Advances in clinical and molecular understanding of the FMR1 premutation and fragile X-associated tremor/ataxia syndrome

Research output: Contribution to journalArticle

186 Citations (Scopus)

Abstract

Fragile X syndrome, the most common heritable form of cognitive impairment, is caused by epigenetic silencing of the fragile X (. FMR1) gene owing to large expansions (>200 repeats) of a non-coding CGG-repeat element. Smaller, so-called premutation expansions (55-200 repeats) can cause a family of neurodevelopmental phenotypes (attention deficit hyperactivity disorder, autism spectrum disorder, seizure disorder) and neurodegenerative (fragile X-associated tremor/ataxia syndrome [FXTAS]) phenotypes through an entirely distinct molecular mechanism involving increased FMR1 mRNA production and toxicity. Results of basic cellular, animal, and human studies have helped to elucidate the underlying RNA toxicity mechanism, while clinical research is providing a more nuanced picture of the range of clinical manifestations. Advances of knowledge on both mechanistic and clinical fronts are driving new approaches to targeted treatment, but two important necessities are emerging: to define the extent to which the mechanisms contributing to FXTAS also contribute to other neurodegenerative and medical disorders, and to redefine FXTAS in view of its differing presentations and associated features.

Original languageEnglish (US)
Pages (from-to)786-798
Number of pages13
JournalThe Lancet Neurology
Volume12
Issue number8
DOIs
StatePublished - Aug 2013

Fingerprint

Phenotype
Fragile X Syndrome
Attention Deficit Disorder with Hyperactivity
Epigenomics
Neurodegenerative Diseases
Epilepsy
RNA
Messenger RNA
Research
Genes
Fragile X Tremor Ataxia Syndrome
Autism Spectrum Disorder
Cognitive Dysfunction

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

@article{4627749366244e95a6fe03ff09b63fe2,
title = "Advances in clinical and molecular understanding of the FMR1 premutation and fragile X-associated tremor/ataxia syndrome",
abstract = "Fragile X syndrome, the most common heritable form of cognitive impairment, is caused by epigenetic silencing of the fragile X (. FMR1) gene owing to large expansions (>200 repeats) of a non-coding CGG-repeat element. Smaller, so-called premutation expansions (55-200 repeats) can cause a family of neurodevelopmental phenotypes (attention deficit hyperactivity disorder, autism spectrum disorder, seizure disorder) and neurodegenerative (fragile X-associated tremor/ataxia syndrome [FXTAS]) phenotypes through an entirely distinct molecular mechanism involving increased FMR1 mRNA production and toxicity. Results of basic cellular, animal, and human studies have helped to elucidate the underlying RNA toxicity mechanism, while clinical research is providing a more nuanced picture of the range of clinical manifestations. Advances of knowledge on both mechanistic and clinical fronts are driving new approaches to targeted treatment, but two important necessities are emerging: to define the extent to which the mechanisms contributing to FXTAS also contribute to other neurodegenerative and medical disorders, and to redefine FXTAS in view of its differing presentations and associated features.",
author = "Hagerman, {Randi J} and Hagerman, {Paul J}",
year = "2013",
month = "8",
doi = "10.1016/S1474-4422(13)70125-X",
language = "English (US)",
volume = "12",
pages = "786--798",
journal = "The Lancet Neurology",
issn = "1474-4422",
publisher = "Lancet Publishing Group",
number = "8",

}

TY - JOUR

T1 - Advances in clinical and molecular understanding of the FMR1 premutation and fragile X-associated tremor/ataxia syndrome

AU - Hagerman, Randi J

AU - Hagerman, Paul J

PY - 2013/8

Y1 - 2013/8

N2 - Fragile X syndrome, the most common heritable form of cognitive impairment, is caused by epigenetic silencing of the fragile X (. FMR1) gene owing to large expansions (>200 repeats) of a non-coding CGG-repeat element. Smaller, so-called premutation expansions (55-200 repeats) can cause a family of neurodevelopmental phenotypes (attention deficit hyperactivity disorder, autism spectrum disorder, seizure disorder) and neurodegenerative (fragile X-associated tremor/ataxia syndrome [FXTAS]) phenotypes through an entirely distinct molecular mechanism involving increased FMR1 mRNA production and toxicity. Results of basic cellular, animal, and human studies have helped to elucidate the underlying RNA toxicity mechanism, while clinical research is providing a more nuanced picture of the range of clinical manifestations. Advances of knowledge on both mechanistic and clinical fronts are driving new approaches to targeted treatment, but two important necessities are emerging: to define the extent to which the mechanisms contributing to FXTAS also contribute to other neurodegenerative and medical disorders, and to redefine FXTAS in view of its differing presentations and associated features.

AB - Fragile X syndrome, the most common heritable form of cognitive impairment, is caused by epigenetic silencing of the fragile X (. FMR1) gene owing to large expansions (>200 repeats) of a non-coding CGG-repeat element. Smaller, so-called premutation expansions (55-200 repeats) can cause a family of neurodevelopmental phenotypes (attention deficit hyperactivity disorder, autism spectrum disorder, seizure disorder) and neurodegenerative (fragile X-associated tremor/ataxia syndrome [FXTAS]) phenotypes through an entirely distinct molecular mechanism involving increased FMR1 mRNA production and toxicity. Results of basic cellular, animal, and human studies have helped to elucidate the underlying RNA toxicity mechanism, while clinical research is providing a more nuanced picture of the range of clinical manifestations. Advances of knowledge on both mechanistic and clinical fronts are driving new approaches to targeted treatment, but two important necessities are emerging: to define the extent to which the mechanisms contributing to FXTAS also contribute to other neurodegenerative and medical disorders, and to redefine FXTAS in view of its differing presentations and associated features.

UR - http://www.scopus.com/inward/record.url?scp=84880359647&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84880359647&partnerID=8YFLogxK

U2 - 10.1016/S1474-4422(13)70125-X

DO - 10.1016/S1474-4422(13)70125-X

M3 - Article

C2 - 23867198

AN - SCOPUS:84880359647

VL - 12

SP - 786

EP - 798

JO - The Lancet Neurology

JF - The Lancet Neurology

SN - 1474-4422

IS - 8

ER -