White matter microstructure, cognition, and molecular markers in fragile X premutation females.

Abstract

To examine the interrelationships between fragile X mental retardation 1 (<i>FMR1</i>) mRNA and the <i>FMR1</i> exon 1/intron 1 boundary methylation, white matter microstructure, and executive function, in women with a <i>FMR1</i> premutation expansion (PM; 55-199 CGG repeats) and controls (CGG < 44). Twenty women with PM without fragile X-associated tremor/ataxia syndrome (FXTAS) and 20 control women between 22 and 54 years of age completed this study. <i>FMR1</i> mRNA and methylation levels for 9 CpG sites within the <i>FMR1</i> exon 1/intron 1 boundary from peripheral blood samples were analyzed. To measure white matter microstructure, diffusion-weighted imaging was used, from which fractional anisotropy (FA) and mean diffusivity (MD) values from anatomic regions within the corpus callosum and cerebellar peduncles were extracted. Executive function was assessed across a range of tasks. No differences were revealed in white matter microstructure between women with PM and controls. However, we reveal that for women with PM (but not controls), higher <i>FMR1</i> mRNA correlated with lower MD values within the middle cerebellar peduncle and Paced Auditory Serial Addition Test scores, higher methylation of the <i>FMR1</i> exon 1/intron 1 boundary correlated with lower MD within the inferior and middle cerebellar peduncles and longer prosaccade latencies, and higher FA values within the corpus callosum and cerebellar peduncle regions corresponded to superior executive function. We provide evidence linking white matter microstructure to executive dysfunction and elevated <i>FMR1</i> mRNA and <i>FMR1</i> exon 1/intron 1 boundary methylation in women with PM without FXTAS. This suggests that the FXTAS phenotype may not be distinct but may form part of a spectrum of PM involvement.