scholarly journals Fragile X Syndrome

2014 ◽  
pp. 190-198 ◽  
Author(s):  
Wilmar Saldarriaga ◽  
Flora Tassone ◽  
Laura Yuriko González-Teshima ◽  
Jose Vicente Forero-Forero ◽  
Sebastián Ayala-Zapata ◽  
...  
Keyword(s):  
Mental Retardation ◽  
Intellectual Disability ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Gene Promoter ◽  
Molecular Techniques ◽  
Pharmaceutical Management ◽  
Developmental Problems ◽  
Fragile X Mental Retardation ◽  
Cgg Repeats

Fragile X Syndrome (FXS) is a genetic disease due to a CGG trinucleotide expansion, named full mutation (greater than 200 CGG repeats), in the fragile X mental retardation 1 gene locus Xq27.3; which leads to an hypermethylated region in the gene promoter therefore silencing it and lowering the expression levels of the fragile X mental retardation 1, a protein involved in synaptic plasticity and maturation. Individuals with FXS present with intellectual disability, autism, hyperactivity, long face, large or prominent ears and macroorchidism at puberty and thereafter. Most of the young children with FXS will present with language delay, sensory hyper arousal and anxiety. Girls are less affected than boys, only 25% have intellectual disability. Given the genomic features of the syndrome, there are patients with a number of triplet repeats between 55 and 200, known as premutation carriers. Most carriers have a normal IQ but some have developmental problems. The diagnosis of FXS has evolved from karyotype with special culture medium, to molecular techniques that are more sensitive and specific including PCR and Southern Blot. During the last decade, the advances in the knowledge of FXS, has led to the development of investigations on pharmaceutical management or targeted treatments for FXS. Minocycline and sertraline have shown efficacy in children.

scholarly journals New Targeted Treatments for Fragile X Syndrome

2019 ◽  
Vol 15 (4) ◽  
pp. 251-258 ◽  
Author(s):  
Dragana Protic ◽  
Maria J. Salcedo-Arellano ◽  
Jeanne Barbara Dy ◽  
Laura A. Potter ◽  
Randi J. Hagerman
Keyword(s):  
Mental Retardation ◽  
Intellectual Disability ◽  
Fragile X Syndrome ◽  
Behavioral Problems ◽  
Rna Binding ◽  
Fragile X ◽  
Symptomatic Treatment ◽  
Fmr1 Gene ◽  
Fragile X Mental Retardation ◽  
Cgg Repeats

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.

scholarly journals FMRP Levels in Human Peripheral Blood Leukocytes Correlates with Intellectual Disability

Diagnostics ◽  
2021 ◽  
Vol 11 (10) ◽  
pp. 1780
Author(s):  
Mark Roth ◽  
Lucienne Ronco ◽  
Diego Cadavid ◽  
Blythe Durbin-Johnson ◽  
Randi J. Hagerman ◽  
...  
Keyword(s):  
Mental Retardation ◽  
Intellectual Disability ◽  
Peripheral Blood ◽  
Fragile X ◽  
Repeat Expansion ◽  
Repeat Number ◽  
Cgg Repeat ◽  
Fragile X Mental Retardation ◽  
Cgg Repeats ◽  
Fmr1 Mrna

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability. FXS is an X-linked, neurodevelopmental disorder caused by a CGG trinucleotide repeat expansion in the 5′ untranslated region (UTR) of the Fragile X Mental Retardation gene, FMR1. Greater than 200 CGG repeats results in epigenetic silencing of the gene leading to the deficiency or absence of Fragile X mental retardation protein (FMRP). The loss of FMRP is considered the root cause of FXS. The relationship between neurological function and FMRP expression in peripheral blood mononuclear cells (PBMCs) has not been well established. Assays to detect and measure FMR1 and FMRP have been described; however, none are sufficiently sensitive, precise, or quantitative to properly characterize the relationships between cognitive ability and CGG repeat number, FMR1 mRNA expression, or FMRP expression measured in PBMCs. To address these limitations, two novel immunoassays were developed and optimized, an electro-chemiluminescence immunoassay and a multiparameter flow cytometry assay. Both assays were performed on PMBCs isolated from 27 study participants with FMR1 CGG repeats ranging from normal to full mutation. After correcting for methylation, a significant positive correlation between CGG repeat number and FMR1 mRNA expression levels and a significant negative correlation between FMRP levels and CGG repeat expansion was observed. Importantly, a high positive correlation was observed between intellectual quotient (IQ) and FMRP expression measured in PBMCs.

scholarly journals An Origin of DNA Replication in the Promoter Region of the Human Fragile X Mental Retardation (FMR1) Gene

2006 ◽  
Vol 27 (2) ◽  
pp. 426-437 ◽  
Author(s):  
Steven J. Gray ◽  
Jeannine Gerhardt ◽  
Walter Doerfler ◽  
Lawrence E. Small ◽  
Ellen Fanning
Keyword(s):  
Mental Retardation ◽  
Dna Replication ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Model Systems ◽  
Fmr1 Gene ◽  
Fragile X Mental Retardation ◽  
Cgg Repeats ◽  
Origin Of Dna Replication ◽  
Transformed Cell Lines

ABSTRACT Fragile X syndrome, the most common form of inherited mental retardation in males, arises when the normally stable 5 to 50 CGG repeats in the 5′ untranslated region of the fragile X mental retardation protein 1 (FMR1) gene expand to over 200, leading to DNA methylation and silencing of the FMR1 promoter. Although the events that trigger local CGG expansion remain unknown, the stability of trinucleotide repeat tracts is affected by their position relative to an origin of DNA replication in model systems. Origins of DNA replication in the FMR1 locus have not yet been described. Here, we report an origin of replication adjacent to the FMR1 promoter and CGG repeats that was identified by scanning a 35-kb region. Prereplication proteins Orc3p and Mcm4p bind to chromatin in the FMR1 initiation region in vivo. The position of the FMR1 origin relative to the CGG repeats is consistent with a role in repeat maintenance. The FMR1 origin is active in transformed cell lines, fibroblasts from healthy individuals, fibroblasts from patients with fragile X syndrome, and fetal cells as early as 8 weeks old. The potential role of the FMR1 origin in CGG tract instability is discussed.

scholarly journals Clinical Development of Targeted Fragile X Syndrome Treatments: An Industry Perspective

2018 ◽  
Vol 8 (12) ◽  
pp. 214 ◽  
Author(s):  
Anna Lee ◽  
Pamela Ventola ◽  
Dejan Budimirovic ◽  
Elizabeth Berry-Kravis ◽  
Jeannie Visootsak
Keyword(s):  
Clinical Trials ◽  
Mental Retardation ◽  
Intellectual Disability ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Basic Research ◽  
Autism Spectrum ◽  
Pharmacological Agents ◽  
Fragile X Mental Retardation ◽  
Wide Range

Fragile X syndrome (FXS) is the leading known cause of inherited intellectual disability and autism spectrum disorder. It is caused by a mutation of the fragile X mental retardation 1 (FMR1) gene, resulting in a deficit of fragile X mental retardation protein (FMRP). The clinical presentation of FXS is variable, and is typically associated with developmental delays, intellectual disability, a wide range of behavioral issues, and certain identifying physical features. Over the past 25 years, researchers have worked to understand the complex relationship between FMRP deficiency and the symptoms of FXS and, in the process, have identified several potential targeted therapeutics, some of which have been tested in clinical trials. Whereas most of the basic research to date has been led by experts at academic institutions, the pharmaceutical industry is becoming increasingly involved with not only the scientific community, but also with patient advocacy organizations, as more promising pharmacological agents are moving into the clinical stages of development. The objective of this review is to provide an industry perspective on the ongoing development of mechanism-based treatments for FXS, including identification of challenges and recommendations for future clinical trials.

scholarly journals Molecular Biomarkers in Fragile X Syndrome

2019 ◽  
Vol 9 (5) ◽  
pp. 96 ◽  
Author(s):  
Zafarullah ◽  
Tassone
Keyword(s):  
Clinical Trials ◽  
Mental Retardation ◽  
Intellectual Disability ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Autism Spectrum ◽  
Molecular Biomarkers ◽  
Synaptic Function ◽  
Primary Role ◽  
Fragile X Mental Retardation

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability (ID) and a known monogenic cause of autism spectrum disorder (ASD). It is a trinucleotide repeat disorder, in which more than 200 CGG repeats in the 5’ untranslated region (UTR) of the fragile X mental retardation 1 (FMR1) gene causes methylation of the promoter with consequent silencing of the gene, ultimately leading to the loss of the encoded fragile X mental retardation 1 protein, FMRP. FMRP is an RNA binding protein that plays a primary role as a repressor of translation of various mRNAs, many of which are involved in the maintenance and development of neuronal synaptic function and plasticity. In addition to intellectual disability, patients with FXS face several behavioral challenges, including anxiety, hyperactivity, seizures, repetitive behavior, and problems with executive and language performance. Currently, there is no cure or approved medication for the treatment of the underlying causes of FXS, but in the past few years, our knowledge about the proteins and pathways that are dysregulated by the loss of FMRP has increased, leading to clinical trials and to the path of developing molecular biomarkers for identifying potential targets for therapies. In this paper, we review candidate molecular biomarkers that have been identified in preclinical studies in the FXS mouse animal model and are now under validation for human applications or have already made their way to clinical trials.

scholarly journals Experiences of the Molecular Diagnosis of Fragile X Syndrome in Ecuador

2021 ◽  
Vol 12 ◽  
Author(s):  
Juan Pozo-Palacios ◽  
Arianne Llamos-Paneque ◽  
Christian Rivas ◽  
Emily Onofre ◽  
Andrea López-Cáceres ◽  
...  
Keyword(s):  
Mental Retardation ◽  
Intellectual Disability ◽  
Fragile X Syndrome ◽  
Molecular Diagnosis ◽  
Fragile X ◽  
Neurodevelopmental Disorder ◽  
Geographical Area ◽  
Cgg Repeat ◽  
Common Cause ◽  
Fragile X Mental Retardation

Fragile X syndrome (FXS) is the most common cause of hereditary intellectual disability and the second most common cause of intellectual disability of genetic etiology. This complex neurodevelopmental disorder is caused by an alteration in the CGG trinucleotide expansion in fragile X mental retardation gene 1 (FMR1) leading to gene silencing and the subsequent loss of its product: fragile X mental retardation protein 1 (FMRP). Molecular diagnosis is based on polymerase chain reaction (PCR) screening followed by Southern blotting (SB) or Triplet primer-PCR (TP-PCR) to determine the number of CGG repeats in the FMR1 gene. We performed, for the first time, screening in 247 Ecuadorian male individuals with clinical criteria to discard FXS. Analysis was carried out by the Genetics Service of the Hospital de Especialidades No. 1 de las Fuerzas Armadas (HE-1), Ecuador. The analysis was performed using endpoint PCR for CGG fragment expansion analysis of the FMR1 gene. Twenty-two affected males were identified as potentially carrying the full mutation in FMR1 and thus diagnosed with FXS that is 8.1% of the sample studied. The average age at diagnosis of the positive cases was 13 years of age, with most cases from the geographical area of Pichincha (63.63%). We confirmed the familial nature of the disease in four cases. The range of CGG variation in the population was 12–43 and followed a modal distribution of 27 repeats. Our results were similar to those reported in the literature; however, since it was not possible to differentiate between premutation and mutation cases, we can only establish a molecular screening approach to identify an expanded CGG repeat, which makes it necessary to generate national strategies to optimize molecular tests and establish proper protocols for the diagnosis, management, and follow-up of patients, families, and communities at risk of presenting FXS.

scholarly journals Fragile X Mental Retardation 1 (FMR1) Intron 1 Methylation in Blood Predicts Verbal Cognitive Impairment in Female Carriers of Expanded FMR1 Alleles: Evidence from a Pilot Study

2012 ◽  
Vol 58 (3) ◽  
pp. 590-598 ◽  
Author(s):  
David E Godler ◽  
Howard R Slater ◽  
Quang M Bui ◽  
Elsdon Storey ◽  
Michele Y Ono ◽  
...  
Keyword(s):  
Mental Retardation ◽  
Cognitive Impairment ◽  
Fragile X ◽  
Cognitive Status ◽  
Verbal Iq ◽  
Fragile X Mental Retardation ◽  
Cpg Sites ◽  
Cgg Repeats ◽  
Intron 1 ◽  
Study Participants

Abstract BACKGROUND Cognitive status in females with mutations in the FMR1 (fragile X mental retardation 1) gene is highly variable. A biomarker would be of value for predicting which individuals were liable to develop cognitive impairment and could benefit from early intervention. A detailed analysis of CpG sites bridging exon 1 and intron 1 of FMR1, known as fragile X–related epigenetic element 2 (FREE2), suggests that a simple blood test could identify these individuals. METHODS Study participants included 74 control females (<40 CGG repeats), 62 premutation (PM) females (55–200 CGG repeats), and 18 full-mutation (FM) females assessed with Wechsler intelligence quotient (IQ) tests. We used MALDI-TOF mass spectrometry to determine the methylation status of FREE2 CpG sites that best identified low-functioning (IQ <70) FM females (>200 CGG repeats), compared the results with those for Southern blot FMR1 activation ratios, and related these assessments to the level of production of the FMR1 protein product in blood. RESULTS A methylation analysis of intron 1 CpG sites 10–12 showed the highest diagnostic sensitivity (100%) and specificity (98%) of all the molecular measures tested for detecting females with a standardized verbal IQ of <70 among the study participants. In the group consisting of only FM females, methylation of these sites was significantly correlated with full-scale IQ, verbal IQ, and performance IQ. Several verbal subtest scores showed strong correlation with the methylation of these sites (P = 1.2 × 10−5) after adjustment for multiple measures. CONCLUSIONS The data suggest that hypermethylation of the FMR1 intron 1 sites in blood is predictive of cognitive impairment in FM females, with implications for improved fragile X syndrome diagnostics in young children and screening of the newborn population.

scholarly journals Role of microRNA Pathway in Mental Retardation

2007 ◽  
Vol 7 ◽  
pp. 146-154 ◽  
Author(s):  
Abrar Qurashi ◽  
Shuang Chang ◽  
Peng Jin
Keyword(s):  
Mental Retardation ◽  
Fragile X Syndrome ◽  
Genetic Basis ◽  
Fragile X ◽  
Biological Pathways ◽  
Fragile X Mental Retardation ◽  
Mental Retardation Protein ◽  
Mirna Pathway ◽  
Microrna Pathway

Deficits in cognitive functions lead to mental retardation (MR). Understanding the genetic basis of inherited MR has provided insights into the pathogenesis of MR. Fragile X syndrome is one of the most common forms of inherited MR, caused by the loss of functional Fragile X Mental Retardation Protein (FMRP).MicroRNAs (miRNAs) are endogenous, single-stranded RNAs between 18 and 25 nucleotides in length, which have been implicated in diversified biological pathways. Recent studies have linked the miRNA pathway to fragile X syndrome. Here we review the role of the miRNA pathway in fragile X syndrome and discuss its implication in MR in general.

scholarly journals Comparative Behavioral Phenotypes of Fmr1 KO, Fxr2 Het, and Fmr1 KO/Fxr2 Het Mice

2019 ◽  
Vol 9 (1) ◽  
pp. 13 ◽  
Author(s):  
Rachel Saré ◽  
Christopher Figueroa ◽  
Abigail Lemons ◽  
Inna Loutaev ◽  
Carolyn Beebe Smith
Keyword(s):  
Mental Retardation ◽  
Intellectual Disability ◽  
Fragile X ◽  
Protein Product ◽  
Behavioral Phenotypes ◽  
Memory Impairments ◽  
Fragile X Mental Retardation ◽  
Behavioral Abnormalities ◽  
Mental Retardation Protein ◽  
Functional Consequences

Fragile X syndrome (FXS) is caused by silencing of the FMR1 gene leading to loss of the protein product fragile X mental retardation protein (FMRP). FXS is the most common monogenic cause of intellectual disability. There are two known mammalian paralogs of FMRP, FXR1P, and FXR2P. The functions of FXR1P and FXR2P and their possible roles in producing or modulating the phenotype observed in FXS are yet to be identified. Previous studies have revealed that mice lacking Fxr2 display similar behavioral abnormalities as Fmr1 knockout (KO) mice. In this study, we expand upon the behavioral phenotypes of Fmr1 KO and Fxr2+/− (Het) mice and compare them with Fmr1 KO/Fxr2 Het mice. We find that Fmr1 KO and Fmr1 KO/Fxr2 Het mice are similarly hyperactive compared to WT and Fxr2 Het mice. Fmr1 KO/Fxr2 Het mice have more severe learning and memory impairments than Fmr1 KO mice. Fmr1 KO mice display significantly impaired social behaviors compared to WT mice, which are paradoxically reversed in Fmr1 KO/Fxr2 Het mice. These results highlight the important functional consequences of loss or reduction of FMRP and FXR2P.

Focal areas of a high rate of fragile X in Indonesia: a long term follow up

2019 ◽  
Vol 5 (2) ◽  
pp. 67-68
Author(s):  
Sultana MH Faradz ◽  
Tri Indah Winarni
Keyword(s):  
Mental Retardation ◽  
Behavioral Problems ◽  
Fragile X ◽  
Autism Spectrum ◽  
High Rate ◽  
Learning Ability ◽  
Fragile X Mental Retardation ◽  
Cgg Repeats ◽  
Long Term Follow Up

Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability (ID) and a leading cause of autism spectrum disorder (ASD). FXS is caused by an expansion of CGG repeats >200 in the 5′ untranslated region of the promotor region fragile X mental retardation 1 gene (FMR1), which is located on Xq27.3.  The abnormal CGG expansion leads to methylation and transcriptional silencing of the FMR1 gene, resulting in a reduction or loss of fragile X mental retardation 1 protein (FMRP) and causes long, thin, and immature dendritic spines, which lead to deficits in cognitive function, behavioral problems, and learning ability

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