Fragile X syndrome is a neurodevelopmental disorder which represents one of the most common genetic risk factors for autism. Fragile X syndrome is the consequence of a large (>200) trinucleotide CGG repeat expansion, in the 5' UTR region of the Fragile X mental retardation gene 1 (FMR1), located on the X chromosome. However, smaller FMR1 premutation (PM) expansions (55-199 CGG repeats) are more common (approximately 1 in 209 females and 1 in 430 males), and confer a risk of a number of medical,

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... psychiatric and cognitive conditions, as well as Fragile X tremor-ataxia syndrome (FXTAS). Estimated to effect up to 40% of PM males, and up to 16% of PM females over 50 years of age, FXTAS is characterised by intention tremor, cerebellar gait ataxia, and cognitive dysfunction (specifically executive dysfunction and dementia), corresponding with changes in neuroanatomy (generalised atrophy as well as hyperintensities in the middle cerebellar peduncles, brainstem and corpus callosum). It is hypothesised that FXTAS is the consequence of an FMR1 mRNA toxic-gain of function, given that PM individuals tend to exhibit increased levels of FMR1 mRNA, compared to those with normal FMR1 alleles (<45 CGG repeats). However, there is increasing evidence of both neuroanatomical changes and cognitive dysfunction in PM-carriers without FXTAS. Specifically, cortical and subcortical atrophy, a reduction in white matter integrity, and compensatory patterns of neural activation, have been well documented in PM males without FXTAS, as well as executive dysfunction on tasks reliant on response inhibition and working memory processes. These changes indicate disruption to cortico-cerebellar processing. It does however; remain unclear whether PM females without FXTAS experience analogous deficits and whether genetic and neural changes (within the cortico-cerebellar network) influence PM-related dysfunction. Accordingly, the principal aim of this thesis was to investigate whether PM females without FXTAS, like their male counterparts, ex [...]