Fragile X syndrome and selective mutism

Hagerman, Randi J; Hills, J.; Scharfenaker, S.; Lewis, Hal C.

doi:10.1002/(sici)1096-8628(19990402)83:4<313::aid-ajmg15>3.0.co;2-f

Cited by 63 publications

(9 citation statements)

References 30 publications

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“…FXS patients exhibit hyper-reactivity to visual, olfactory, tactile and auditory stimulation [1], [66]–[69]. This hypersensitivity phenotype is manifested as AGS in Fmr1 KO mice [20].…”

Section: Discussionmentioning

confidence: 99%

Reversal of Fragile X Phenotypes by Manipulation of AβPP/Aβ Levels in Fmr1KO Mice

et al. 2011

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Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and the leading known genetic cause of autism. Fragile X mental retardation protein (FMRP), which is absent or expressed at substantially reduced levels in FXS, binds to and controls the postsynaptic translation of amyloid β-protein precursor (AβPP) mRNA. Cleavage of AβPP can produce β-amyloid (Aβ), a 39–43 amino acid peptide mis-expressed in Alzheimer's disease (AD) and Down syndrome (DS). Aβ is over-expressed in the brain of Fmr1KO mice, suggesting a pathogenic role in FXS. To determine if genetic reduction of AβPP/Aβ rescues characteristic FXS phenotypes, we assessed audiogenic seizures (AGS), anxiety, the ratio of mature versus immature dendritic spines and metabotropic glutamate receptor (mGluR)-mediated long-term depression (LTD) in Fmr1KO mice after removal of one App allele. All of these phenotypes were partially or completely reverted to normal. Plasma Aβ1–42 was significantly reduced in full-mutation FXS males compared to age-matched controls while cortical and hippocampal levels were somewhat increased, suggesting that Aβ is sequestered in the brain. Evolving therapies directed at reducing Aβ in AD may be applicable to FXS and Aβ may serve as a plasma-based biomarker to facilitate disease diagnosis or assess therapeutic efficacy.

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“…FXS patients exhibit hyper-reactivity to visual, olfactory, tactile and auditory stimulation [1], [66]–[69]. This hypersensitivity phenotype is manifested as AGS in Fmr1 KO mice [20].…”

Section: Discussionmentioning

confidence: 99%

Reversal of Fragile X Phenotypes by Manipulation of AβPP/Aβ Levels in Fmr1KO Mice

et al. 2011

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“…Of note, the effect of VPA on reactivation of the FMR1 gene in other types of tissue may be varied and still remains unclear. In addition, VPA has already been proven to be an effective treatment of behavioral and psychiatric symptoms in patients with autism or FXS (Sovner, 1989;Hagerman et al, 1999;Torrioli et al, 2010). For these reasons, using VPA to treat FXS cannot be excluded, although further research on its basic mechanisms is needed.…”

Section: F Fxsmentioning

confidence: 99%

Therapeutic Potential of Mood Stabilizers Lithium and Valproic Acid: Beyond Bipolar Disorder

et al. 2013

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“…Studies have suggested that fluoxetine may be beneficial to individuals with autism (Hollander et al, 2005, 2012; Kolevzon et al, 2006). Treatment with fluoxetine has shown some effect in fragile X mice and patients (Hagerman et al, 1999; Uutela et al, 2014). However, fluoxetine has some possible side effects in clinic, such as mood changes, agitation, restlessness, and aggression, and may not be suitable to all individuals with fragile X syndrome and other ASDs (Wernicke, 2004; Kolevzon et al, 2006; Uutela et al, 2014).…”

Section: Targeted Pharmacotherapy For Fragile X Syndromementioning

confidence: 99%

Targeted pharmacological treatment of autism spectrum disorders: fragile X and Rett syndromes

Wang

Pati

Pozzo-Miller

et al. 2015

Front. Cell. Neurosci.

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Autism spectrum disorders (ASDs) are genetically and clinically heterogeneous and lack effective medications to treat their core symptoms. Studies of syndromic ASDs caused by single gene mutations have provided insights into the pathophysiology of autism. Fragile X and Rett syndromes belong to the syndromic ASDs in which preclinical studies have identified rational targets for drug therapies focused on correcting underlying neural dysfunction. These preclinical discoveries are increasingly translating into exciting human clinical trials. Since there are significant molecular and neurobiological overlaps among ASDs, targeted treatments developed for fragile X and Rett syndromes may be helpful for autism of different etiologies. Here, we review the targeted pharmacological treatment of fragile X and Rett syndromes and discuss related issues in both preclinical studies and clinical trials of potential therapies for the diseases.

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Fragile X syndrome and selective mutism

Cited by 63 publications

References 30 publications

Reversal of Fragile X Phenotypes by Manipulation of AβPP/Aβ Levels in Fmr1KO Mice

Reversal of Fragile X Phenotypes by Manipulation of AβPP/Aβ Levels in Fmr1KO Mice

Therapeutic Potential of Mood Stabilizers Lithium and Valproic Acid: Beyond Bipolar Disorder

Targeted pharmacological treatment of autism spectrum disorders: fragile X and Rett syndromes

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