the most prevalent and well-studied monogenetic causes of intellectual disability and autism and, although rare, its high penetrance makes it a desirable model for the study of neurodevelopmental disorders more generally. Indeed recent studies suggest that there is functional convergence of a number of genes that are implicated in intellectual disability and autism indicating that an understanding of the cellular and biochemical dysfunction that occurs in monogenic forms of these disorders are likely to reveal common targets for therapeutic intervention. Fundamental research into FXS has provided a wealth of information about how the loss of function of the fragile X mental retardation protein results in biochemical, anatomical and physiological dysfunction leading to the discovery of interventions that correct many of the core pathological phenotypes associated with animal models of FXS. Most promisingly such strategies have led to development of drugs that are now in clinical trials. This review highlights how progress in understanding disorders such as FXS has led to a new era in which targeted molecular treatment towards neurodevelopmental disorders is becoming a reality.

This article is part of the Special Issue entitled ‘Neurodevelopmental Disorders’.

Highlights

► Genotype to Phenotype of FXS. ► Mouse models of FXS: understanding the core neuropathology. ► From theory to therapeutic strategies for FXS. ► Clinical Trials for FXS and future considerations.

Section snippets

Fragile X gene and protein

FXS is the most common inherited form of ID affecting 1 in every 4000 males and 1 in every 6000–8000 females. It was originally called Martin–Bell syndrome after the clinicians who first described it as an X-linked heritable disorder of development (Martin and Bell, 1943). In 1969, Herbert Lubs described a constriction near the end of the long arm of the X chromosome (Lubs, 1969) that gave it a “fragile” appearance (Hecht and Bixenman, 1990). This constriction arises from the expansion of the

Modelling FXS: core phenotypes identified in the mouse

The development of rational therapies for FXS requires a detailed understanding of the genetic and cellular mechanisms that underlie its associated endophenotypes. Such an understanding can only come from the study of effective animal models of the disorder, which in turn relies on an evolutionary conservation of the affected gene and the normal function of the protein it encodes. The FMR1 gene is highly conserved among species showing a 95% homology in DNA sequence between mouse and human and

Identifying and testing targeted treatments for FXS

Advances in our understanding of FXS are now leading to promising targeted treatments for NDDs (Table 1). As discussed earlier FXS is a synaptopathy, i.e. alterations in synaptic structure and function are believed to underlie the disease symptoms (Zoghbi and Warren, 2010). Considerable effort has been made to understand the cellular events that give rise to the synaptic dysfunctions that characterise FXS and related forms of ID/ASD, with the hope that potential targets for pharmaceutical

Concepts of critical periods and developmental disorders

In the 1930's Konrad Lorenz described the imprinting of young geese with their mother. He defined a narrow time-window during the first day of life, termed the critical period, when the goslings became attached to their mother (or indeed, any moving object including Lorenz himself). Several decades later, Hubel and Wiesel described critical periods during the development of the visual system when the physiological and anatomical properties of the visual cortex can be manipulated by altering an

Acknowledgements

We would like to thank Dr Emily Osterweil and Dr. Andrew Stanfield along with the anonymous reviewers for their helpful comments. We would also like to thank Professor Randi Hagerman and Dr. Mary Jacena S. Leigh for sharing their data from the minocycline trials. We acknowledge the support from the Patrick Wild Centre and the Medical Research Council UK. We would also like to thank Dr. Gus Alusi and Reem Waines for their continued support and helpful insights into living with FXS.

References (167)

  • J.C. Darnell et al.

    FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism

    Cell

    (2011)
  • F.M. De Vrij et al.

    Rescue of behavioral phenotype and neuronal protrusion morphology in Fmr1 KO mice

    Neurobiol. Dis.

    (2008)
  • G. Dolen et al.

    Correction of fragile X syndrome in mice

    Neuron

    (2007)
  • A. Entezam et al.

    Regional FMRP deficits and large repeat expansions into the full mutation range in a new Fragile X premutation mouse model

    Gene

    (2007)
  • F. Farzin et al.

    Contrast detection in infants with fragile X syndrome

    Vision Res.

    (2008)
  • Y.H. Fu et al.

    Variation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox

    Cell

    (1991)
  • C.L. Gatto et al.

    Drosophila modeling of heritable neurodevelopmental disorders

    Curr. Opin. Neurobiol.

    (2011)
  • A.W. Grossman et al.

    Developmental characteristics of dendritic spines in the dentate gyrus of Fmr1 knockout mice

    Brain Res.

    (2010)
  • S.S. Hall et al.

    Autism in fragile X syndrome: a category mistake?

    J. Am. Acad. Child. Adolesc. Psychiatry

    (2010)
  • E.G. Harlow et al.

    Critical period plasticity is disrupted in the barrel cortex of FMR1 knockout mice

    Neuron

    (2010)
  • F. Hecht et al.

    Location of FRAXD in Xq27.2. Fragile sites on the X chromosome

    Cancer Genet. Cytogenet.

    (1990)
  • I. Heulens et al.

    Pharmacological treatment of fragile X syndrome with GABAergic drugs in a knockout mouse model

    Behav. Brain Res.

    (2012)
  • W. Jacob et al.

    The anxiolytic and analgesic properties of fenobam, a potent mGlu5 receptor antagonist, in relation to the impairment of learning

    Neuropharmacology

    (2009)
  • W.R. Kates et al.

    Reliability and validity of MRI measurement of the amygdala and hippocampus in children with fragile X syndrome

    Psychiatry Res.

    (1997)
  • S.K. Koekkoek et al.

    Deletion of FMR1 in Purkinje cells enhances parallel fiber LTD, enlarges spines, and attenuates cerebellar eyelid conditioning in Fragile X syndrome

    Neuron

    (2005)
  • S. Lefort et al.

    The excitatory neuronal network of the C2 barrel column in mouse primary somatosensory cortex

    Neuron

    (2009)
  • J. Levenga et al.

    Subregion-specific dendritic spine abnormalities in the hippocampus of Fmr1 KO mice

    Neurobiol. Learn. Mem.

    (2011)
  • Z.H. Liu et al.

    Lithium reverses increased rates of cerebral protein synthesis in a mouse model of fragile X syndrome

    Neurobiol. Dis.

    (2012)
  • Z.H. Liu et al.

    Dissociation of social and nonsocial anxiety in a mouse model of fragile X syndrome

    Neurosci. Lett.

    (2009)
  • R.M. Meredith et al.

    Functional rescue of excitatory synaptic transmission in the developing hippocampus in Fmr1-KO mouse

    Neurobiol. Dis.

    (2011)
  • A. Michalon et al.

    Chronic pharmacological mGlu5 inhibition corrects fragile X in adult mice

    Neuron

    (2012)
  • E.J. Mientjes et al.

    The generation of a conditional Fmr1 knock out mouse model to study Fmrp function in vivo

    Neurobiol. Dis.

    (2006)
  • W.W. Min et al.

    Elevated glycogen synthase kinase-3 activity in Fragile X mice: key metabolic regulator with evidence for treatment potential

    Neuropharmacology

    (2009)
  • M.R. Akins et al.

    Presynaptic translation: stepping out of the postsynaptic shadow

    Front. Neural Circuits

    (2009)
  • A. Aschrafi et al.

    The fragile X mental retardation protein and group I metabotropic glutamate receptors regulate levels of mRNA granules in brain

    Proc. Natl. Acad. Sci. U.S.A.

    (2005)
  • C.T. Ashley et al.

    FMR1 protein: conserved RNP family domains and selective RNA binding

    Science

    (1993)
  • C.T. Ashley et al.

    Human and murine FMR-1: alternative splicing and translational initiation downstream of the CGG-repeat

    Nat. Genet.

    (1993)
  • B.D. Auerbach et al.

    Mutations causing syndromic autism define an axis of synaptic pathophysiology

    Nature

    (2011)
  • D.B. Bailey et al.

    Autistic behavior, FMR1 protein, and developmental trajectories in young males with fragile X syndrome

    J. Autism Dev. Disord.

    (2001)
  • E. Berry-Kravis

    Epilepsy in fragile X syndrome

    Dev. Med. Child. Neurol.

    (2002)
  • E. Berry-Kravis et al.

    A pilot open label, single dose trial of fenobam in adults with fragile X syndrome

    J. Med. Genet.

    (2009)
  • E. Berry-Kravis et al.

    Targeted treatments for fragile X syndrome

    J. Neurodev. Disord.

    (2011)
  • E. Berry-Kravis et al.

    Seizures in fragile X syndrome: characteristics and comorbid diagnoses

    Am. J. Intellect. Dev. Disabil.

    (2010)
  • E. Berry-Kravis et al.

    Open-label treatment trial of lithium to target the underlying defect in fragile X syndrome

    J. Dev. Behav. Pediatr.

    (2008)
  • E.M. Berry-Kravis et al.

    Effects of STX209 (Arbaclofen) on neurobehavioral function in children and adults with fragile X syndrome: a randomized, controlled, phase 2 trial

    Sci. Transl. Med.

    (2012)
  • A.L. Bhakar et al.

    The pathophysiology of fragile x (and what it teaches us about synapses)

    Annu. Rev. Neurosci.

    (2012)
  • T.V. Bilousova et al.

    Minocycline promotes dendritic spine maturation and improves behavioural performance in the fragile X mouse model

    J. Med. Genet.

    (2009)
  • T.V. Bilousova et al.

    Matrix metalloproteinase-7 disrupts dendritic spines in hippocampal neurons through NMDA receptor activation

    J. Neurochem.

    (2006)
  • S.A. Brody et al.

    Interactions of the mGluR5 gene with breeding and maternal factors on startle and prepulse inhibition in mice

    Neurotox. Res.

    (2004)
  • N. Brose et al.

    Synaptopathy: dysfunction of synaptic function?

    Biochem. Soc. Trans.

    (2010)
  • Cited by (0)

    View full text