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

Research output: Contribution to journalArticle

87 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)1-19
Number of pages19
JournalActa Neuropathologica
Volume126
Issue number1
DOIs
StatePublished - Jul 2013

Fingerprint

Pathology
Intranuclear Inclusion Bodies
Movement Disorders
Nuclear Proteins
MicroRNAs
Neurodegenerative Diseases
Fragile X Tremor Ataxia Syndrome
Alleles
Genes
Therapeutics

Keywords

  • DGCR8
  • Fragile X
  • MicroRNA
  • Neurodegeneration
  • Premutation
  • RNA toxicity

ASJC Scopus subject areas

  • Clinical Neurology
  • Pathology and Forensic Medicine
  • Cellular and Molecular Neuroscience

Cite this

Fragile X-associated tremor/ataxia syndrome (FXTAS) : Pathology and mechanisms. / Hagerman, Paul J.

In: Acta Neuropathologica, Vol. 126, No. 1, 07.2013, p. 1-19.

Research output: Contribution to journalArticle

@article{2a543022df424d51a06d85ff4a10e940,
title = "Fragile X-associated tremor/ataxia syndrome (FXTAS): Pathology and mechanisms",
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.",
keywords = "DGCR8, Fragile X, MicroRNA, Neurodegeneration, Premutation, RNA toxicity",
author = "Hagerman, {Paul J}",
year = "2013",
month = "7",
doi = "10.1007/s00401-013-1138-1",
language = "English (US)",
volume = "126",
pages = "1--19",
journal = "Acta Neuropathologica",
issn = "0001-6322",
publisher = "Springer Verlag",
number = "1",

}

TY - JOUR

T1 - Fragile X-associated tremor/ataxia syndrome (FXTAS)

T2 - Pathology and mechanisms

AU - Hagerman, Paul J

PY - 2013/7

Y1 - 2013/7

N2 - 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.

AB - 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.

KW - DGCR8

KW - Fragile X

KW - MicroRNA

KW - Neurodegeneration

KW - Premutation

KW - RNA toxicity

UR - http://www.scopus.com/inward/record.url?scp=84879068188&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84879068188&partnerID=8YFLogxK

U2 - 10.1007/s00401-013-1138-1

DO - 10.1007/s00401-013-1138-1

M3 - Article

C2 - 23793382

AN - SCOPUS:84879068188

VL - 126

SP - 1

EP - 19

JO - Acta Neuropathologica

JF - Acta Neuropathologica

SN - 0001-6322

IS - 1

ER -