Recent advances in fragile X: a model for autism and neurodegeneration

@article{Hagerman2005RecentAI,
  title={Recent advances in fragile X: a model for autism and neurodegeneration},
  author={Randi J. Hagerman and Michele Y. Ono and Paul J. Hagerman},
  journal={Current Opinion in Psychiatry},
  year={2005},
  volume={18},
  pages={490–496}
}
Purpose of review This review will describe recent developments in the neurobiology of fragile X syndrome (FXS), the association between FXS and autism, and involvement in premutation carriers. Recent findings Metabotropic glutamate receptor 5 (mGluR5)-coupled pathways are dysregulated in individuals with FXS and this is thought to relate to the FXS phenotype. The mGluR5 model suggests that mGluR5 antagonists, including downstream effectors such as lithium, could be useful for treating FXS. Two… 
Neurobehavioral features and targeted treatments in fragile X syndrome: Current insights and future directions
Fragile X syndrome (FXS) is the leading known monogenetic cause of autism spectrum disorder (ASD) and inherited form of intellectual disability (ID). As the major and growing public health problem
The State of Synapses in Fragile X Syndrome
  • Brad E. Pfeiffer, K. M. Huber
  • Biology, Medicine
    The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry
  • 2009
TLDR
The authors review the synaptic changes observed in FXS and try to relate these changes to what is known about the molecular function of FMRP.
Review of targeted treatments in fragile X syndrome.
TLDR
This review will summarize relevant pre-clinical data and results from clinical trials in human subjects with FXS and highlight upcoming studies and future directions for clinical trials as well.
Review Article The role of glycogen synthase kinase-3 signaling in neurodevelopment and fragile X syndrome
TLDR
Understanding how FXS results from FMRP-mediated GSK3 dysregulation may pro-vide novel therapeutic targets for disease-modifying interventions for FXS and related ASDs is understood.
Recent Advances in the Pathogenesis of Syndromic Autisms
TLDR
Altering of the neocortical excitatory/inhibitory balance and perturbations of interneurons' development represent the most probable pathogenetic mechanisms underlying the autistic phenotype in Fragile X-Syndrome and Tuberous Sclerosis Complex.
Molecular Pathogenesis of Fragile X-Associated Tremor/Ataxia Syndrome
TLDR
Overexpression of the expanded CGG repeat messenger RNA results in a direct gain-of-function cellular toxicity that is believed to form the pathogenic basis for fragile X-associated tremor/ataxia syndrome.
The role of fragile X mental retardation protein in major mental disorders
TLDR
The mutation in the fragile X mental retardation-1 gene (FMR1), that leads to FXS, the role FMRP plays in neuronal cells, experiments from the authors' own laboratory that demonstrate reductions of FMRp in additional psychiatric disorders (autism, schizophrenia, bipolar disorder, and major depressive disorder), and potential therapies to ameliorate the loss of F MRP are discussed.
Autism-lessons from the X chromosome.
  • E. Marco, D. Skuse
  • Medicine, Psychology
    Social cognitive and affective neuroscience
  • 2006
TLDR
Three categories of genetic disease that highlight the importance of X-linked genes in the manifestation of an autistic phenotype are discussed: aneuploides (Turner syndrome and Klinefelter syndrome), trinucleotide expansions (Fragile X syndrome) and nucleotide mutations (Rett Syndrome, Neuroligins 3 & 4, and SLC6A8).
Fmr1 KO Mice as a Possible Model of Autistic Features
TLDR
An assessment of autistic features in this candidate model of the Fragile X Syndrome is presented, concluding that Fmr1 KO mice display several autistic-like features, but more work is needed to validate this model.
iPSC-derived forebrain neurons from FXS individuals show defects in initial neurite outgrowth.
TLDR
Human induced pluripotent stem cell lines from fibroblasts obtained from individuals with FXS are created to enable in vitro modeling of the human disease and provide a well-characterized resource to examine potential neuronal deficits caused by FXS as well as the function of FMRP in human neurons.
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References

SHOWING 1-10 OF 107 REFERENCES
The emerging fragile X premutation phenotype: Evidence from the domain of social cognition
TLDR
The results suggest that premutation males display a pattern of deficit similar in profile, albeit milder in presentation, to that of the full mutation, however, little evidence emerged for a correlation between CGG repeat length and severity of phenotypic outcomes.
FMR1 RNA within the Intranuclear Inclusions of Fragile X-Associated Tremor/Ataxia Syndrome (FXTAS)
TLDR
FMR1 mRNA is identified within the intranuclear inclusions isolated from post-mortem (FXTAS) brain tissue, consistent with the proposed RNA toxic gain-of-function model for FXTAS.
Sensorimotor gating abnormalities in young males with fragile X syndrome and Fmr1-knockout mice
TLDR
It is shown that young males with FXS have profound deficits in prepulse inhibition (PPI), a basic marker of sensorimotor gating that has been extensively studied in rodents, and this suggests that murine compensatory mechanisms following loss of FMR1 function differ from those in humans.
Penetrance of the fragile X-associated tremor/ataxia syndrome in a premutation carrier population.
TLDR
It is demonstrated that older male carriers of premutation alleles of the FMR1 gene are at high risk of developing fragile X-associated tremor/ataxia syndrome (FXTAS), and older men with ataxia and intention tremor should be screened for the F MR1 mutation.
A neuropsychological investigation of male premutation carriers of fragile X syndrome
TLDR
It is suggested that CGG trinucleotide repeats in the premutation range affect specific neuronal circuits that are concordant with specific neuropsychological deficits; and that these deficits reflect an emerging neuropsychologically phenotype of premutation FraX.
The mGluR theory of fragile X mental retardation
TLDR
Loss of fragile X mental retardation protein (FMRP), the defect responsible for fragile X syndrome in humans, increases LTD in mouse hippocampus, consistent with the growing evidence that FMRP normally functions as a repressor of translation of specific mRNAs.
Aging in individuals with the FMR1 mutation.
TLDR
The premutation is associated with elevated messenger RNA levels leading to the formation of intranuclear inclusions in neurons and astrocytes associated with FXTAS, and this review is a summary of the experience withFXTAS in male carriers of the premutation.
Intranuclear inclusions in neural cells with premutation alleles in fragile X associated tremor/ataxia syndrome
TLDR
Analysis of multiple brain regions was undertaken to demonstrate that premutation alleles were directly associated with inclusion formation, and that full mutation alleles, even if present at low levels, would not affect clinical involvement.
Fragile-X-associated tremor/ataxia syndrome (FXTAS) in females with the FMR1 premutation.
We describe five female carriers of the FMR1 premutation who presented with symptoms of tremor and ataxia and who received a diagnosis of definite or probable fragile-X-associated tremor/ataxia
Screen for expanded FMR1 alleles in patients with essential tremor
TLDR
Screening of movement disorder patients with other clinical features of FXTAS may be more likely to yield expanded FMR1 alleles, which raises the possibility that some patients presenting with essential tremor (ET) may harbor expanded F MR2 alleles.
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