Fragile X-associated tremor/ataxia syndrome (FXTAS) is generally considered to be uncommon in older female carriers of premutation alleles (55-200 CGG repeats) of the fragile X mental retardation 1 (FMR1) gene; however, neither prevalence, nor the nature of the clinical phenotype, has been well characterized in female carriers. In this study, we evaluated 146 female carriers (mean, 42.3 years; range, 20-75 years) with and without core features of FXTAS (tremor; gait ataxia), and 69 age-matched controls (mean, 45.8 years; range, 21-78 years). Compared with controls, carriers with definite or probable FXTAS had greater medical co-morbidity, with increased prevalence of thyroid disease (P ¼ 0.0096), hypertension (P ¼ 0.0020), seizures (P ¼ 0.0077), peripheral neuropathy (P ¼ 0.0040), and fibromyalgia (P ¼ 0.0097), in addition to the typical symptoms of FXTAS-tremor (P < 0.0001) and ataxia (P < 0.0001). The non-FXTAS premutation group had more complaints of chronic muscle pain (P ¼ 0.0097), persistent paraesthesias in extremities (P < 0.0001), and history of tremor (P < 0.0123) than controls. The spectrum of clinical involvement in female carriers with FXTAS is quite broad, encompassing a number of medical co-morbidities as well as the core movement disorder. The remarkable degree of thyroid dysfunction (17% in the non-FXTAS group and 50% in the FXTAS group) warrants consideration of thyroid function studies in all female premutation carriers, particularly those with core features of FXTAS. ß

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]

Although fragile X syndrome (FXS) is a single gene disorder with a well-described phenotype, it is not known why some individuals develop more significant maladaptive behaviors such as aggression or autistic symptoms. Here, we studied two candidate genes known to affect mood and aggression, the serotonin transporter (5-HTTLPR) and monoamine oxidase A (MAOA-VNTR) polymorphisms, in 50 males with FXS ages 8-24 years. Mothers and fathers of participants reported the frequency and severity of aggressive/destructive, self-injurious, and stereotypic behaviors. Polymorphism genotypes were unrelated to age and IQ. Results showed a significant effect of 5-HTTLPR genotype on aggressive/destructive and stereotypic behavior; males with FXS who were homozygous for the high-transcribing long (L/L) genotype had the most aggressive and destructive behavior, and individuals homozygous for the short (S/S) genotype had the least aggression. Those with the L/L genotype also had the highest levels of stereotypic behavior. There was no effect of MAOA-VNTR on behavior; however those with the high-activity, 4-repeat genotype were more likely to be taking SSRI or SNRI medication. This preliminary study prompts consideration of secondary genes that may modify behavioral phenotype expression in neurodevelopmental disorders, even those with a single gene etiology such as FXS.

Background-Pharmacological rescue of behavioral, cognitive and synaptic abnormalities in the animal models of fragile X syndrome (FXS) has prompted the initiation of clinical trials of targeted treatments in humans with this condition. Objective, well-validated outcome measures that are reflective of FXS deficits and can be modeled similarly in animal and human studies are urgently needed.

Prepulse inhibition (PPI) may useful for exploring the proposed shared neurobiology between idiopathic autism and autism caused by FXS. We compared PPI in four groups: typically developing controls (n = 18), FXS and autism (FXS+A; n = 15), FXS without autism spectrum disorder (FXS−A; n = 17), and idiopathic autism (IA; n = 15). Relative to controls, the FXS+A (p < 0.002) and FXS−A (p < 0.003) groups had impaired PPI. The FXS+A (p < 0.01) and FXS−A (p < 0.03) groups had lower PPI than the IA group. Prolonged startle latency was seen in the IA group. The differing PPI profiles seen in the FXS+A and IA indicates these groups may not share a common neurobiological abnormality of sensorimotor gating.