The Experts below are selected from a list of 13014 Experts worldwide ranked by ideXlab platform
Stephen T. Warren - One of the best experts on this subject based on the ideXlab platform.
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Fragile X Syndrome
European Journal of Human Genetics, 2008Co-Authors: Kathryn B Garber, Jeannie Visootsak, Stephen T. WarrenAbstract:Fragile X Syndrome, an X-linked dominant disorder with reduced penetrance, is associated with intellectual and emotional disabilities ranging from learning problems to mental retardation, and mood instability to autism. It is most often caused by the transcriptional silencing of the FMR1 gene, due to an eXpansion of a CGG repeat found in the 5′-untranslated region. The FMR1 gene product, FMRP, is a selective RNA-binding protein that negatively regulates local protein synthesis in neuronal dendrites. In its absence, the transcripts normally regulated by FMRP are over translated. The resulting over abundance of certain proteins results in reduced synaptic strength due to AMPA receptor trafficking abnormalities that lead, at least in part, to the Fragile X phenotype.
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mosaic fmr1 deletion causes Fragile X Syndrome and can lead to molecular misdiagnosis a case report and review of the literature
American Journal of Medical Genetics Part A, 2008Co-Authors: Bradford Coffee, Morna Ikeda, Dejan B Budimirovic, Lawrence N Hjelm, Walter E. Kaufmann, Stephen T. WarrenAbstract:The most common cause of Fragile X Syndrome is eXpansion of a CGG trinucleotide repeat in the 5′UTR of FMR1. This eXpansion leads to transcriptional silencing of the gene. However, other mutational mechanisms, such as deletions of FMR1, also cause Fragile X Syndrome. The result is the same for both the eXpansion mediated silencing and deletion, absence of the gene product, FMRP. We report here on an 11-year-old boy with a cognitive and behavioral profile with features compatible with, but not specific to, Fragile X Syndrome. A mosaic deletion of 1,013,395 bp was found using high-density X chromosome microarray analysis followed by sequencing of the deletion breakpoints. We review the literature of FMR1 deletions and present this case in the conteXt of other FMR1 deletions having mental retardation that may or may not have the classic Fragile X phenotype. © 2008 Wiley-Liss, Inc.
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mosaic fmr1 deletion causes Fragile X Syndrome and can lead to molecular misdiagnosis a case report and review of the literature
American Journal of Medical Genetics Part A, 2008Co-Authors: Bradford Coffee, Morna Ikeda, Dejan B Budimirovic, Lawrence N Hjelm, Walter E. Kaufmann, Stephen T. WarrenAbstract:The most common cause of Fragile X Syndrome is eXpansion of a CGG trinucleotide repeat in the 5'UTR of FMR1. This eXpansion leads to transcriptional silencing of the gene. However, other mutational mechanisms, such as deletions of FMR1, also cause Fragile X Syndrome. The result is the same for both the eXpansion mediated silencing and deletion, absence of the gene product, FMRP. We report here on an 11-year-old boy with a cognitive and behavioral profile with features compatible with, but not specific to, Fragile X Syndrome. A mosaic deletion of 1,013,395 bp was found using high-density X chromosome microarray analysis followed by sequencing of the deletion breakpoints. We review the literature of FMR1 deletions and present this case in the conteXt of other FMR1 deletions having mental retardation that may or may not have the classic Fragile X phenotype.
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Identification of small molecules rescuing Fragile X Syndrome phenotypes in Drosophila
Nature Chemical Biology, 2008Co-Authors: Shuang Chang, Steven M Bray, Daniela C Zarnescu, Peng Jin, Stephen T. WarrenAbstract:Fragile X Syndrome is caused by the functional loss of the Fragile X mental retardation 1 ( FMR1 ) gene. Deletion of the FMR1 ortholog in Drosophila melanogaster ( Fmr1 ) recapitulates many phenotypes associated with Fragile X Syndrome. We have discovered that Fmr1 mutant Drosophila die during development when reared on food containing increased levels of glutamate, which is consistent with the theory that FMR1 loss results in eXcess glutamate signaling. Using this lethal phenotype, we screened a chemical library of 2,000 compounds and identified nine molecules that rescued the lethality, including three that implicate the GABAergic inhibitory pathway. Indeed, GABA treatment rescued several known Fmr1 mutant phenotypes in flies, including mushroom bodies defects, eXcess Futsch translation and abnormal male courtship behavior. These data are consistent with GABAergic inhibition of the enhanced eXcitatory pathway in Fragile X Syndrome. In addition, our screen reveals that the muscarinic cholinergic receptors may have a role in Fragile X Syndrome in parallel to the GABAergic pathway. These results point to potential therapeutic approaches for treating Fragile X Syndrome.
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Fragile X Syndrome an update and review for the primary pediatrician
Clinical Pediatrics, 2005Co-Authors: Jeannie Visootsak, Stephen T. Warren, Aimee Anido, John M GrahamAbstract:Fragile X Syndrome (FXS) is the most common inherited cause of mental retardation. Since the initial identification of the responsible gene more than a decade ago, substantial progress has been made in both the clinical aspects of the disorder and its mechanistic basis; hence, it is important for primary care physicians to be familiar with these advances when providing anticipatory guidance. Timely diagnosis allows children to receive early intervention services and families to receive genetic counseling. Here the current state of knowledge is reviewed and a framework is provided for early recognition and diagnosis, along with counseling and treatment implications for the children and family members.
Stephanie L Sherman - One of the best experts on this subject based on the ideXlab platform.
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fmr1 and the Fragile X Syndrome human genome epidemiology review
Genetics in Medicine, 2001Co-Authors: Dana C Crawford, Juan M Acuna, Stephanie L ShermanAbstract:The Fragile X Syndrome, an X-linked dominant disorder with reduced penetrance, is one of the most common forms of inherited mental retardation. The cognitive, behavioral, and physical phenotype varies by seX, with males being more severely affected because of the X-linked inheritance of the mutation. The disorder-causing mutation is the amplification of a CGG repeat in the 5′ untranslated region of FMR1 located at Xq27.3. The Fragile X CGG repeat has four forms: common (6–40 repeats), intermediate (41–60 repeats), premutation (61–200 repeats), and full mutation (>200–230 repeats). Population-based studies suggest that the prevalence of the full mutation, the disorder-causing form of the repeat, ranges from 1/3,717 to 1/8,918 Caucasian males in the general population. The full mutation is also found in other racial/ethnic populations; however, few population-based studies eXist for these populations. No population-based studies eXist for the full mutation in a general female population. In contrast, several large, population-based studies eXist for the premutation or carrier form of the disorder, with prevalence estimates ranging from 1/246 to 1/468 Caucasian females in the general population. For Caucasian males, the prevalence of the premutation is ∼1/1,000. Like the full mutation, little information eXists for the premutation in other populations. Although no effective cure or treatment eXists for the Fragile X Syndrome, all persons affected with the Syndrome are eligible for early intervention services. The relatively high prevalence of the premutation and full mutation genotypes coupled with technological advances in genetic testing make the Fragile X Syndrome amenable to screening. The timing as well as benefits and harms associated with the different screening strategies are the subject of current research and discussion.
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fmr1 and the Fragile X Syndrome human genome epidemiology review
Genetics in Medicine, 2001Co-Authors: Dana C Crawford, Juan M Acuna, Stephanie L ShermanAbstract:The Fragile X Syndrome, an X-linked dominant disorder with reduced penetrance, is one of the most common forms of inherited mental retardation. The cognitive, behavioral, and physical phenotype varies by seX, with males being more severely affected because of the X-linked inheritance of the mutation. The disorder-causing mutation is the amplification of a CGG repeat in the 5' untranslated region of FMR1 located at Xq27.3. The Fragile X CGG repeat has four forms: common (6-40 repeats), intermediate (41-60 repeats), premutation (61-200 repeats), and full mutation (>200-230 repeats). Population-based studies suggest that the prevalence of the full mutation, the disorder-causing form of the repeat, ranges from 1/3,717 to 1/8,918 Caucasian males in the general population. The full mutation is also found in other racial/ethnic populations; however, few population-based studies eXist for these populations. No population-based studies eXist for the full mutation in a general female population. In contrast, several large, population-based studies eXist for the premutation or carrier form of the disorder, with prevalence estimates ranging from 1/246 to 1/468 Caucasian females in the general population. For Caucasian males, the prevalence of the premutation is approXimately 1/1,000. Like the full mutation, little information eXists for the premutation in other populations. Although no effective cure or treatment eXists for the Fragile X Syndrome, all persons affected with the Syndrome are eligible for early intervention services. The relatively high prevalence of the premutation and full mutation genotypes coupled with technological advances in genetic testing make the Fragile X Syndrome amenable to screening. The timing as well as benefits and harms associated with the different screening strategies are the subject of current research and discussion.
Randi J Hagerman - One of the best experts on this subject based on the ideXlab platform.
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Fragile X Syndrome
Nature reviews. Disease primers, 2017Co-Authors: Randi J Hagerman, Ilse Gantois, Flora Tassone, Elizabeth Berry-kravis, Heather Cody Hazlett, Donald B. Bailey, Hervé Moine, R. Frank Kooy, Nahum Sonenberg, Jean-louis MandelAbstract:Fragile X Syndrome (FXS) is the leading inherited form of intellectual disability and autism spectrum disorder, and patients can present with severe behavioural alterations, including hyperactivity, impulsivity and anXiety, in addition to poor language development and seizures. FXS is a trinucleotide repeat disorder, in which >200 repeats of the CGG motif in FMR1 leads to silencing of the gene and the consequent loss of its product, Fragile X mental retardation 1 protein (FMRP). FMRP has a central role in gene eXpression and regulates the translation of potentially hundreds of mRNAs, many of which are involved in the development and maintenance of neuronal synaptic connections. Indeed, disturbances in neuroplasticity is a key finding in FXS animal models, and an imbalance in inhibitory and eXcitatory neuronal circuits is believed to underlie many of the clinical manifestations of this disorder. Our knowledge of the proteins that are regulated by FMRP is rapidly growing, and this has led to the identification of multiple targets for therapeutic intervention, some of which have already moved into clinical trials or clinical practice.
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Fragile X Syndrome
Colombia Medica, 2014Co-Authors: Wilmar Saldarriaga, Flora Tassone, Laura Yuriko Gonzalezteshima, Jose Vicente Foreroforero, Sebastian Ayalazapata, Randi J HagermanAbstract: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.
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Fragile X Syndrome causes diagnosis mechanisms and therapeutics
Journal of Clinical Investigation, 2012Co-Authors: Claudia Bagni, Flora Tassone, Giovanni Neri, Randi J HagermanAbstract:Fragile X Syndrome (FXS) is the most frequent form of inherited intellectual disability and is also linked to other neurologic and psychiatric disorders. FXS is caused by a triplet eXpansion that inhibits eXpression of the FMR1 gene; the gene product, FMRP, regulates mRNA metabolism in the brain and thus controls the eXpression of key molecules involved in receptor signaling and spine morphology. While there is no definitive cure for FXS, the understanding of FMRP function has paved the way for rational treatment designs that could potentially reverse many of the neurobiological changes observed in FXS. Additionally, behavioral, pharmacological, and cognitive interventions can raise the quality of life for both patients and their families.
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agg interruptions within the maternal fmr1 gene reduce the risk of offspring with Fragile X Syndrome
Genetics in Medicine, 2012Co-Authors: Carolyn M Yrigollen, Randi J Hagerman, Blythe Durbinjohnson, Louise W Gane, David L Nelson, Paul J Hagerman, Flora TassoneAbstract:AGG interruptions within the maternal FMR1 gene reduce the risk of offspring with Fragile X Syndrome
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prepulse inhibition in Fragile X Syndrome feasibility reliability and implications for treatment
American Journal of Medical Genetics, 2009Co-Authors: David R Hessl, Elizabeth Berrykravis, Lisa Cordeiro, Jennifer Yuhas, Edward M Ornitz, Aaron Campbell, Elizabeth Chruscinski, Crystal Hervey, James M Long, Randi J HagermanAbstract: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.
Juan M Acuna - One of the best experts on this subject based on the ideXlab platform.
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fmr1 and the Fragile X Syndrome human genome epidemiology review
Genetics in Medicine, 2001Co-Authors: Dana C Crawford, Juan M Acuna, Stephanie L ShermanAbstract:The Fragile X Syndrome, an X-linked dominant disorder with reduced penetrance, is one of the most common forms of inherited mental retardation. The cognitive, behavioral, and physical phenotype varies by seX, with males being more severely affected because of the X-linked inheritance of the mutation. The disorder-causing mutation is the amplification of a CGG repeat in the 5′ untranslated region of FMR1 located at Xq27.3. The Fragile X CGG repeat has four forms: common (6–40 repeats), intermediate (41–60 repeats), premutation (61–200 repeats), and full mutation (>200–230 repeats). Population-based studies suggest that the prevalence of the full mutation, the disorder-causing form of the repeat, ranges from 1/3,717 to 1/8,918 Caucasian males in the general population. The full mutation is also found in other racial/ethnic populations; however, few population-based studies eXist for these populations. No population-based studies eXist for the full mutation in a general female population. In contrast, several large, population-based studies eXist for the premutation or carrier form of the disorder, with prevalence estimates ranging from 1/246 to 1/468 Caucasian females in the general population. For Caucasian males, the prevalence of the premutation is ∼1/1,000. Like the full mutation, little information eXists for the premutation in other populations. Although no effective cure or treatment eXists for the Fragile X Syndrome, all persons affected with the Syndrome are eligible for early intervention services. The relatively high prevalence of the premutation and full mutation genotypes coupled with technological advances in genetic testing make the Fragile X Syndrome amenable to screening. The timing as well as benefits and harms associated with the different screening strategies are the subject of current research and discussion.
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fmr1 and the Fragile X Syndrome human genome epidemiology review
Genetics in Medicine, 2001Co-Authors: Dana C Crawford, Juan M Acuna, Stephanie L ShermanAbstract:The Fragile X Syndrome, an X-linked dominant disorder with reduced penetrance, is one of the most common forms of inherited mental retardation. The cognitive, behavioral, and physical phenotype varies by seX, with males being more severely affected because of the X-linked inheritance of the mutation. The disorder-causing mutation is the amplification of a CGG repeat in the 5' untranslated region of FMR1 located at Xq27.3. The Fragile X CGG repeat has four forms: common (6-40 repeats), intermediate (41-60 repeats), premutation (61-200 repeats), and full mutation (>200-230 repeats). Population-based studies suggest that the prevalence of the full mutation, the disorder-causing form of the repeat, ranges from 1/3,717 to 1/8,918 Caucasian males in the general population. The full mutation is also found in other racial/ethnic populations; however, few population-based studies eXist for these populations. No population-based studies eXist for the full mutation in a general female population. In contrast, several large, population-based studies eXist for the premutation or carrier form of the disorder, with prevalence estimates ranging from 1/246 to 1/468 Caucasian females in the general population. For Caucasian males, the prevalence of the premutation is approXimately 1/1,000. Like the full mutation, little information eXists for the premutation in other populations. Although no effective cure or treatment eXists for the Fragile X Syndrome, all persons affected with the Syndrome are eligible for early intervention services. The relatively high prevalence of the premutation and full mutation genotypes coupled with technological advances in genetic testing make the Fragile X Syndrome amenable to screening. The timing as well as benefits and harms associated with the different screening strategies are the subject of current research and discussion.
Mark F Bear - One of the best experts on this subject based on the ideXlab platform.
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pharmacological reversal of synaptic plasticity deficits in the mouse model of Fragile X Syndrome by group ii mglur antagonist or lithium treatment
Brain Research, 2011Co-Authors: Catherine H Choi, Brian P Schoenfeld, Aaron J Bell, Paul Hinchey, Maria Kollaros, Michael Gertner, Newton H Woo, Michael R Tranfaglia, Mark F Bear, Suzanne R ZukinAbstract:Fragile X Syndrome is the leading single gene cause of intellectual disabilities. Treatment of a Drosophila model of Fragile X Syndrome with metabotropic glutamate receptor (mGluR) antagonists or lithium rescues social and cognitive impairments. A hallmark feature of the Fragile X mouse model is enhanced mGluR-dependent long-term depression (LTD) at Schaffer collateral to CA1 pyramidal synapses of the hippocampus. Here we eXamine the effects of chronic treatment of Fragile X mice in vivo with lithium or a group II mGluR antagonist on mGluR-LTD at CA1 synapses. We find that long-term lithium treatment initiated during development (5-6 weeks of age) and continued throughout the lifetime of the Fragile X mice until 9-11 months of age restores normal mGluR-LTD. Additionally, chronic short-term treatment beginning in adult Fragile X mice (8 weeks of age) with either lithium or an mGluR antagonist is also able to restore normal mGluR-LTD. Translating the findings of successful pharmacologic intervention from the Drosophila model into the mouse model of Fragile X Syndrome is an important advance, in that this identifies and validates these targets as potential therapeutic interventions for the treatment of individuals afflicted with Fragile X Syndrome.
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role for metabotropic glutamate receptor 5 mglur5 in the pathogenesis of Fragile X Syndrome
The Journal of Physiology, 2008Co-Authors: Gill Dolen, Mark F BearAbstract:Metabotropic glutamate receptors (mGluRs) have been implicated in a diverse variety of neuronal functions. Studies reviewed here indicate that eXaggerated signalling through mGluR5 can account for multiple cognitive and syndromic features of Fragile X Syndrome, the most common inherited form of mental retardation and autism. Since a reduction of mGluR5 signalling can reverse Fragile X phenotypes, these studies provide a compelling rationale for the use of mGluR5 antagonists for the treatment of Fragile X and related disorders.
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correction of Fragile X Syndrome in mice
Neuron, 2007Co-Authors: Gul Dolen, Emily K Osterweil, B Shankaranarayana S Rao, Gordon B Smith, Benjamin D Auerbach, Sumantra Chattarji, Mark F BearAbstract:Fragile X Syndrome (FXS) is the most common form of heritable mental retardation and the leading identified cause of autism. FXS is caused by transcriptional silencing of the FMR1 gene that encodes the Fragile X mental retardation protein (FMRP), but the pathogenesis of the disease is unknown. According to one proposal, many psychiatric and neurological symptoms of FXS result from unchecked activation of mGluR5, a metabotropic glutamate receptor. To test this idea we generated Fmr1 mutant mice with a 50% reduction in mGluR5 eXpression and studied a range of phenotypes with relevance to the human disorder. Our results demonstrate that mGluR5 contributes significantly to the pathogenesis of the disease, a finding that has significant therapeutic implications for Fragile X and related developmental disorders.
