scholarly journals Neocortical Localization and Thalamocortical Modulation of Neuronal Hyperexcitability in Fragile X Syndrome

2021 ◽  
Author(s):  
Ernest V. Pedapati ◽  
Lauren M. Schmitt ◽  
Rui Liu ◽  
Lauren E. Ethridge ◽  
Elizabeth Smith ◽  
...  
Keyword(s):  
Intellectual Disability ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Gamma Activity ◽  
Neuronal Hyperexcitability ◽  
Gamma Frequency ◽  
Genetic Mosaicism ◽  
Gamma Power ◽  
Relationship Of ◽  
Minimum Norm Estimate

Fragile X Syndrome (FXS) is a monogenetic form of intellectual disability and autism in which well-established knockout (KO) animal models point to neuronal hyperexcitability and abnormal gamma-frequency physiology as a basis for key illness features. Translating these findings into patients may identify tractable treatment targets. Using a minimum norm estimate of resting state electroencephalography data, we report novel findings in FXS including: 1) increases in gamma activity across functional networks, 2) pervasive changes of theta/alpha activity, indicative of disrupted thalamocortical modulation coupled with elevated gamma power, 3) stepwise moderation of these abnormalities based on female sex and genetic mosaicism, and 4) relationship of this physiology to intellectual disability and anxiety. Our observations extend findings in Fmr1-/- KO mice to patients with FXS and raise a key role for disrupted thalamocortical modulation in local hyperexcitability, a mechanism that has received limited preclinical attention, but has significant implications for understanding fundamental disease mechanisms.

scholarly journals Baclofen-Associated Neurophysiologic Target Engagement Across Species in Fragile X Syndrome

2021 ◽  
Author(s):  
Carrie R. Jonak ◽  
Ernest V. Pedapati ◽  
Lauren M. Schmitt ◽  
Samantha A. Assad ◽  
Manbir S. Sandhu ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Sensory Processing ◽  
Fragile X ◽  
Repetitive Behavior ◽  
Gamma Activity ◽  
Multielectrode Array ◽  
Target Engagement ◽  
Human Experiments ◽  
Gamma Power ◽  
Delayed Language Development

Abstract Background: Fragile X Syndrome (FXS) is the most common inherited form of neurodevelopmental disability. It is often characterized, especially in males, by intellectual disability, anxiety, repetitive behavior, social communication deficits, delayed language development and abnormal sensory processing. Recently, we identified electroencephalographic (EEG) biomarkers that are conserved between the mouse model of FXS (Fmr1 KO mice) and humans with FXS. Methods: In this report, we evaluate small molecule target engagement utilizing multielectrode array electrophysiology in the Fmr1 KO mouse and in humans with FXS. Neurophysiologic target engagement was evaluated using single doses of the GABAB selective agonist racemic baclofen (RBAC). Results: In Fmr1 KO mice and in humans with FXS, baclofen use was synchronously associated with suppression of elevated gamma power and increase in theta power at rest. In the Frm1 KO mice, a baclofen-associated improvement in auditory chirp synchronization was also noted. Conclusions: Overall, we noted synchronized target engagement of RBAC on resting state electrophysiology, in particular the reduction of aberrant high frequency gamma activity, across species in FXS. This finding holds promise for translational medicine approaches to drug development for FXS, synchronizing treatment study across species using well-established EEG biological markers in this field. Trial Registration: The human experiments are registered under NCT02998151.

scholarly journals Gamma power abnormalities in a Fmr1-targeted transgenic rat model of fragile X syndrome

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Naoki Kozono ◽  
Ai Okamura ◽  
Sokichi Honda ◽  
Mitsuyuki Matsumoto ◽  
Takuma Mihara
Keyword(s):  
Fragile X Syndrome ◽  
Fragile X ◽  
Transgenic Rat ◽  
Preclinical Model ◽  
Alpha Power ◽  
Preclinical Research ◽  
Knock Out ◽  
Gamma Frequency ◽  
Eeg Abnormalities ◽  
Gamma Power

Abstract Fragile X syndrome (FXS) is characteristically displayed intellectual disability, hyperactivity, anxiety, and abnormal sensory processing. Electroencephalography (EEG) abnormalities are also observed in subjects with FXS, with many researchers paying attention to these as biomarkers. Despite intensive preclinical research using Fmr1 knock out (KO) mice, an effective treatment for FXS has yet to be developed. Here, we examined Fmr1-targeted transgenic rats (Fmr1-KO rats) as an alternative preclinical model of FXS. We characterized the EEG phenotypes of Fmr1-KO rats by measuring basal EEG power and auditory steady state response (ASSR) to click trains of stimuli at a frequency of 10–80 Hz. Fmr1-KO rats exhibited reduced basal alpha power and enhanced gamma power, and these rats showed enhanced locomotor activity in novel environment. While ASSR clearly peaked at around 40 Hz, both inter-trial coherence (ITC) and event-related spectral perturbation (ERSP) were significantly reduced at the gamma frequency band in Fmr1-KO rats. Fmr1-KO rats showed gamma power abnormalities and behavioral hyperactivity that were consistent with observations reported in mouse models and subjects with FXS. These results suggest that gamma power abnormalities are a translatable biomarker among species and demonstrate the utility of Fmr1-KO rats for investigating drugs for the treatment of FXS.

scholarly journals Autism Profiles of Males With Fragile X Syndrome

2008 ◽  
Vol 113 (6) ◽  
pp. 427-438 ◽  
Author(s):  
Susan W. Harris ◽  
David Hessl ◽  
Beth Goodlin-Jones ◽  
Jessica Ferranti ◽  
Susan Bacalman ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Fragile X ◽  
Autism Diagnosis ◽  
Cgg Repeat ◽  
Molecular Features ◽  
Fmr1 Mrna ◽  
Two Measures ◽  
Dsm Iv ◽  
Relationship Of ◽  
The Relationship

Abstract Autism, which is common in individuals with fragile X syndrome, is often difficult to diagnose. We compared the diagnostic classifications of two measures for autism diagnosis, the ADOS and the ADI-R, in addition to the DSM-IV-TR in 63 males with this syndrome. Overall, 30% of the subjects met criteria for autistic disorder and 30% met criteria for PDD-NOS. The classifications on the ADOS and DSM-IV-TR were most similar, whereas the ADI-R classified subjects as autistic much more frequently. We further investigated the relationship of both FMRP and FMR1 mRNA to symptoms of autism in this cohort and found no significant relationship between the measures of autism and molecular features, including FMRP, FMR1 mRNA, and CGG repeat number.

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.

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.

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 [...]

scholarly journals Single-Nucleotide Mutations in FMR1 Reveal Novel Functions and Regulatory Mechanisms of the Fragile X Syndrome Protein FMRP

2015 ◽  
Vol 9s2 ◽  
pp. JEN.S25524 ◽  
Author(s):  
Joshua A. Suhl ◽  
Stephen T. Warren
Keyword(s):  
Intellectual Disability ◽  
Fragile X Syndrome ◽  
Fragile X ◽  
Point Mutations ◽  
Regulatory Mechanisms ◽  
Cgg Repeat ◽  
Novel Variants ◽  
Sequencing Studies ◽  
The Cost ◽  
Syndrome Protein

Fragile X syndrome is a monogenic disorder and a common cause of intellectual disability. Despite nearly 25 years of research on FMR1, the gene underlying the syndrome, very few pathological mutations other than the typical CGG-repeat expansion have been reported. This is in contrast to other X-linked, monogenic, intellectual disability disorders, such as Rett syndrome, where many point mutations have been validated as causative of the disorder. As technology has improved and significantly driven down the cost of sequencing, allowing for whole genes to be sequenced with relative ease, in-depth sequencing studies on FMR1 have recently been performed. These studies have led to the identification of novel variants in FMR1, where some of which have been functionally evaluated and are likely pathogenic. In this review, we discuss recently identified FMR1 variants, the ways these novel variants cause dysfunction, and how they reveal new regulatory mechanisms and functionalities of the gene.

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