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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 <41, gray zone 45–54, premutation 55–200, full mutation >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 …
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