Executive dysfunction in young FMR1 premutation carriers

Abstract

Identification of specific cognitive profiles associated with genetic neurodegenerative disorders is important, allowing early identification of at-risk individuals who can receive disease-modifying therapies before the condition fully manifests. In addition, characterization of neurologic signs in genetic diseases enhances understanding of the localization, timing, and mechanism of a given genetic lesion on brain wiring and function, and may even help to distinguish developmental from degenerative effects of a particular gene defect. For example, executive dysfunction and behavioral changes can predict risk for cognitive decline in adults with Down syndrome.1 Fragile X–associated disorders (FXD) result from a CGG repeat expansion mutation in the promoter region of the fragile X mental retardation 1 ( FMR1 ) gene and are associated with both developmental and degenerative neurologic problems, depending on the size of the CGG repeat sequence (normal 200).2,3 The full mutation is associated with hypermethylation and transcriptional silencing of FMR1 and results in fragile X syndrome (FXS), due to the absence of fragile X mental retardation protein (FMRP), which is a key modulator of synaptic plasticity. Premutation alleles are not associated with FMR1 methylation and, in fact, undergo excessive transcription, yielding elevated CGG-containing FMR1 mRNA levels and resultant CGG-mediated RNA toxicity which is thought to cause fragile X–associated primary ovarian …