scholarly journals The Implication of AMPA Receptor in Synaptic Plasticity Impairment and Intellectual Disability in Fragile X Syndrome

2017 ◽  
pp. 715-727 ◽  
Author(s):  
G.-R. CHENG ◽  
X.-Y. LI ◽  
Y.-D. XIANG ◽  
D. LIU ◽  
S. M. MCCLINTOCK ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Intellectual Disability ◽  
Fragile X Syndrome ◽  
Ampa Receptors ◽  
Molecular Mechanisms ◽  
Neuronal Development ◽  
Current Knowledge ◽  
Fragile X ◽  
Single Gene ◽  
Poor Mental Health

Fragile X syndrome (FXS) is the most frequently inherited form of intellectual disability and prevalent single-gene cause of autism. A priority of FXS research is to determine the molecular mechanisms underlying the cognitive and social functioning impairments in humans and the FXS mouse model. Glutamate ionotropic alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (AMPARs) mediate a majority of fast excitatory neurotransmission in the central nervous system and are critically important for nearly all aspects of brain function, including neuronal development, synaptic plasticity, and learning and memory. Both preclinical and clinical studies have indicated that expression, trafficking, and functions of AMPARs are altered and result in altered synapse development and plasticity, cognitive impairment, and poor mental health in FXS. In this review, we discuss the contribution of AMPARs to disorders of FXS by highlighting recent research advances with a specific focus on change in AMPARs expression, trafficking, and dependent synaptic plasticity. Since changes in synaptic strength underlie the basis of learning, development, and disease, we suggest that the current knowledge base of AMPARs has reached a unique point to permit a comprehensive re-evaluation of their roles in FXS.

Fragile X: A Family of Disorders

2010 ◽  
Author(s):  
Ann M. Mastergeorge ◽  
Jacky Au
Keyword(s):  
Intellectual Disability ◽  
Fragile X Syndrome ◽  
X Chromosome ◽  
Culture Media ◽  
Fragile Site ◽  
Fragile X ◽  
Single Gene ◽  
Repeat Sequence ◽  
Full Mutation ◽  
Tissue Culture Media

Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability known, and it is the most common single gene disorder associated with autism (Belmonte and Bourgeron 2006; Reddy 2005). It is caused by the lack or deficiency of the FMR1 protein, FMRP (Loesch et al. 2004b). The typical physical features of FXS include prominent ears, hyperextensible finger joints, flat feet, soft skin, and in adolescence and adulthood large testicles (macroorchidism) and a long face (Hagerman 2002b). The behavioral features include poor eye contact, hyperarousal to stimuli, anxiety, hyperactivity, attention deficit, impulsivity, hand stereotypies (such as hand biting and hand flapping), and social deficits including autism and autism spectrum disorder (ASD) (Budimirovic et al. 2006; Clifford et al. 2007; Hall et al. 2008b; Hatton et al. 2006b; Sullivan et al. 2007b). Fragile-X syndrome was first reported by Lubs (1969) in two brothers who had intellectual disability and the appearance of a marker X chromosome, which is a fragile site on their X chromosome. It was later detected that this fragile site on the X chromosome only occurred when the chromosomes were studied in a folate-deficient tissue culture media (Sutherland 1977). Therefore cytogenetic studies were utilized to document cases of FXS throughout the 1980s until the Fragile X Mental Retardation 1 gene (FMR1) was discovered in 1991 (Verkerk et al. 1991). The FMR1 gene was found to have a trinucleotide (CGG) repeat sequence at the 5’ untranslated region, with the normal range later determined to be up to 44 repeats, a gray zone of 45–54 repeats, a premutation of 55–200 repeats, and a full mutation range of more than 200 repeats (Maddalena et al. 2001). Those individuals with the full mutation have a deficit or absence of the FMR1 protein (FMRP) that causes the physical, behavioral, and cognitive features of FXS (Loesch et al. 2004b). Females with the full mutation have another X chromosome that is producing FMRP, depending on the activation ratio (AR) or the percentage of cells that have the normal X chromosome as the active X chromosome.

Molecular studies in children with fragile X syndrome

2017 ◽  
Vol 5 (10) ◽  
pp. 4348
Author(s):  
Manjula Thulasi S.
Keyword(s):  
Differential Diagnosis ◽  
Intellectual Disability ◽  
Fragile X Syndrome ◽  
Chromosomal Aberrations ◽  
Fragile X ◽  
Single Gene ◽  
Blood Samples ◽  
Genetic Abnormalities ◽  
Molecular Studies ◽  
Iq Scores

Background: Fragile X Syndrome (FXS) is the most common single gene cause of Learning (intellectual) Disability (LD). FMR1 gene mutation is the commonest cause for this syndrome. The present study aims to analyze the incidence of the syndrome in Kerala population.Methods: Study was conducted among 86 children belonging to different places of Kerala. Children were selected on the basis of IQ scores and typical features of FXS. Blood samples were taken and routine karyotype was performed. PCR analyses were also conducted.Results: Majority of the children showed typical features of FXS. Out of 86 samples, six showed chromosomal aberrations were excluded. PCR analyses in 55 samples, screened 35 samples with FMR1 mutation, in which 26 samples having pre- mutation and 9 samples with full mutation.Conclusions: Through this genetic study, differential diagnosis of LD children with FXS, LD children with constitutional chromosome abnormalities, and LD children without any apparent genetic abnormalities could be established.

scholarly journals DNA Methylation, Mechanisms of FMR1 Inactivation and Therapeutic Perspectives for Fragile X Syndrome

Biomolecules ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 296
Author(s):  
Veronica Nobile ◽  
Cecilia Pucci ◽  
Pietro Chiurazzi ◽  
Giovanni Neri ◽  
Elisabetta Tabolacci
Keyword(s):  
Dna Methylation ◽  
Fragile X Syndrome ◽  
Intellectual Development ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Fragile X ◽  
Fmr1 Gene ◽  
Critical Question ◽  
Cgg Repeat

Among the inherited causes of intellectual disability and autism, Fragile X syndrome (FXS) is the most frequent form, for which there is currently no cure. In most FXS patients, the FMR1 gene is epigenetically inactivated following the expansion over 200 triplets of a CGG repeat (FM: full mutation). FMR1 encodes the Fragile X Mental Retardation Protein (FMRP), which binds several mRNAs, mainly in the brain. When the FM becomes methylated at 10–12 weeks of gestation, the FMR1 gene is transcriptionally silent. The molecular mechanisms involved in the epigenetic silencing are not fully elucidated. Among FXS families, there is a rare occurrence of males carrying a FM, which remains active because it is not methylated, thus ensuring enough FMRPs to allow for an intellectual development within normal range. Which mechanisms are responsible for sparing these individuals from being affected by FXS? In order to answer this critical question, which may have possible implications for FXS therapy, several potential epigenetic mechanisms have been described. Here, we focus on current knowledge about the role of DNA methylation and other epigenetic modifications in FMR1 gene silencing.

Molecular Mechanisms of Fragile X Syndrome: A Twenty-Year Perspective

2012 ◽  
Vol 7 (1) ◽  
pp. 219-245 ◽  
Author(s):  
Michael R. Santoro ◽  
Steven M. Bray ◽  
Stephen T. Warren
Keyword(s):  
Fragile X Syndrome ◽  
Molecular Mechanisms ◽  
Fragile X

scholarly journals Fragile X syndrome patient-derived neurons developing in the mouse brain show FMR1 -dependent phenotypes

2021 ◽  
Author(s):  
Marine A Krzisch ◽  
Hao A Wu ◽  
Bingbing Yuan ◽  
Troy W. Whitfield ◽  
X. Shawn Liu ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Neuronal Development ◽  
Fragile X ◽  
In Vitro Models ◽  
Synaptic Activity ◽  
Human Neurons ◽  
Induced Pluripotent ◽  
And Function ◽  
The Brain

Abnormal neuronal development in Fragile X syndrome (FXS) is poorly understood. Data on FXS patients remain scarce and FXS animal models have failed to yield successful therapies. In vitro models do not fully recapitulate the morphology and function of human neurons. Here, we co-injected neural precursor cells (NPCs) from FXS patient-derived and corrected isogenic control induced pluripotent stem cells into the brain of neonatal immune-deprived mice. The transplanted cells populated the brain and a proportion differentiated into neurons and glial cells. Single-cell RNA sequencing of transplanted cells revealed upregulated excitatory synaptic transmission and neuronal differentiation pathways in FXS neurons. Immunofluorescence analyses showed accelerated maturation of FXS neurons after an initial delay. Additionally, increased percentages of Arc- and Egr1-positive FXS neurons and wider dendritic protrusions of mature FXS striatal medium spiny neurons pointed to an increase in synaptic activity and synaptic strength as compared to control. This transplantation approach provides new insights into the alterations of neuronal development in FXS by facilitating physiological development of cells in a 3D context, and could be used to test new therapeutic compounds correcting neuronal development defects in FXS.

scholarly journals Blood spots screening for identification of Fragile X Syndrome among intellectual disability students in Flores Island, INDONESIA

2013 ◽  
Vol 2013 (S1) ◽  
Author(s):  
Agustini Utari ◽  
Joyce Lo ◽  
Tzuhan Tong ◽  
Tri Indah Winarni ◽  
Sultana MH Faradz ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Blood Spots

Validation of Hagerman’s behavioral phenotype for fragile X syndrome among men with intellectual disability

2021 ◽  
Vol ahead-of-print (ahead-of-print) ◽  
Author(s):  
Jacques Bellavance ◽  
Morin Diane ◽  
Catherine Mello
Keyword(s):  
Down Syndrome ◽  
Intellectual Disability ◽  
Fragile X Syndrome ◽  
Design Methodology ◽  
Fragile X ◽  
Behavioral Phenotype ◽  
Care Providers ◽  
Content Type

Purpose The behavioral phenotype of fragile X syndrome (FXS) and intellectual disability (ID) proposed by Hagerman et al. (2009) was primarily based on data from male children and teens. The purpose of this study was to promote a better understanding of how this condition manifests in adults. Design/methodology/approach A total of 18 men of FXS were paired with men with Down syndrome on the basis of age and level of ID. A screening checklist was created on the basis of existing scales and the Hagerman et al. (2009) behavioral phenotype and completed by care providers. Findings Five of the 12 features of the phenotype were significantly more present among men with FXS than in men with Down syndrome. Originality/value This study provides partial confirmation for Hagerman et al.’s (2009) behavioral phenotype of FXS among men with moderate ID and identified some traits that warrant further investigation.

scholarly journals Towards Mechanism-Based Treatments for Fragile X Syndrome

2019 ◽  
Vol 9 (8) ◽  
pp. 202
Author(s):  
Daman Kumari ◽  
Inbal Gazy
Keyword(s):  
Autism Spectrum Disorder ◽  
Intellectual Disability ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Autism Spectrum ◽  
Spectrum Disorder

Fragile X syndrome (FXS) is the most common heritable form of intellectual disability, as well as the most common known monogenic cause of autism spectrum disorder (ASD), affecting 1 in 4000–8000 people worldwide [...]

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