Fragile X Mental Retardation 1 Gene Research Articles

The Prognostic and Therapeutic Potential of Fragile X Mental Retardation 1 (FMR1) Gene Expression in Prostate Adenocarcinoma: Insights into Survival Outcomes and Oncogenic Pathway Modulation.

Prostate adenocarcinoma (PRAD) is the second most common tumor associated with death. The role and mechanisms of the fragile X mental retardation 1 (FMR1) gene in PRAD remain unknown. We conducted an analysis of FMR1 expression in PRAD to determine its prognostic importance and connection to carcinogenic pathways such as PI3K_AKT_mTOR. Survival analyses were utilized to establish a correlation between FMR1 expression and patient outcomes. We used the integration of genomic data with bioinformatic predictions to predict the regulatory factors of the FMR1 gene in PRAD. Our data revealed that individuals with higher levels of FMR1 expression experience worse survival outcomes compared to those with lower expression (hazard ratio [HR] = 5.08, 95% confidence interval [CI] = 1.07 - 24, p = 0.0412). FMR1 expression was significantly higher in patients with advanced pathological tumor stages, particularly in the pT3 and pT4 combined stages and the pN1 nodal stage. Furthermore, patients with high Gleason scores (GSs) (combined GSs 8 and 9) exhibited increased levels of FMR1 expression. Our results further identify a possible regulatory link between FMR1 and key oncogenic pathways, including PI3K_AKT_mTOR, and predict the possible mechanism by which FMR1 is regulated in PRAD. Our data suggest that the FMR1 gene could serve as a biomarker for PRAD progression. However, in-depth investigations, including those with large patient samples and in vitro studies, are needed to validate this finding and understand the mechanisms involved.

A280 HEPATOBILIARY DISEASE IN INDIVIDUALS LIVING WITH FRAGILE X SYNDROME: A CASE SERIES

Abstract Background Fragile X syndrome is a genetic disorder known to cause intellectual disability through decreased or absent FMR protein (FMRP). Basic science studies have identified potential associations with hepatobiliary inflammation. Clinical reports of liver disease in Fragile X syndrome are however infrequent. Aims We describe 3 individuals living with Fragile X syndrome and chronic liver disease. Methods A case series and literature review were performed. Results The 1st person is a woman with concurrent Fragile X and autosomal recessive polycystic kidney disease, initially seen by Hepatology at 18 y.o. with evidence of hepatic fibrosis on abdominal ultrasound with normal liver enzymes (Table 1). She subsequently developed liver cirrhosis and portal hypertension, as well as biliary duct dilatation seen on MRI. Her overall presentation was thought to be in keeping with Caroli syndrome and congenital hepatic fibrosis, and she is currently pending genetic screening for hepatorenal ciliopathy. The 2nd person is a woman with Fragile X syndrome and ulcerative colitis, who initially presented to Hepatology at 24 y.o. with mixed liver enzyme abnormalities. Lab tests over time revealed immunology suggestive of autoimmune hepatitis (AIH) (Table 1). Subsequent investigations demonstrated primary sclerosing cholangitis (PSC) with cirrhosis. Her disease is currently managed as AIH/PSC overlap syndrome with ursodeoxycholic acid (UDCA), tacrolimus, mycophenolate, and budesonide. The 3rd person is a man with Fragile X syndrome who initially presented to Hepatology at 17 y.o. with acute hepatitis with AIH immunology (Table 1). Liver biopsy at the time demonstrated findings suggestive of early PSC as well as possible AIH. He continued to have progressive cirrhosis as well as overt PSC on subsequent abdominal imaging and is currently managed as AIH/PSC overlap syndrome with UDCA, azathioprine, and budesonide. A review of literature revealed that asides from known intellectual, behavioral, and physical effects of Fragile X syndrome, there are minimal reports of other associated medical complications including liver problems or autoimmune conditions including IBD. There are however reports of autoimmunity in those with altered FMR1 (Fragile X Mental Retardation 1) gene mutations. Conclusions These 3 cases of liver disease in Fragile X highlight young age of presentation for chronic liver disease with both biliary and immune-mediated characteristics, along with progression to cirrhosis. Additional review for liver manifestations in people living with Fragile X would help understand if this association is incidental or causal. Investigations of individuals with Fragile X syndrome and liver disease Funding Agencies None

Histone modifications and FMR role in Fragile X syndrome: A review

Fragile X syndrome is the most common cause of genetically acquired mental disability and one of the most frequent single-gene disorders. FXS serves as an excellent model disorder for studies investigating disturbed molecular mechanisms and synapse function. FXS is an X-linked disorder that affects approximately 1 in 4000 males and females, with females experiencing milder cognitive deficits. It is caused due to expansion of trinucleotide CGG repeat above the normal range (>54 repeats) in the 5’ noncoding region of the fragile x mental retardation 1 (FMR1) gene located in the q27.3 loci of the X chromosome, which results in hypermethylation of CpG islands and eventually to transcriptional silencing of the gene hence suppressing the production of the Fragile X mental retardation protein (FMRP). The lack of FMRP, involved in multiple aspects of mRNA metabolism in the brain causing intellectual disability, autism spectrum disorder, and deregulation of multiple pathways, is thought to be the direct cause of the FXS phenotypes. The purpose of this review is to summarize the basic models used to study the aspects of fragile x syndrome, the relation of FMR1 gene and FMRP with the disease, histone modifications, and various targeted molecular therapy used for cure.

Síndrome de temblor y ataxia asociado a frágil X (FXTAS): revisión de la literatura

El síndrome de temblor y ataxia asociado al síndrome del cromosoma X frágil (FXTAS) es un desorden neurodegenerativo progresivo (1), de inicio tardío, que ocurre entre los portadores de la premutación del gen FMR1 (Fragile X Mental Retardation 1), el cual está estrechamente asociado con el síndrome del cromosoma X frágil (FXS). El FXTAS se caracteriza por déficits neurológicos que incluyen temblor de intención progresivo, ataxia cerebelosa, parkinsonismo, neuropatía periférica, déficits cognitivos y disfunción autonómica (2-4).
 El FXTAS surge como una importante opción diagnóstica en hombres con temblor, alteraciones en la marcha y síntomas neurodegenerativos. En general existe subregistro de esta patología dado que es un síndrome recientemente descrito y falta conocimiento de los profesionales de salud al respecto, los cuales, debido a la similitud de su presentación clínica con otros desórdenes neurológicos, generalmente suelen confundir el diagnóstico (5).
 En Colombia no se ha documentado la prevalencia de SXF o de FXTAS. Sin embargo, se ha descrito un corregimiento en el Valle del Cauca que tiene una prevalencia de más de cien veces lo reportado en la literatura de SFX, lo que nos sugiere que en Colombia existe subregistro del SFX y de FXTAS.
 Esta revisión tiene por objeto difundir los avances del conocimiento de las manifestaciones clínicas, la neurofisiopatología y las posibilidades de tratamiento de los pacientes con FXTAS, y así aumentar diagnóstico y aportar a mejorar la calidad de vida de los afectados y de sus familias.

PGT-M With or Without Triplet Repeat Detection for Fragile X Syndrome

Background: Fragile X syndrome (FraX) is the most common single gene cause of intellectual disability. It is caused by an unstable triplet repeat expansion in the Fragile X Mental Retardation 1 ( FMR1 ) gene. Female pre-mutation carriers are at-risk of passing a full-mutation onto their offspring, resulting in intellectual disability. A reproductive option to reduce the risk of having an affected child is Pre-implantation Genetic Testing for a monogenetic condition (PGT-M). Various methods exist to perform PGT-M for FraX. Aim: To explore the option of PGT-M with and without triplet repeat detection for FraX, consider the potential advantages and disadvantages of each approach, and examine the decision of six couples undertaking PGT-M for FraX through our service. Method: Patients were offered the choice of two testing methods of PGT-M for FraX. The first was haplotype analysis of markers linked to the FMR1 gene. The second was haplotype analysis of linked markers with simultaneous triplet repeat detection. Advantages and disadvantages of testing with and without triplet repeat detection were identified. Each couple’s clinical history and opinion regarding transfer of pre-mutation embryos were elicited. The couples final decision and reasoning was explored. Results: Despite differing clinical histories and opinions on whether they would transfer a pre-mutation embryo or not, all six couples decided to proceed with PGT-M for FraX with triplet repeat detection. Reasons given included maximising information, treatment options, and pregnancy rate. Conclusion: PGT-M for FraX should be offered with triplet repeat detection to improve the robustness of the diagnosis and to maximise patient choice. All couples decided to have PGT-M for FraX with triplet repeat detection which ultimately allows them to consider transfer of a pre-mutation embryo if no unaffected embryos are available for transfer.

Genome-wide screening for genes involved in the epigenetic basis of fragile X syndrome.

SummaryFragile X syndrome (FXS), the most prevalent heritable form of intellectual disability, is caused by the transcriptional silencing of the FMR1 gene. The epigenetic factors responsible for FMR1 inactivation are largely unknown. Here, we initially demonstrated the feasibility of FMR1 reactivation by targeting a single epigenetic factor, DNMT1. Next, we established a model system for FMR1 silencing using a construct containing the FXS-related mutation upstream to a reporter gene. This construct was methylated in vitro and introduced into a genome-wide loss-of-function (LOF) library established in haploid human pluripotent stem cells (PSCs), allowing the identification of genes whose functional loss reversed the methylation-induced silencing of the FMR1 reporter. Selected candidate genes were further analyzed in haploid- and FXS-patient-derived PSCs, highlighting the epigenetic and metabolic pathways involved in FMR1 regulation. Our work sheds light on the mechanisms responsible for CGG-expansion-mediated FMR1 inactivation and offers novel targets for therapeutic FMR1 reactivation.

Understanding the Molecular Basis of Fragile X Syndrome Using Differentiated Mesenchymal Stem Cells.

ObjectivesFragile X syndrome (FXS) has been known as the most common cause of inherited intellectual disability and autism. This disease results from the loss of fragile X mental retardation protein expression due to the expansion of CGG repeats located on the 5’ untranslated region of the fragile X mental retardation 1 (FMR1) gene. Materials & Methods In the present study, the peripheral blood-mesenchymal stem cells (PB-MSCs) of two female full mutation carriers were differentiated into neuronal cells by the suppression of bone morphogenesis pathway signaling. Then, the expression of genes adjacent to CGG repeats expansion, including SLIT and NTRK-like protein 2 (SLITRK2), SLIT and NTRK-like protein 4 (SLITRK4), methyl CpG binding protein 2 (MECP2), and gamma-aminobutyric acid receptor subunit alpha-3 (GABRA3), were evaluated in these cells using SYBR Green real-time polymerase chain reaction. ResultsThe obtained results indicated that the expression of SLITRK2 and SLITRK4 were upregulated and downregulated in the neuron-like cells differentiated from the PB-MSCs of females with FMR1 full mutation, compared to that of the normal females, respectively. Furthermore, the expression of MECP2 and GABRA3 genes were observed to be related to the phenotypic differences observed in the female FMR1 full mutation carriers. Conclusion The observed association of expression of genes located upstream of the FMR1 gene with phenotypic differences in the female carriers could increase the understanding of novel therapeutic targets for patients with mild symptoms of FXS and the patients affected by other FMR1-related disorders.

Altered expression of fragile X mental retardation-1 (FMR1) in the thymus in autoimmune myasthenia gravis

Predisposition to autoimmunity and inflammatory disorders is observed in patients with fragile X-associated syndromes. These patients have increased numbers of CGG triplets in the 5’ UTR region of FMR1 (Fragile X Mental Retardation 1) gene, that affects its expression. FMR1 is decreased in the thymus of myasthenia gravis (MG) patients, a prototypical autoimmune disease. We thus analyzed the number of CGG triplets in FMR1 in MG, and explored the regulatory mechanisms affecting thymic FMR1 expression. We measured the number of CGGs using thymic DNA from MG and controls, but no abnormalities in CGGs were found in MG that could explain thymic decrease of FMR1. We next analyzed by RT-PCR the expression of FMR1 and its transcription factors in thymic samples, and in thymic epithelial cell cultures in response to inflammatory stimuli. In control thymuses, FMR1 expression was higher in males than females, and correlated with CTCF (CCCTC-binding factor) expression. In MG thymuses, decreased expression of FMR1 was correlated with both CTCF and MAX (Myc-associated factor X) expression. Changes in FMR1 expression were supported by western blot analyses for FMRP. In addition, we demonstrated that FMR1, CTCF and MAX expression in thymic epithelial cells was also sensitive to inflammatory signals. Our results suggest that FMR1 could play a central role in the thymus and autoimmunity. First, in relation with the higher susceptibility of females to autoimmune diseases. Second, due to the modulation of its expression by inflammatory signals that are known to be altered in MG thymuses.

Early Onset of Fragile X Associated Tremor and Ataxia Syndrome: A Case Report from Iran

Background: Different alleles of Fragile X Mental Retardation1 (FMR1) gene with separate molecular etiologies cause Fragile X Syndrome (FXS) and Fragile X-associated Tremor and Ataxia Syndrome (FXTAS). Premutation alleles with 55 to 200 repeats in the FMR1 gene lead to FXTAS. It is carried by 1 in 209 women and 1 in 430 men. FXTAS commonly appears in 50- to 70-year-old adults. Case Presentation: An 11 months old boy was referred to the hospital due to clinical presentations of productive cough seizure, mental disability, and ataxia. Magnetic Resonance Imaging (MRI), Electroencephalography (EEG), hematology, biochemistry, hormone, and genetic tests were done. Triplet repeat PCR (TP PCR) showed 99 CGG repeats as permutation alleles. Conclusion: In this study, the authors reported the early onset of FXTAS in an 11 months old boy for the first time.

Mosaicism in Fragile X syndrome: A family case series.

Fragile X syndrome (FXS) has a classic phenotype, however its expression can be variable among full mutation males. This is secondary to variable methylation mosaicisms and the number of CGG triplet repeats in the non-coding region of the Fragile X Mental Retardation 1 (FMR1) gene, producing a variable expression of the Fragile X Mental Retardation Protein (FMRP). Here we report a family with several individuals affected by FXS: a boy with a hypermethylated FMR1 mutation and a classic phenotype; a man with an FMR1 gene mosaicism in the range of premutation (PM) and full mutation (FM), who has a mild phenotype due to which FXS was initially disregarded; and the cases of four women with a FM and mosaicism. This report highlights the importance of DNA molecular testing for the diagnosis of FXS in patients with developmental delay, intellectual disability and/or autism due to the variable phenotype that occurs in individuals with FMR1 mosaicisms.

Significance and case analysis of FMR1 mutation screening during early and middle pregnancy

To screen for mutations of fragile X mental retardation 1 (FMR1) gene during early and middle pregnancy and provide prenatal diagnosis for those carrying high-risk CGG trinucleotide expansions. Peripheral blood samples of 2316 pregnant women at 12 to 21(+6) gestational weeks were collected for the extraction of genomic DNA. CGG repeats of the FMR1 gene were detected by fluorescence PCR and capillary electrophoresis. Genetic counseling and prenatal diagnosis were provided for 3 women carrying the premutations. The carrier rate of CGG repeats of the FMR1 gene was 1 in 178 for the intermediate type and 1 in 772 for the premutation types. The highest frequency allele of CGG was 29 repeats, which accounted for 49.29%, followed by 30 repeats (28.56%) and 36 repeats (8.83%). In case 1, the fetus had a karyotype of 45,X, in addition with premutation type of CGG expansion of the FMR1 gene. Following genetic counseling, the couple chose to terminate the pregnancy through induced labor. The numbers of CGG repeats were respectively 70/- and 29/30 for the husband and wife. In case 2, amniocentesis was performed at 20 weeks of gestation. The number of CGG repeats of the FMR1 gene was 29/-. No abnormality was found in the fetal karyotype and chromosomal copy number variations. The couple chose to continue with the pregnancy. Case 3 refused prenatal diagnosis after genetic counseling and gave birth to a girl at full term, who had a birth weight of 2440 g and no obvious abnormality found during follow-up. Pregnant women should be screened for FMR1 gene mutations during early and middle pregnancy, and those with high-risk CGG expansions should undergo prenatal diagnosis, genetic counseling and family study.

FMR1 loss in a human stem cell model reveals early changes to intrinsic membrane excitability

Fragile X mental retardation 1 (FMR1) encodes the RNA binding protein FMRP. Loss of FMRP drives Fragile X syndrome (FXS), the leading inherited cause of intellectual disability and a leading monogenic cause of autism. While cortical hyperexcitability is a hallmark of FXS, the reported phenotypes and underlying mechanisms, including alterations in synaptic transmission and ion channel properties, are heterogeneous and at times contradictory. Here, we report the generation of new isogenic FMR1y/+ and FMR1y/- human pluripotent stem cell (hPSC) lines using CRISPR-Cas9 to facilitate the study of how complete FMRP loss, independent of genetic background, drives molecular and cellular alterations relevant for FXS. After differentiating these stem cell tools into excitatory neurons, we systematically assessed the impact of FMRP loss on intrinsic membrane and synaptic properties over time. Using whole-cell patch clamp analyses, we found that FMR1y/- neurons overall showed an increased intrinsic membrane excitability compared to age-matched FMR1y/+ controls, with no discernable alternations in synaptic transmission. Surprisingly, longitudinal analyses of cell intrinsic defects revealed that a majority of significant changes emerged early following in vitro differentiation and some were not stable over time. Collectively, this study provides a new isogenic hPSC model which can be further leveraged by the scientific community to investigate basic mechanisms of FMR1 gene function relevant for FXS. Moreover, our results suggest that precocious changes in the intrinsic membrane properties during early developmental could be a critical cellular pathology ultimately contributing to cortical hyperexcitability in FXS.

Generation of Induced Pluripotent Stem Cells from a Female Patient with a Xq27.3-q28 Deletion to Establish Disease Models and Identify Therapies.

Since it is extremely difficult to establish an animal model for human chromosomal abnormalities, induced pluripotent stem cells (iPSCs) provide a powerful alternative to study underlying mechanisms of these disorders and identify potential therapeutic interventions. In this study we established iPSCs from a young girl with a hemizygous deletion of Xq27.3-q28 who exhibited global developmental delay and intellectual disability from early in infancy. The deletion site on the X chromosome includes Fragile X Mental Retardation 1 (FMR1), the gene responsible for fragile X syndrome, which likely contributes to the patient's neurodevelopmental abnormalities. The FMR1 gene was expressed in approximately half of the iPSC clones we generated while it was absent in the other half due to the random inactivation of normal and abnormal X chromosomes. The normal or absent expression pattern of the FMR1 gene was not altered when the iPSCs were differentiated into neural progenitor cells (NPCs). Moreover, chromosome reactivating reagents such as 5-aza-2-deoxycytidine, trichostatin A, and UNC0638, were tested in an attempt to reactivate the suppressed FMR1 gene in affected iPSC-NPCs. The affected and control isogenic iPSCs developed in this study are ideal models with which to identify downstream consequences caused by the Xq27.3-q28 deletion and also to provide tools for high-throughput screening to identify compounds potentially improving the well-being of this patient population.

Fragile X Gray Zone Alleles Are Associated With Signs of Parkinsonism and Earlier Death.

Premutation size (55-199 CGG repeats) in the fragile X mental retardation 1 (FMR1) gene cause fragile X-associated tremor/ataxia syndrome, but it is unclear whether smaller "gray" zone expansions of 41-54 repeats are also associated with movement disorders. The objectives of this study were to determine the association between the FMR1 gene gray zone expansions, AGG interspersions, and the presence of parkinsonism and motor and cognitive function in an elderly community-based population. Automated FMR1 polymerase chain reaction was performed on existing samples from 2 longitudinal aging studies whose subjects agreed to brain donation. A detailed clinical evaluation including a modified Unified Parkinson's Disease Rating Scale score, a composite score of global motor function, 17 cognitive tests summarized as a global measure of cognition, and neuropathological examination were obtained for genotyped participants. The average age of the population (n = 2362) was 85.9 ± 7.3 years, and average age at death was 88.6 ± 6.4 years (n = 1326), with 72% women. The prevalence of FMR1 gray zone alleles was 5.2% (122 of 2362). There was no difference between participants with gray zone expansions or those lacking AGG interspersions compared with normal participants in global cognition, global motor function, clinical diagnosis, or pathological changes. Gray zone alleles were associated with signs of parkinsonism in men (P = 0.01), and gray zone carrier men were more likely to die (hazard ratio, 2.34; 95% confidence interval, 1.31-4.16). This is the largest study to investigate gray zone alleles in a community population. The key findings are that in men, the gray zone allele is associated with signs of parkinsonism and higher risk of death, but not with intranuclear neuronal inclusions. © 2020 International Parkinson and Movement Disorder Society.

Molecular analysis of FMR1 gene in a population in Southern Brazil: Comparison of four methods

ObjectivesFragile X syndrome (FXS) is caused by expansion of the number of cytosine-guanine-guanine (CGG) repeats in the regulatory region of the gene fragile X mental retardation 1 (FMR1). The molecular diagnoses of FXS can be performed using two tests based on two different techniques, namely polymerase chain reaction (PCR) and Southern blotting (SB). However, both of these techniques have limitations. The purpose of this study was to evaluate the performance of the commercial FragilEase™ PCR kit for FXS diagnosis comparing to other laboratory methods. Designand methods: This study had a retrospective design. We analyzed the performance of the FragilEase™ PCR kit using 90 DNA samples from patients with clinical suspicion of FXS or a family history of the syndrome using capillary electrophoresis and compared with the results obtained for the same samples using PCR, SB, and AmplideX FMR1 PCR. ResultsFragilEase™ PCR kit displayed high concordance with the results obtained using PCR, SB, and AmplideX FMR1 PCR regarding the detection of normal, intermediate/gray zone, premutation, and full mutation alleles, as well as female homozygosity and mosaicism. The replicate sizes found using the FragilEase™ PCR assay varied on average by two CGG repeats. ConclusionFragilEase™ PCR, as well as other commercially available kits, efficiently detect FMR1 mutations and simplify the workflow in laboratories that performing FXS diagnoses.

A Chinese case of fragile X-associated tremor/ataxia syndrome (FXTAS) with orthostatic tremor:case report and literature review on tremor in FXTAS

BackgroundFragile X-associated tremor/ataxia syndrome (FXTAS) is a late onset, X-linked genetic, neurodegenerative disorder caused by a “premutation (PM)” in the fragile X mental retardation 1 (FMR1) gene. Here we report a case of FXTAS from mainland of China who presented with rare orthostatic tremor. A review of tremor of FXTAS in the literature is also included.Case presentationA 67-year-old right-handed farmer started with tremor of both legs 8 years ago which was present while standing but absent when sitting or lying and progressed with unsteady gait one and a half years ago. The brain MRI showed high intensity signal in the bilateral middle cerebellar peduncles (MCP) in T2-weighted and fluid-attenuated inversion recovery (FLAIR) images and gene test for premutation for FMR1 was positive with 101 CGG repeats. The patient met the the diagnosis of definite FXTAS. Clonazepam and topiramate were administered to control tremor. We reviewed the literature and identified 64 cases with detailed clinical and genetic information. Orthostatic tremor associated with FXTAS is very rare. We found 85.2% patients reported tremor,42.6% with intention tremor,36.1% with kinetic tremor,32.8% with rest tremor and 29.5% with posture tremor. 37.7% of patients who have tremor showed at least two types of tremor. There were 6 patients with isolated rest tremor. There was 2 patient with voice tremor and 6 with head tremor. We also found that 74.6% FXTAS patients had family history of FMR1 gene associated diseases including Fragile X syndrome (FXS), FXTAS or fragile X-associated primary ovarian insufficiency (FXPOI).ConclusionsAdding our data to the available literature suggests that orthostatic tremor could be a rare initial manifestation of FXTAS and the review will increasing our understanding the phenotype of tremor in FXTAS. Family history of FMR1 gene associated diseases might be an important clue to the diagnosis.

Association between IQ and FMR1 protein (FMRP) across the spectrum of CGG repeat expansions

Fragile X syndrome, the leading heritable form of intellectual disability, is caused by hypermethylation and transcriptional silencing of large (CGG) repeat expansions (> 200 repeats) in the 5′ untranslated region of the fragile X mental retardation 1 (FMR1) gene. As a consequence of FMR1 gene silencing, there is little or no production of FMR1 protein (FMRP), an important element in normal synaptic function. Although the absence of FMRP has long been known to be responsible for the cognitive impairment in fragile X syndrome, the relationship between FMRP level and cognitive ability (IQ) is only imprecisely understood. To address this issue, a high-throughput, fluorescence resonance energy transfer (FRET) assay has been used to quantify FMRP levels in dermal fibroblasts, and the relationship between FMRP and IQ measures was assessed by statistical analysis in a cohort of 184 individuals with CGG-repeat lengths spanning normal (< 45 CGGs) to full mutation (> 200 CGGs) repeat ranges in fibroblasts. The principal findings of the current study are twofold: i) For those with normal CGG repeats, IQ is no longer sensitive to further increases in FMRP above an FMRP threshold of ~70% of the mean FMRP level; below this threshold, IQ decreases steeply with further decreases in FMRP; and ii) For the current cohort, a mean IQ of 85 (lower bound for the normal IQ range) is attained for FMRP levels that are only ~35% of the mean FMRP level among normal CGG-repeat controls. The current results should help guide expectations for efforts to induce FMR1 gene activity and for the levels of cognitive function expected for a given range of FMRP levels.

New Targeted Treatments for Fragile X Syndrome.

Fragile X Syndrome (FXS) is the most common cause of inherited intellectual disability with prevalence rates estimated to be 1:5,000 in males and 1:8,000 in females. The increase of >200 Cytosine Guanine Guanine (CGG) repeats in the 5’ untranslated region of the Fragile X Mental Retardation 1 (FMR1) gene results in transcriptional silencing on the FMR1 gene with a subsequent reduction or absence of fragile X mental retardation protein (FMRP), an RNA binding protein involved in the maturation and elimination of synapses. In addition to intellectual disability, common features of FXS are behavioral problems, autism, language deficits and atypical physical features. There are still no currently approved curative therapies for FXS, and clinical management continues to focus on symptomatic treatment of comorbid behaviors and psychiatric problems. Here we discuss several treatments that target the neurobiological pathway abnormal in FXS. These medications are clinically available at present and the data suggest that these medications can be helpful for those with FXS.

Defining the role of FMR1 gene in unexplained recurrent spontaneous abortion.

Recurrent spontaneous abortion is a multifactorial disorder and till date, various factors have been attributed in its pathogenesis. Still, approximately 50% of RSA cases remain unexplained. Premutation (PM) expanded allele of fragile-X mental retardation 1 (FMR1) gene is known to contribute to ovarian dysfunction in 20% of the cases. Recently, the link between expanded FMR1 allele and recurrent miscarriages has been reported. In the present prospective case-control study, we have investigated the status of CGG repeat size at 5'UTR of the FMR1 gene in women with unexplained RSA in comparison to age-matched healthy control women (n = 100 each). The genomic DNA from these samples was subjected to molecular analysis for characterization of CGG repeat size and composition at FMR1 gene RESULTS: As compared to the control women, the RSA women cohort had a higher frequency of carriers with alleles in gray zone (GZ) and expanded PM range, i.e., 2% (2/100) versus 5% (5/100), respectively. Also, the RSA cohort had a significantly higher number of normal alleles with ≥ 35 CGG repeats (24 out of 200 alleles) as compared to control cohort (8 out of 200 alleles). The number of larger FMR1 alleles with pure CGG repeat tract was found to be significantly higher (P = 0.0063) in the RSA cohort (15 out of 200 alleles) as compared to that in control cohort (3 out of 200 alleles). Henceforth, the CGG expanded uninterrupted FMR1 allele might be associated with recurrent abortions and may help to explain many of these unexplained cases.

Reduction of Fmr1 mRNA Levels Rescues Pathological Features in Cortical Neurons in a Model of FXTAS

Fragile X-associated tremor ataxia syndrome (FXTAS) is a rare disorder associated to the presence of the fragile X premutation, a 55–200 CGG repeat expansion in the 5′ UTR of the FMR1 gene. Two main neurological phenotypes have been described in carriers of the CGG premutation: (1) neurodevelopmental disorders characterized by anxiety, attention deficit hyperactivity disorder (ADHD), social deficits, or autism spectrum disorder (ASD); and (2) after 50 years old, the FXTAS phenotype. This neurodegenerative disorder is characterized by ataxia and a form of parkinsonism. The molecular pathology of this disorder is characterized by the presence of elevated levels of Fragile X Mental Retardation 1 (FMR1) mRNA, presence of a repeat-associated non-AUG (RAN) translated peptide, and FMR1 mRNA-containing nuclear inclusions. Whereas in the past FXTAS was mainly considered as a late-onset disorder, some phenotypes of patients and altered learning and memory behavior of a mouse model of FXTAS suggested that this disorder involves neurodevelopment. To better understand the physiopathological role of the increased levels of Fmr1 mRNA during neuronal differentiation, we used a small interfering RNA (siRNA) approach to reduce the abundance of this mRNA in cultured cortical neurons from the FXTAS mouse model. Morphological alterations of neurons were rescued by this approach. This cellular phenotype is associated to differentially expressed proteins that we identified by mass spectrometry analysis. Interestingly, phenotype rescue is also associated to the rescue of the abundance of 29 proteins that are involved in various pathways, which represent putative targets for early therapeutic approaches.