41 recherche sur le mot-clé 'GABA'

Clinical and molecular outcomes from the 5-Year natural history study of SSADH Deficiency, a model metabolic neurodevelopmental disorder / Itay TOKATLY LATZER in Journal of Neurodevelopmental Disorders, 16 (2024)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 16 (2024) Titre : Clinical and molecular outcomes from the 5-Year natural history study of SSADH Deficiency, a model metabolic neurodevelopmental disorder Type de document : texte imprimé Auteurs : Itay TOKATLY LATZER, Auteur ; Jean-Baptiste ROULLET, Auteur ; Wardiya AFSHAR-SABER, Auteur ; Henry H.C. LEE, Auteur ; Mariarita BERTOLDI, Auteur ; Gabrielle E. MCGINTY, Auteur ; Melissa L. DIBACCO, Auteur ; Erland ARNING, Auteur ; Melissa TSUBOYAMA, Auteur ; Alexander ROTENBERG, Auteur ; Thomas OPLADEN, Auteur ; Kathrin JELTSCH, Auteur ; Àngels GARCÍA-CAZORLA, Auteur ; Natalia JULIÁ-PALACIOS, Auteur ; K Michael GIBSON, Auteur ; Mustafa SAHIN, Auteur ; Phillip L.. PEARL, Auteur Langues : Anglais (eng) Mots-clés : Adolescent  Animals  Child  Child, Preschool  Female  Humans  Male  Mice  Amino Acid Metabolism, Inborn  Errors/therapy/physiopathology/genetics/complications/metabolism  Brain/metabolism/physiopathology  Developmental Disabilities  Disease Models, Animal  GABAergic Neurons/metabolism  gamma-Aminobutyric Acid/metabolism  Induced Pluripotent Stem Cells/metabolism  Neurodevelopmental Disorders/metabolism/etiology/genetics  Succinate-Semialdehyde Dehydrogenase/deficiency/metabolism/genetics  Development  Gaba  Neurotransmitters  Succinic semialdehyde dehydrogenase  Inc., which develops treatments for SSADHD including gene replacement therapy  discussed in this study. Index. décimale : PER Périodiques Résumé : BACKGROUND: Succinic semialdehyde dehydrogenase deficiency (SSADHD) represents a model neurometabolic disease at the fulcrum of translational research within the Boston Children's Hospital Intellectual and Developmental Disabilities Research Centers (IDDRC), including the NIH-sponsored natural history study of clinical, neurophysiological, neuroimaging, and molecular markers, patient-derived induced pluripotent stem cells (iPSC) characterization, and development of a murine model for tightly regulated, cell-specific gene therapy. METHODS: SSADHD subjects underwent clinical evaluations, neuropsychological assessments, biochemical quantification of γ-aminobutyrate (GABA) and related metabolites, electroencephalography (standard and high density), magnetoencephalography, transcranial magnetic stimulation, magnetic resonance imaging and spectroscopy, and genetic tests. This was parallel to laboratory molecular investigations of in vitro GABAergic neurons derived from induced human pluripotent stem cells (hiPSCs) of SSADHD subjects and biochemical analyses performed on a versatile murine model that uses an inducible and reversible rescue strategy allowing on-demand and cell-specific gene therapy. RESULTS: The 62 SSADHD subjects [53% females, median (IQR) age of 9.6 (5.4-14.5) years] included in the study had a reported symptom onset at ∼ 6 months and were diagnosed at a median age of 4 years. Language developmental delays were more prominent than motor. Autism, epilepsy, movement disorders, sleep disturbances, and various psychiatric behaviors constituted the core of the disorder's clinical phenotype. Lower clinical severity scores, indicating worst severity, coincided with older age (R= -0.302, p = 0.03), as well as age-adjusted lower values of plasma γ-aminobutyrate (GABA) (R = 0.337, p = 0.02) and γ-hydroxybutyrate (GHB) (R = 0.360, p = 0.05). While epilepsy and psychiatric behaviors increase in severity with age, communication abilities and motor function tend to improve. iPSCs, which were differentiated into GABAergic neurons, represent the first in vitro neuronal model of SSADHD and express the neuronal marker microtubule-associated protein 2 (MAP2), as well as GABA. GABA-metabolism in induced GABAergic neurons could be reversed using CRISPR correction of the pathogenic variants or mRNA transfection and SSADHD iPSCs were associated with excessive glutamatergic activity and related synaptic excitation. CONCLUSIONS: Findings from the SSADHD Natural History Study converge with iPSC and animal model work focused on a common disorder within our IDDRC, deepening our knowledge of the pathophysiology and longitudinal clinical course of a complex neurodevelopmental disorder. This further enables the identification of biomarkers and changes throughout development that will be essential for upcoming targeted trials of enzyme replacement and gene therapy. En ligne : https://dx.doi.org/10.1186/s11689-024-09538-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=575 [article] Clinical and molecular outcomes from the 5-Year natural history study of SSADH Deficiency, a model metabolic neurodevelopmental disorder [texte imprimé] / Itay TOKATLY LATZER, Auteur ; Jean-Baptiste ROULLET, Auteur ; Wardiya AFSHAR-SABER, Auteur ; Henry H.C. LEE, Auteur ; Mariarita BERTOLDI, Auteur ; Gabrielle E. MCGINTY, Auteur ; Melissa L. DIBACCO, Auteur ; Erland ARNING, Auteur ; Melissa TSUBOYAMA, Auteur ; Alexander ROTENBERG, Auteur ; Thomas OPLADEN, Auteur ; Kathrin JELTSCH, Auteur ; Àngels GARCÍA-CAZORLA, Auteur ; Natalia JULIÁ-PALACIOS, Auteur ; K Michael GIBSON, Auteur ; Mustafa SAHIN, Auteur ; Phillip L.. PEARL, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 16 (2024) Mots-clés : Adolescent  Animals  Child  Child, Preschool  Female  Humans  Male  Mice  Amino Acid Metabolism, Inborn  Errors/therapy/physiopathology/genetics/complications/metabolism  Brain/metabolism/physiopathology  Developmental Disabilities  Disease Models, Animal  GABAergic Neurons/metabolism  gamma-Aminobutyric Acid/metabolism  Induced Pluripotent Stem Cells/metabolism  Neurodevelopmental Disorders/metabolism/etiology/genetics  Succinate-Semialdehyde Dehydrogenase/deficiency/metabolism/genetics  Development  Gaba  Neurotransmitters  Succinic semialdehyde dehydrogenase  Inc., which develops treatments for SSADHD including gene replacement therapy  discussed in this study. Index. décimale : PER Périodiques Résumé : BACKGROUND: Succinic semialdehyde dehydrogenase deficiency (SSADHD) represents a model neurometabolic disease at the fulcrum of translational research within the Boston Children's Hospital Intellectual and Developmental Disabilities Research Centers (IDDRC), including the NIH-sponsored natural history study of clinical, neurophysiological, neuroimaging, and molecular markers, patient-derived induced pluripotent stem cells (iPSC) characterization, and development of a murine model for tightly regulated, cell-specific gene therapy. METHODS: SSADHD subjects underwent clinical evaluations, neuropsychological assessments, biochemical quantification of γ-aminobutyrate (GABA) and related metabolites, electroencephalography (standard and high density), magnetoencephalography, transcranial magnetic stimulation, magnetic resonance imaging and spectroscopy, and genetic tests. This was parallel to laboratory molecular investigations of in vitro GABAergic neurons derived from induced human pluripotent stem cells (hiPSCs) of SSADHD subjects and biochemical analyses performed on a versatile murine model that uses an inducible and reversible rescue strategy allowing on-demand and cell-specific gene therapy. RESULTS: The 62 SSADHD subjects [53% females, median (IQR) age of 9.6 (5.4-14.5) years] included in the study had a reported symptom onset at ∼ 6 months and were diagnosed at a median age of 4 years. Language developmental delays were more prominent than motor. Autism, epilepsy, movement disorders, sleep disturbances, and various psychiatric behaviors constituted the core of the disorder's clinical phenotype. Lower clinical severity scores, indicating worst severity, coincided with older age (R= -0.302, p = 0.03), as well as age-adjusted lower values of plasma γ-aminobutyrate (GABA) (R = 0.337, p = 0.02) and γ-hydroxybutyrate (GHB) (R = 0.360, p = 0.05). While epilepsy and psychiatric behaviors increase in severity with age, communication abilities and motor function tend to improve. iPSCs, which were differentiated into GABAergic neurons, represent the first in vitro neuronal model of SSADHD and express the neuronal marker microtubule-associated protein 2 (MAP2), as well as GABA. GABA-metabolism in induced GABAergic neurons could be reversed using CRISPR correction of the pathogenic variants or mRNA transfection and SSADHD iPSCs were associated with excessive glutamatergic activity and related synaptic excitation. CONCLUSIONS: Findings from the SSADHD Natural History Study converge with iPSC and animal model work focused on a common disorder within our IDDRC, deepening our knowledge of the pathophysiology and longitudinal clinical course of a complex neurodevelopmental disorder. This further enables the identification of biomarkers and changes throughout development that will be essential for upcoming targeted trials of enzyme replacement and gene therapy. En ligne : https://dx.doi.org/10.1186/s11689-024-09538-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=575

Age-related parietal GABA alterations in children with autism spectrum disorder / Marilena M. DEMAYO in Autism Research, 14-5 (May 2021)  

Public ISBD [article]  inAutism Research > 14-5 (May 2021) . - p.859-872 Titre : Age-related parietal GABA alterations in children with autism spectrum disorder Type de document : texte imprimé Auteurs : Marilena M. DEMAYO, Auteur ; Ashley D. HARRIS, Auteur ; Yun Ju C. SONG, Auteur ; Izabella POKORSKI, Auteur ; Rinku THAPA, Auteur ; Shrujna PATEL, Auteur ; Zahava AMBARCHI, Auteur ; Emma E. THOMAS, Auteur ; Ian B. HICKIE, Auteur ; Adam J. GUASTELLA, Auteur Article en page(s) : p.859-872 Langues : Anglais (eng) Mots-clés : GABA (gamma-aminobutyric acid)  biomarker  children  magnetic resonance spectroscopy (MRS)  neurochemistry  parietal lobe Index. décimale : PER Périodiques Résumé : GABA is the primary inhibitory neurotransmitter in the brain, and is essential to the balance of cortical excitation and inhibition. Reductions in GABA are proposed to result in an overly excitatory cortex that may cause, or contribute to, symptoms of autism spectrum disorder (ASD). This study employed a cross-sectional design to explore GABA+ differences in ASD and the impact of age, comparing 4-12 year olds with ASD (N = 24) to typically developing children (N = 35). GABA+ concentration was measured using edited magnetic resonance spectroscopy in the left parietal lobe. This study used a mixed model to investigate group differences between children with ASD and typically developing children. There was a significant difference in GABA+ levels between the groups, a significant effect of age and interaction between age and diagnostic group. The ASD group showed an association between GABA+ and age, with GABA+ levels gradually increasing with age (r = 0.59, p = 0.003). Typically developing children did not show age-related change in GABA+ concentration (r = 0.09, p = 0.60). By the age of 9, children with ASD showed GABA+ levels that were comparable to their typically developing peers. This study suggests that children with ASD have initially lower levels of GABA+ in the left parietal lobe compared to typically developing children, and that these initially lower levels of GABA+ increase with age in ASD within this region. It is suggested that this developmental shift of GABA+ levels within the left parietal lobe provides a possible explanation for the previously found reductions in childhood that does not persist in adults. LAY SUMMARY: This study measured levels of GABA in the left parietal lobe using magnetic resonance spectroscopy in children with ASD and typically developing children. GABA levels were initially lower in the ASD group, and increased with age, while GABA did not change with age in the typically developing group. This suggests that alterations in GABA signaling may be associated with ASD in childhood. Autism Res 2021, 14: 859-872. © 2021 International Society for Autism Research, Wiley Periodicals LLC. En ligne : http://dx.doi.org/10.1002/aur.2487 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=444 [article] Age-related parietal GABA alterations in children with autism spectrum disorder [texte imprimé] / Marilena M. DEMAYO, Auteur ; Ashley D. HARRIS, Auteur ; Yun Ju C. SONG, Auteur ; Izabella POKORSKI, Auteur ; Rinku THAPA, Auteur ; Shrujna PATEL, Auteur ; Zahava AMBARCHI, Auteur ; Emma E. THOMAS, Auteur ; Ian B. HICKIE, Auteur ; Adam J. GUASTELLA, Auteur . - p.859-872. Langues : Anglais (eng) in Autism Research > 14-5 (May 2021) . - p.859-872 Mots-clés : GABA (gamma-aminobutyric acid)  biomarker  children  magnetic resonance spectroscopy (MRS)  neurochemistry  parietal lobe Index. décimale : PER Périodiques Résumé : GABA is the primary inhibitory neurotransmitter in the brain, and is essential to the balance of cortical excitation and inhibition. Reductions in GABA are proposed to result in an overly excitatory cortex that may cause, or contribute to, symptoms of autism spectrum disorder (ASD). This study employed a cross-sectional design to explore GABA+ differences in ASD and the impact of age, comparing 4-12 year olds with ASD (N = 24) to typically developing children (N = 35). GABA+ concentration was measured using edited magnetic resonance spectroscopy in the left parietal lobe. This study used a mixed model to investigate group differences between children with ASD and typically developing children. There was a significant difference in GABA+ levels between the groups, a significant effect of age and interaction between age and diagnostic group. The ASD group showed an association between GABA+ and age, with GABA+ levels gradually increasing with age (r = 0.59, p = 0.003). Typically developing children did not show age-related change in GABA+ concentration (r = 0.09, p = 0.60). By the age of 9, children with ASD showed GABA+ levels that were comparable to their typically developing peers. This study suggests that children with ASD have initially lower levels of GABA+ in the left parietal lobe compared to typically developing children, and that these initially lower levels of GABA+ increase with age in ASD within this region. It is suggested that this developmental shift of GABA+ levels within the left parietal lobe provides a possible explanation for the previously found reductions in childhood that does not persist in adults. LAY SUMMARY: This study measured levels of GABA in the left parietal lobe using magnetic resonance spectroscopy in children with ASD and typically developing children. GABA levels were initially lower in the ASD group, and increased with age, while GABA did not change with age in the typically developing group. This suggests that alterations in GABA signaling may be associated with ASD in childhood. Autism Res 2021, 14: 859-872. © 2021 International Society for Autism Research, Wiley Periodicals LLC. En ligne : http://dx.doi.org/10.1002/aur.2487 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=444

Altered tactile processing in children with autism spectrum disorder / Teresa TAVASSOLI in Autism Research, 9-6 (June 2016)  

Public ISBD [article]  inAutism Research > 9-6 (June 2016) . - p.616-620 Titre : Altered tactile processing in children with autism spectrum disorder Type de document : texte imprimé Auteurs : Teresa TAVASSOLI, Auteur ; Katherine BELLESHEIM, Auteur ; Mark TOMMERDAHL, Auteur ; Jameson M. HOLDEN, Auteur ; Alexander KOLEVZON, Auteur ; Joseph D. BUXBAUM, Auteur Article en page(s) : p.616-620 Langues : Anglais (eng) Mots-clés : tactile processing  inhibition  autism spectrum disorder  GABA Index. décimale : PER Périodiques Résumé : Although tactile reactivity issues are commonly reported in children with autism spectrum disorder (ASD), the underlying mechanisms are poorly understood. Less feed-forward inhibition has been proposed as a potential mechanism for some symptoms of ASD. We tested static and dynamic tactile thresholds as a behavioral proxy of feed-forward inhibition in 42 children (21 children with ASD and 21 typically developing [TD] children). Subthreshold conditioning typically raises the dynamic detection threshold, thus comparison of the dynamic to the static threshold generates a metric that predicts gamma-aminobutyric acid (GABA) mediated feed-forward inhibition. Children with ASD had marginally higher static thresholds and a significantly lower ratio between thresholds as compared with TD children. The lower ratio, only seen in children with ASD, might be indicative of less inhibition. Static thresholds were correlated with autism spectrum quotient scores, indicating the higher the tactile threshold, the more ASD traits. The amount of feed-forward inhibition (ratio between dynamic/static) was negatively correlated with autism diagnostic observation schedule repetitive behavior scores, meaning the less inhibition the more ASD symptoms. In summary, children with ASD showed altered tactile processing compared with TD children; thus measuring static and dynamic thresholds could be a potential biomarker for ASD and might be useful for prediction of treatment response with therapeutics, including those that target the GABAergic system. Autism Res 2016, 9: 616–620. © 2015 International Society for Autism Research, Wiley Periodicals, Inc. En ligne : http://dx.doi.org/10.1002/aur.1563 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=290 [article] Altered tactile processing in children with autism spectrum disorder [texte imprimé] / Teresa TAVASSOLI, Auteur ; Katherine BELLESHEIM, Auteur ; Mark TOMMERDAHL, Auteur ; Jameson M. HOLDEN, Auteur ; Alexander KOLEVZON, Auteur ; Joseph D. BUXBAUM, Auteur . - p.616-620. Langues : Anglais (eng) in Autism Research > 9-6 (June 2016) . - p.616-620 Mots-clés : tactile processing  inhibition  autism spectrum disorder  GABA Index. décimale : PER Périodiques Résumé : Although tactile reactivity issues are commonly reported in children with autism spectrum disorder (ASD), the underlying mechanisms are poorly understood. Less feed-forward inhibition has been proposed as a potential mechanism for some symptoms of ASD. We tested static and dynamic tactile thresholds as a behavioral proxy of feed-forward inhibition in 42 children (21 children with ASD and 21 typically developing [TD] children). Subthreshold conditioning typically raises the dynamic detection threshold, thus comparison of the dynamic to the static threshold generates a metric that predicts gamma-aminobutyric acid (GABA) mediated feed-forward inhibition. Children with ASD had marginally higher static thresholds and a significantly lower ratio between thresholds as compared with TD children. The lower ratio, only seen in children with ASD, might be indicative of less inhibition. Static thresholds were correlated with autism spectrum quotient scores, indicating the higher the tactile threshold, the more ASD traits. The amount of feed-forward inhibition (ratio between dynamic/static) was negatively correlated with autism diagnostic observation schedule repetitive behavior scores, meaning the less inhibition the more ASD symptoms. In summary, children with ASD showed altered tactile processing compared with TD children; thus measuring static and dynamic thresholds could be a potential biomarker for ASD and might be useful for prediction of treatment response with therapeutics, including those that target the GABAergic system. Autism Res 2016, 9: 616–620. © 2015 International Society for Autism Research, Wiley Periodicals, Inc. En ligne : http://dx.doi.org/10.1002/aur.1563 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=290

Annual Research Review: Development of the cerebral cortex: implications for neurodevelopmental disorders / John L.R. RUBENSTEIN in Journal of Child Psychology and Psychiatry, 52-4 (April 2011)  

Public ISBD [article]  inJournal of Child Psychology and Psychiatry > 52-4 (April 2011) . - p.339-355 Titre : Annual Research Review: Development of the cerebral cortex: implications for neurodevelopmental disorders Type de document : texte imprimé Auteurs : John L.R. RUBENSTEIN, Auteur Année de publication : 2011 Article en page(s) : p.339-355 Langues : Anglais (eng) Mots-clés : Cortex  development  autism  brain development  fibroblast growth factor  GABA Index. décimale : PER Périodiques Résumé : The cerebral cortex has a central role in cognitive and emotional processing. As such, understanding the mechanisms that govern its development and function will be central to understanding the bases of severe neuropsychiatric disorders, particularly those that first appear in childhood. In this review, I highlight recent progress in elucidating genetic, molecular and cellular mechanisms that control cortical development. I discuss basic aspects of cortical developmental anatomy, and mechanisms that regulate cortical size and area formation, with an emphasis on the roles of fibroblast growth factor (Fgf) signaling and specific transcription factors. I then examine how specific types of cortical excitatory projection neurons are generated, and how their axons grow along stereotyped pathways to their targets. Next, I address how cortical inhibitory (GABAergic) neurons are generated, and point out the role of these cells in controlling cortical plasticity and critical periods. The paper concludes with an examination of four possible developmental mechanisms that could contribute to some forms of neurodevelopmental disorders, such as autism. En ligne : http://dx.doi.org/10.1111/j.1469-7610.2010.02307.x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=119 [article] Annual Research Review: Development of the cerebral cortex: implications for neurodevelopmental disorders [texte imprimé] / John L.R. RUBENSTEIN, Auteur . - 2011 . - p.339-355. Langues : Anglais (eng) in Journal of Child Psychology and Psychiatry > 52-4 (April 2011) . - p.339-355 Mots-clés : Cortex  development  autism  brain development  fibroblast growth factor  GABA Index. décimale : PER Périodiques Résumé : The cerebral cortex has a central role in cognitive and emotional processing. As such, understanding the mechanisms that govern its development and function will be central to understanding the bases of severe neuropsychiatric disorders, particularly those that first appear in childhood. In this review, I highlight recent progress in elucidating genetic, molecular and cellular mechanisms that control cortical development. I discuss basic aspects of cortical developmental anatomy, and mechanisms that regulate cortical size and area formation, with an emphasis on the roles of fibroblast growth factor (Fgf) signaling and specific transcription factors. I then examine how specific types of cortical excitatory projection neurons are generated, and how their axons grow along stereotyped pathways to their targets. Next, I address how cortical inhibitory (GABAergic) neurons are generated, and point out the role of these cells in controlling cortical plasticity and critical periods. The paper concludes with an examination of four possible developmental mechanisms that could contribute to some forms of neurodevelopmental disorders, such as autism. En ligne : http://dx.doi.org/10.1111/j.1469-7610.2010.02307.x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=119

Arbaclofen in fragile X syndrome: results of phase 3 trials / Elizabeth BERRY-KRAVIS in Journal of Neurodevelopmental Disorders, 9-1 (December 2017)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 9-1 (December 2017) . - p.3 Titre : Arbaclofen in fragile X syndrome: results of phase 3 trials Type de document : texte imprimé Auteurs : Elizabeth BERRY-KRAVIS, Auteur ; Randi J. HAGERMAN, Auteur ; Jeannie VISOOTSAK, Auteur ; Dejan B. BUDIMIROVIC, Auteur ; Walter E. KAUFMANN, Auteur ; Maryann CHERUBINI, Auteur ; Peter ZAREVICS, Auteur ; Karen WALTON-BOWEN, Auteur ; Ping WANG, Auteur ; Mark F. BEAR, Auteur ; Randall L. CARPENTER, Auteur Article en page(s) : p.3 Langues : Anglais (eng) Mots-clés : Arbaclofen  Fmr1  Fragile X syndrome  GABA agonist  Neurodevelopmental disorder  Targeted treatment Index. décimale : PER Périodiques Résumé : BACKGROUND: Arbaclofen improved multiple abnormal phenotypes in animal models of fragile X syndrome (FXS) and showed promising results in a phase 2 clinical study. The objective of the study is to determine safety and efficacy of arbaclofen for social avoidance in FXS. METHODS: Two phase 3 placebo-controlled trials were conducted, a flexible dose trial in subjects age 12-50 (209FX301, adolescent/adult study) and a fixed dose trial in subjects age 5-11 (209FX302, child study). The primary endpoint for both trials was the Social Avoidance subscale of the Aberrant Behavior Checklist-Community Edition, FXS-specific (ABC-CFX). Secondary outcomes included other ABC-CFX subscale scores, Clinical Global Impression-Improvement (CGI-I), Clinical Global Impression-Severity (CGI-S), and Vineland Adaptive Behavior Scales, Second Edition (Vineland-II) Socialization domain score. RESULTS: A total 119 of 125 randomized subjects completed the adolescent/adult study (n = 57 arbaclofen, 62 placebo) and 159/172 completed the child study (arbaclofen 5 BID n = 38; 10 BID n = 39; 10 TID n = 38; placebo n = 44). There were no serious adverse events (AEs); the most common AEs included somatic (headache, vomiting, nausea), neurobehavioral (irritability/agitation, anxiety, hyperactivity), decreased appetite, and infectious conditions, many of which were also common on placebo. In the combined studies, there were 13 discontinuations (n = 12 arbaclofen, 1 placebo) due to AEs (all neurobehavioral). The adolescent/adult study did not show benefit for arbaclofen over placebo for any measure. In the child study, the highest dose group showed benefit over placebo on the ABC-CFX Irritability subscale (p = 0.03) and Parenting Stress Index (PSI, p = 0.03) and trends toward benefit on the ABC-CFX Social Avoidance and Hyperactivity subscales (both p < 0.1) and CGI-I (p = 0.119). Effect size in the highest dose group was similar to effect sizes for FDA-approved serotonin reuptake inhibitors (SSRIs). CONCLUSIONS: Arbaclofen did not meet the primary outcome of improved social avoidance in FXS in either study. Data from secondary measures in the child study suggests younger patients may derive benefit, but additional studies with a larger cohort on higher doses would be required to confirm this finding. The reported studies illustrate the challenges but represent a significant step forward in translating targeted treatments from preclinical models to clinical trials in humans with FXS. En ligne : http://dx.doi.org/10.1186/s11689-016-9181-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=349 [article] Arbaclofen in fragile X syndrome: results of phase 3 trials [texte imprimé] / Elizabeth BERRY-KRAVIS, Auteur ; Randi J. HAGERMAN, Auteur ; Jeannie VISOOTSAK, Auteur ; Dejan B. BUDIMIROVIC, Auteur ; Walter E. KAUFMANN, Auteur ; Maryann CHERUBINI, Auteur ; Peter ZAREVICS, Auteur ; Karen WALTON-BOWEN, Auteur ; Ping WANG, Auteur ; Mark F. BEAR, Auteur ; Randall L. CARPENTER, Auteur . - p.3. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 9-1 (December 2017) . - p.3 Mots-clés : Arbaclofen  Fmr1  Fragile X syndrome  GABA agonist  Neurodevelopmental disorder  Targeted treatment Index. décimale : PER Périodiques Résumé : BACKGROUND: Arbaclofen improved multiple abnormal phenotypes in animal models of fragile X syndrome (FXS) and showed promising results in a phase 2 clinical study. The objective of the study is to determine safety and efficacy of arbaclofen for social avoidance in FXS. METHODS: Two phase 3 placebo-controlled trials were conducted, a flexible dose trial in subjects age 12-50 (209FX301, adolescent/adult study) and a fixed dose trial in subjects age 5-11 (209FX302, child study). The primary endpoint for both trials was the Social Avoidance subscale of the Aberrant Behavior Checklist-Community Edition, FXS-specific (ABC-CFX). Secondary outcomes included other ABC-CFX subscale scores, Clinical Global Impression-Improvement (CGI-I), Clinical Global Impression-Severity (CGI-S), and Vineland Adaptive Behavior Scales, Second Edition (Vineland-II) Socialization domain score. RESULTS: A total 119 of 125 randomized subjects completed the adolescent/adult study (n = 57 arbaclofen, 62 placebo) and 159/172 completed the child study (arbaclofen 5 BID n = 38; 10 BID n = 39; 10 TID n = 38; placebo n = 44). There were no serious adverse events (AEs); the most common AEs included somatic (headache, vomiting, nausea), neurobehavioral (irritability/agitation, anxiety, hyperactivity), decreased appetite, and infectious conditions, many of which were also common on placebo. In the combined studies, there were 13 discontinuations (n = 12 arbaclofen, 1 placebo) due to AEs (all neurobehavioral). The adolescent/adult study did not show benefit for arbaclofen over placebo for any measure. In the child study, the highest dose group showed benefit over placebo on the ABC-CFX Irritability subscale (p = 0.03) and Parenting Stress Index (PSI, p = 0.03) and trends toward benefit on the ABC-CFX Social Avoidance and Hyperactivity subscales (both p < 0.1) and CGI-I (p = 0.119). Effect size in the highest dose group was similar to effect sizes for FDA-approved serotonin reuptake inhibitors (SSRIs). CONCLUSIONS: Arbaclofen did not meet the primary outcome of improved social avoidance in FXS in either study. Data from secondary measures in the child study suggests younger patients may derive benefit, but additional studies with a larger cohort on higher doses would be required to confirm this finding. The reported studies illustrate the challenges but represent a significant step forward in translating targeted treatments from preclinical models to clinical trials in humans with FXS. En ligne : http://dx.doi.org/10.1186/s11689-016-9181-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=349

Associations between sensory processing and electrophysiological and neurochemical measures in children with ASD: an EEG-MRS study / Sarah PIERCE in Journal of Neurodevelopmental Disorders, 13 (2021)  

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Common circuit defect of excitatory-inhibitory balance in mouse models of autism / Nadine GOGOLLA in Journal of Neurodevelopmental Disorders, 1-2 (June 2009)  

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Consistency of parent-report SLC6A1 data in Simons Searchlight with Provider-Based Publications / Jennifer M. BAIN in Journal of Neurodevelopmental Disorders, 14 (2022)  

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Decreased parvalbumin mRNA levels in cerebellar Purkinje cells in autism / Jean-Jacques SOGHOMONIAN in Autism Research, 10-11 (November 2017)  

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Downregulation of GABAA Receptor Protein Subunits α6, β2, δ, ε, γ2, θ, and ρ2 in Superior Frontal Cortex of Subjects with Autism / S. Hossein FATEMI in Journal of Autism and Developmental Disorders, 44-8 (August 2014)  

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