Abstract
Mutations of the FMR1 (fragile X mental retardation 1) gene produce a diverse range of clinical and behavioral pheno-types.Expansions of the CGG repeat over 200 result in the deficiency of FMRP that underlies the fragile X syndrome (FXS). CGG repeat expansions in the premutation range (55-200 CGGs) are associated with different types of clinical phenotypes including the fragile X-related tremor and ataxia syndrome (FXTAS), a late onset neurodegenerative disorder primarily affecting older male premutation careers. Although its molecular mechanism is still unclear, a hypothesis of mRNA-gain-of-function has been proposed, which proposes that abnormally elevated levels of FMR1 mRNA are responsible for degenerative processes affecting the FXTAS brain. Here we review recent findings of patients with FXTAS and unaffected premutation careers using multiple MRI modalities including the high-resolution structural MRI, functional MRI, and diffusion tensor imaging (DTI) to bridge the gap between molecular biological processes and their clinical manifestations. These studies revealed patterns of abnormalities characteristic to FXTAS, some of which were identified in the milder form among unaffected premutation careers. In addition, the studies found several MRI measures that are correlated with molecular variables of FMR1, including the CGG repeat number and the levels of mRNA and FMRP. These findings indicate that the brain imaging studies of FMR1 premutation provide unique opportunities to investigate the relationships of the molecular mechanisms, neural systems, and clinical observations.
