The FMR1 mutations can cause a variety of disabilities, including cognitive deficits, attention-deficit/ hyperactivity disorder, autism, and other socioemotional problems, in individuals with the full mutation form (fragile X syndrome) and distinct difficulties, including primary ovarian insufficiency, neuropathy and the fragile X-associated tremor/ataxia syndrome, in some older premutation carriers. Therefore, multigenerational family involvement is commonly encountered when a proband is identified with a FMR1 mutation. Studies of metabotropic glutamate receptor 5 pathway antagonists in animal models of fragile X syndrome have demonstrated benefits in reducing seizures, improving behavior, and enhancing cognition. Trials of metabotropic glutamate receptor 5 antagonists are beginning with individuals with fragile X syndrome. Targeted treatments, medical and behavioral interventions, genetic counseling, and family supports are reviewed here. NIH Public Access Author ManuscriptPediatrics. Author manuscript; available in PMC 2010 June 21. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptKeywords fragile X syndrome; autism; behavioral interventions; fragile X mental retardation protein; targeted treatments; fenobam FRAGILE X SYNDROME (FXS) is associated with an array of intellectual and emotional disabilities, ranging from mental retardation (hereafter referred to as intellectual disability) to learning problems, autism, and anxiety. The cause of FXS is decreased or absent levels of fragile X mental retardation protein (FMRP). Decreased levels of FMRP typically are caused by the full mutation (>200 CGG repeats), which usually is methylated, in the proximal regulatory region of FMR1 (fragile X mental retardation 1 gene). 1-3 FXS occasionally occurs because of a point mutation or deletion in FMR1 4,5 or even a smaller expansion in the CGG repeat, which leads to lower levels of FMRP and intellectual disability. 6 Intellectual disability linked to FXS occurs in ~1 per 3600 individuals in the general population, 7,8 whereas milder cognitive and behavioral problems (eg, math and language deficits, social phobia, and attention-deficit/ hyperactivity disorder [ADHD]) associated with FXS may be more common. A more-frequent (1 of 130-250 female individuals and 1 of 250-800 male individuals) but smaller expansion (55-200 CGG repeats) of FMR1 is termed a premutation. [9][10][11][12] In contrast to the full mutation, the premutation usually does not cause decreased FMRP levels but leads to enhanced production of FMR1 mRNA (2-8 times normal levels) 13,14 (Fig 1). The enhanced mRNA production can lead to clinical features in premutation carriers that do not occur in full mutation carriers, including primary ovarian insufficiency and the fragile X-associated tremor/ataxia syndrome (FXTAS).In general terms, the severity of the FXS physical phenotype and intellectual impairment is correlated with the magnitude of the FMRP deficit. 1,2,15 Male individuals with incomplete methylation of a full mutation...

Fragile X Syndrome is the most common form of inherited mental retardation worldwide. A Fragile X mouse model, fmr1(tm1Cgr), with a disruption in the X-linked Fmr1 gene, has three substantial deficits observed in several strains: (1) sensitivity to audiogenic seizures (AGS), (2) tendency to spend significantly more time in the center of an open field, and (3) enlarged testes. Alterations in metabotropic glutamate receptor group I signaling were previously identified in the fmr1(tm1Cgr) mouse. In this study, we examined the effect of MPEP, an antagonist of the group I metabotropic glutamate receptor mGluR5, on audiogenic seizures and open field activity of fmr1(tm1Cgr) mice. Genetic analysis revealed synergistic reactions between fmr1(tm1Cgr) and inbred AGS alleles. In addition, AGS sensitivity due to the fmr1(tm1Cgr) allele was restricted during development. Examination of phenotypes combining mGluR5 inhibition and Fmr1 mutation indicated that absence of FMRP may affect mGluR5 signaling through indirect as well as direct pathways. All strains of fmr1(tm1Cgr) mice tested (FVB/NJ, C57BL/6J, and an F1 hybrid of the two) had a more excitable AGS pathway than wild-type, and consequently required more MPEP to achieve seizure suppression. At high doses of mGluR5 antagonists, a Fragile X specific tolerance (loss of drug activity) was observed. The tolerance effect could be overcome by a further increase in drug dose. In open field tests, MPEP reduced fmr1(tm1Cgr) center field behavior to one indistinguishable from wild-type. Therefore, mGluR5 antagonists were able to rescue two of the major phenotypes of the FX mouse. Modulation of mGluR5 signaling may allow amelioration of symptoms of Fragile X Syndrome.

Objective:A pilot open label, single dose trial of fenobam, an mGluR5 antagonist, was conducted to provide an initial evaluation of safety and pharmacokinetics in adult males and females with fragile X syndrome (FXS). Methods: Twelve subjects, recruited from two fragile X clinics, received a single oral dose of 50-150 mg of fenobam. Blood for pharmacokinetic testing, vital signs and side effect screening was obtained at baseline and numerous time points for 6 h after dosing. Outcome measures included prepulse inhibition (PPI) and a continuous performance test (CPT) obtained before and after dosing to explore the effects of fenobam on core phenotypic measures of sensory gating, attention and inhibition.Results: There were no significant adverse reactions to fenobam administration. Pharmacokinetic analysis showed that fenobam concentrations were dose dependent but variable, with mean (SEM) peak values of 39.7 (18.4) ng/ml at 180 min after the 150 mg dose. PPI met a response criterion of an improvement of at least 20% over baseline in 6 of 12 individuals (4/6 males and 2/6 females). The CPT did not display improvement with treatment due to ceiling effects. Conclusions: Clinically significant adverse effects were not identified in this study of single dose fenobam across the range of dosages utilised. The positive effects seen in animal models of FXS treated with fenobam or other mGluR5 antagonists, the apparent lack of clinically significant adverse effects, and the potential beneficial clinical effects seen in this pilot trial support further study of the compound in adults with FXS.Fragile X syndrome (FXS) is the most common inherited form of intellectual disability, autism, and learning disability, with a broad range of severity and full mutation gene frequency of 1/2500.1 FXS results from an unstable trinucleotide repeat expansion of .200 CGG repeats (full mutation) in the promoter of the FMR1 (fragile X mental retardation-1) gene 2 which leads to transcriptional silencing of FMR1 and thus, absence or significant reduction of the FMR1 protein (FMRP). 3Because FMR1 is located on the X chromosome, females with a full mutation are more mildly affected than males, due to production of FMRP from the normal FMR1 allele on the non-mutated X chromosome. FMRP is an RNA binding protein which modulates dendritic maturation and synaptic plasticity through mechanisms including inhibition of group 1 metabotropic glutamate receptor (mGluR1 and mGluR5) mediated mRNA translation in dendrites. [4][5][6][7]

BackgroundFragile X syndrome (FXS) is a disorder characterized by a variety of disabilities, including cognitive deficits, attention-deficit/hyperactivity disorder, autism, and other socio-emotional problems. It is hypothesized that the absence of the fragile X mental retardation protein (FMRP) leads to higher levels of matrix metallo-proteinase-9 activity (MMP-9) in the brain. Minocycline inhibits MMP-9 activity, and alleviates behavioural and synapse abnormalities in fmr1 knockout mice, an established model for FXS. This open-label add-on pilot trial was conducted to evaluate safety and efficacy of minocycline in treating behavioural abnormalities that occur in humans with FXS.MethodsTwenty individuals with FXS, ages 13-32, were randomly assigned to receive 100 mg or 200 mg of minocycline daily. Behavioural evaluations were made prior to treatment (baseline) and again 8 weeks after daily minocycline treatment. The primary outcome measure was the Aberrant Behaviour Checklist-Community Edition (ABC-C) Irritability Subscale, and the secondary outcome measures were the other ABC-C subscales, clinical global improvement scale (CGI), and the visual analog scale for behaviour (VAS). Side effects were assessed using an adverse events checklist, a complete blood count (CBC), hepatic and renal function tests, and antinuclear antibody screen (ANA), done at baseline and at 8 weeks.ResultsThe ABC-C Irritability Subscale scores showed significant improvement (p < 0.001), as did the VAS (p = 0.003) and the CGI (p < 0.001). The only significant treatment-related side effects were minor diarrhea (n = 3) and seroconversion to a positive ANA (n = 2).ConclusionsResults from this study demonstrate that minocycline provides significant functional benefits to FXS patients and that it is well-tolerated. These findings are consistent with the fmr1 knockout mouse model results, suggesting that minocycline modifies underlying neural defects that account for behavioural abnormalities. A placebo-controlled trial of minocycline in FXS is warranted.Trial registrationClinicalTrials.gov Open-Label Trial NCT00858689.

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.