Abstract
Fragile X syndrome (FXS) is caused by a full mutation of the FMR1 gene (>200 CGG repeats and subsequent methylation), such that there is little or no FMR1 protein (FMRP) produced, leading to intellectual disability (ID). Individuals with the premutation allele (55–200 CGG repeats, generally unmethylated) have elevated FMR1 mRNA levels, a consequence of enhanced transcription, resulting in neuronal toxicity and a spectrum of premutation-associated disorders, including the neurodegenerative disorder fragile X-associated tremor/ataxia syndrome (FXTAS). Here we described 14 patients who had both lowered FMRP and elevated FMR1 mRNA levels, representing dual mechanisms of clinical involvement, which may combine features of both FXS and FXTAS. In addition, the majority of these cases show psychiatric symptoms, including bipolar disorder, and/or psychotic features, which are rarely seen in those with just FXS.
Highlights
Introduction The cause of fragileX syndrome (FXS) is a lack or deficiency of the FMR1 protein (FMRP)
These cases are unusual because many cases include both features of fragile X syndrome (FXS) even though they are premutation carriers, or vice versa – patients with features of premutation involvement, even though they have a full mutation
There is a high frequency of psychotic features that is unusual for FXS or premutation involvement
Summary
Introduction The cause of fragileX syndrome (FXS) is a lack or deficiency of the FMR1 protein (FMRP). Neurodevelopmental problems including hyperactivity, anxiety, social deficits, and autism spectrum disorders (ASD) have been reported in a subgroup of children and adults with the premutation, those who present with full clinical symptoms[11,12,13,14,15,16]. Some of these individuals with the premutation and neurodevelopmental problems have a mild deficit of FMRP16. The level of FMRP gradually decreases as the CGG repeat number increases in the premutation range[17], leading to some features of FXS in the high end of the premutation (over 110 CGG repeats)[2,18,19]
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