Invited reviewFragile X syndrome: From targets to treatments
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.
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