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

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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.

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Acknowledgments

This work was supported by a National Institutes of Health grant, R01 HD040661. The author wishes to thank Dr. Claudia Greco for comments/suggestions pertaining to Table 1; Drs. Renate Hukema, Karen Usdin, and Peter Todd for input on sequences for the Dutch and NIH mice (Table 2); Drs. Ryan Hunsaker and Robert Berman for their comments/corrections pertaining to Table 2; Dr. Rivera for providing her manuscript prior to publication; and Dr. Randi Hagerman and Elisabeth Makhoul for critically reading and editing this manuscript. The author also wishes to thank the many patients with FXTAS and other types of premutation involvement who have participated in FXTAS research. He is grateful for the private donations from families who support FXTAS and fragile X syndrome research.

Conflict of interest

Dr. Hagerman is an uncompensated collaborator with Pacific Biosciences regarding new FMR1 sequencing strategies; he holds patents for FMR1 genotyping and protein tests.

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Hagerman, P. Fragile X-associated tremor/ataxia syndrome (FXTAS): pathology and mechanisms. Acta Neuropathol 126, 1–19 (2013). https://doi.org/10.1007/s00401-013-1138-1

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