Abstract
Fragile X syndrome (FXS) is the most common identifiable genetic cause of intellectual disability and autistic spectrum disorders (ASD), with up to 50% of males and some females with FXS meeting criteria for ASD. Autistic features are present in a very high percent of individuals with FXS, even those who do not meet full criteria for ASD. Recent major advances have been made in the understanding of the neurobiology and functions of FMRP, the FMR1 (fragile X mental retardation 1) gene product, which is absent or reduced in FXS, largely based on work in the fmr1 knockout mouse model. FXS has emerged as a disorder of synaptic plasticity associated with abnormalities of long-term depression and long-term potentiation and immature dendritic spine architecture, related to the dysregulation of dendritic translation typically activated by group I mGluR and other receptors. This work has led to efforts to develop treatments for FXS with neuroactive molecules targeted to the dysregulated translational pathway. These agents have been shown to rescue molecular, spine, and behavioral phenotypes in the FXS mouse model at multiple stages of development. Clinical trials are underway to translate findings in animal models of FXS to humans, raising complex issues about trial design and outcome measures to assess cognitive change that might be associated with treatment. Genes known to be causes of ASD interact with the translational pathway defective in FXS, and it has been hypothesized that there will be substantial overlap in molecular pathways and mechanisms of synaptic dysfunction between FXS and ASD. Therefore, targeted treatments developed for FXS may also target subgroups of ASD, and clinical trials in FXS may serve as a model for the development of clinical trial strategies for ASD and other cognitive disorders.
Highlights
Fragile X syndrome (FXS) is the most common identifiable genetic cause of intellectual disability and autistic spectrum disorders (ASD), with up to 50% of males and some females with FXS meeting criteria for ASD
Fragile X syndrome (FXS) provides an excellent model for the translation of basic molecular neuroscience findings to clinical treatment because FXS is a genetically defined condition in which all affected individuals have a uniform single gene defect as the etiology for their condition, an increasing body of information is available regarding the mechanisms through which the genetic defect in FXS impacts molecular events in neurons and resultant synaptic plasticity, a sufficient number of individuals with FXS can be identified to carry out trials, and aspects of FXS model other more common neurodevelopmental conditions such as autistic spectrum disorders (ASDs), learning disability, and attention deficit/hyperactivity disorder (ADHD)
J Neurodevelop Disord (2011) 3:193–210 long-term outcomes, which are ongoing hurdles that must be addressed. These questions will have to be addressed for targeted treatment of FXS or any neurodevelopmental disorder to be successful, and this paper will review the current state of the translational process for targeted treatment in FXS, including known targets, preclinical work with small molecule therapeutics aimed at those targets, active or completed clinical trials, and issues associated with trial design and outcome measures
Summary
FXS is the most common known inherited cause of intellectual disability (ID), learning disability and ASD, with an estimated frequency of about 1/2,500–1/4,000 (Hagerman 2008; Turner et al 1996). Males with FXS have characteristic behavioral features including hyperactivity, impulsivity, attention problems, anxiety, mood lability, and autistic features such as poor eye contact, shyness, self-talk, hand flapping, hand biting, hyperarousal to sensory stimuli, and substantial perseverative language and behavior (Hagerman et al 2009; Berry-Kravis and Potanos 2004; Wang et al 2010a) They demonstrate an enhanced sympathetic response to sensory stimuli, as measured by electrodermal responses (Miller et al 1999), heart rate variability (Boccia and Roberts 2000), and pupillary responses (Farzin et al 2009); abnormal sensory gating can be demonstrated in prepulse inhibition studies (Hessl et al 2008a). Selective mutism, specific phobias, social anxiety, and social deficits are common in females (Berry-Kravis and Potanos 2004; Wang et al 2010a)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
