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Acta Neuropathol. 2013 Jul;126(1):1-19. doi: 10.1007/s00401-013-1138-1. Epub 2013 Jun 21.

Fragile X-associated tremor/ataxia syndrome (FXTAS): pathology and mechanisms.

Author information

1
Department of Biochemistry and Molecular Medicine, and the MIND Institute, University of California, Davis, Health System, 4303 Tupper Hall, One Shields Ave, Davis, CA 95616, USA. pjhagerman@ucdavis.edu

Abstract

Since its discovery in 2001, our understanding of fragile X-associated tremor/ataxia syndrome (FXTAS) has undergone a remarkable transformation. Initially characterized rather narrowly as an adult-onset movement disorder, the definition of FXTAS is broadening; moreover, the disorder is now recognized as only one facet of a much broader clinical pleiotropy among children and adults who carry premutation alleles of the FMR1 gene. Furthermore, the intranuclear inclusions of FXTAS, once thought to be a CNS-specific marker of the disorder, are now known to be widely distributed in multiple non-CNS tissues; this observation fundamentally changes our concept of the disease, and may provide the basis for understanding the diverse medical problems associated with the premutation. Recent work on the pathogenic mechanisms underlying FXTAS indicates that the origins of the late-onset neurodegenerative disorder actually lie in early development, raising the likelihood that all forms of clinical involvement among premutation carriers have a common underlying mechanistic basis. There has also been great progress in our understanding of the triggering event(s) in FXTAS pathogenesis, which is now thought to involve sequestration of one or more nuclear proteins involved with microRNA biogenesis. Moreover, there is mounting evidence that mitochondrial dysregulation contributes to the decreased cell function and loss of viability, evident in mice even during the neonatal period. Taken together, these recent findings offer hope for early interventions for FXTAS, well before the onset of overt disease, and for the treatment of other forms of clinical involvement among premutation carriers.

PMID:
23793382
PMCID:
PMC3904666
DOI:
10.1007/s00401-013-1138-1
[Indexed for MEDLINE]
Free PMC Article

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