Prospective and detailed behavioral phenotyping in DDX3X syndrome / L. TANG in Molecular Autism, 12 (2021)  

Public ISBD [article]  inMolecular Autism > 12 (2021) . - 36 p. Titre : Prospective and detailed behavioral phenotyping in DDX3X syndrome Type de document : Texte imprimé et/ou numérique Auteurs : L. TANG, Auteur ; T. LEVY, Auteur ; S. GUILLORY, Auteur ; Danielle B. HALPERN, Auteur ; J. ZWEIFACH, Auteur ; I. GISERMAN-KISS, Auteur ; J. H. FOSS-FEIG, Auteur ; Y. FRANK, Auteur ; R. LOZANO, Auteur ; P. BELANI, Auteur ; C. LAYTON, Auteur ; B. LERMAN, Auteur ; E. FROWNER, Auteur ; Michael S. BREEN, Auteur ; S. DE RUBEIS, Auteur ; A. KOSTIC, Auteur ; A. KOLEVZON, Auteur ; Joseph D. BUXBAUM, Auteur ; P. M. SIPER, Auteur ; D. E. GRICE, Auteur Article en page(s) : 36 p. Langues : Anglais (eng) Mots-clés : Autism  DDX3X syndrome  Developmental delay  Genotype–phenotype correlation  Intellectual disability  Therapeutics, Acadia, and Sema4. PMS is the inventor of the SAND, which is licensed  by Mount Sinai to Stoelting Co. No other competing interests to declare. Index. décimale : PER Périodiques Résumé : BACKGROUND: DDX3X syndrome is a recently identified genetic disorder that accounts for 1-3% of cases of unexplained developmental delay and/or intellectual disability (ID) in females, and is associated with motor and language delays, and autism spectrum disorder (ASD). To date, the published phenotypic characterization of this syndrome has primarily relied on medical record review; in addition, the behavioral dimensions of the syndrome have not been fully explored. METHODS: We carried out multi-day, prospective, detailed phenotyping of DDX3X syndrome in 14 females and 1 male, focusing on behavioral, psychological, and neurological measures. Three participants in this cohort were previously reported with limited phenotype information and were re-evaluated for this study. We compared results against population norms and contrasted phenotypes between individuals harboring either (1) protein-truncating variants or (2) missense variants or in-frame deletions. RESULTS: Eighty percent (80%) of individuals met criteria for ID, 60% for ASD and 53% for attention-deficit/hyperactivity disorder (ADHD). Motor and language delays were common as were sensory processing abnormalities. The cohort included 5 missense, 3 intronic/splice-site, 2 nonsense, 2 frameshift, 2 in-frame deletions, and one initiation codon variant. Genotype-phenotype correlations indicated that, on average, missense variants/in-frame deletions were associated with more severe language, motor, and adaptive deficits in comparison to protein-truncating variants. LIMITATIONS: Sample size is modest, however, DDX3X syndrome is a rare and underdiagnosed disorder. CONCLUSION: This study, representing a first, prospective, detailed characterization of DDX3X syndrome, extends our understanding of the neurobehavioral phenotype. Gold-standard diagnostic approaches demonstrated high rates of ID, ASD, and ADHD. In addition, sensory deficits were observed to be a key part of the syndrome. Even with a modest sample, we observe evidence for genotype-phenotype correlations with missense variants/in-frame deletions generally associated with more severe phenotypes. En ligne : http://dx.doi.org/10.1186/s13229-021-00431-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459 [article] Prospective and detailed behavioral phenotyping in DDX3X syndrome [Texte imprimé et/ou numérique] / L. TANG, Auteur ; T. LEVY, Auteur ; S. GUILLORY, Auteur ; Danielle B. HALPERN, Auteur ; J. ZWEIFACH, Auteur ; I. GISERMAN-KISS, Auteur ; J. H. FOSS-FEIG, Auteur ; Y. FRANK, Auteur ; R. LOZANO, Auteur ; P. BELANI, Auteur ; C. LAYTON, Auteur ; B. LERMAN, Auteur ; E. FROWNER, Auteur ; Michael S. BREEN, Auteur ; S. DE RUBEIS, Auteur ; A. KOSTIC, Auteur ; A. KOLEVZON, Auteur ; Joseph D. BUXBAUM, Auteur ; P. M. SIPER, Auteur ; D. E. GRICE, Auteur . - 36 p. Langues : Anglais (eng) in Molecular Autism > 12 (2021) . - 36 p. Mots-clés : Autism  DDX3X syndrome  Developmental delay  Genotype–phenotype correlation  Intellectual disability  Therapeutics, Acadia, and Sema4. PMS is the inventor of the SAND, which is licensed  by Mount Sinai to Stoelting Co. No other competing interests to declare. Index. décimale : PER Périodiques Résumé : BACKGROUND: DDX3X syndrome is a recently identified genetic disorder that accounts for 1-3% of cases of unexplained developmental delay and/or intellectual disability (ID) in females, and is associated with motor and language delays, and autism spectrum disorder (ASD). To date, the published phenotypic characterization of this syndrome has primarily relied on medical record review; in addition, the behavioral dimensions of the syndrome have not been fully explored. METHODS: We carried out multi-day, prospective, detailed phenotyping of DDX3X syndrome in 14 females and 1 male, focusing on behavioral, psychological, and neurological measures. Three participants in this cohort were previously reported with limited phenotype information and were re-evaluated for this study. We compared results against population norms and contrasted phenotypes between individuals harboring either (1) protein-truncating variants or (2) missense variants or in-frame deletions. RESULTS: Eighty percent (80%) of individuals met criteria for ID, 60% for ASD and 53% for attention-deficit/hyperactivity disorder (ADHD). Motor and language delays were common as were sensory processing abnormalities. The cohort included 5 missense, 3 intronic/splice-site, 2 nonsense, 2 frameshift, 2 in-frame deletions, and one initiation codon variant. Genotype-phenotype correlations indicated that, on average, missense variants/in-frame deletions were associated with more severe language, motor, and adaptive deficits in comparison to protein-truncating variants. LIMITATIONS: Sample size is modest, however, DDX3X syndrome is a rare and underdiagnosed disorder. CONCLUSION: This study, representing a first, prospective, detailed characterization of DDX3X syndrome, extends our understanding of the neurobehavioral phenotype. Gold-standard diagnostic approaches demonstrated high rates of ID, ASD, and ADHD. In addition, sensory deficits were observed to be a key part of the syndrome. Even with a modest sample, we observe evidence for genotype-phenotype correlations with missense variants/in-frame deletions generally associated with more severe phenotypes. En ligne : http://dx.doi.org/10.1186/s13229-021-00431-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459

A randomized controlled trial of intranasal oxytocin in Phelan-McDermid syndrome / J. FASTMAN in Molecular Autism, 12 (2021)  

Public ISBD [article]  inMolecular Autism > 12 (2021) . - 62 p. Titre : A randomized controlled trial of intranasal oxytocin in Phelan-McDermid syndrome Type de document : Texte imprimé et/ou numérique Auteurs : J. FASTMAN, Auteur ; J. FOSS-FEIG, Auteur ; Y. FRANK, Auteur ; Danielle B. HALPERN, Auteur ; Hala HARONY-NICOLAS, Auteur ; C. LAYTON, Auteur ; S. SANDIN, Auteur ; P. SIPER, Auteur ; L. TANG, Auteur ; P. TRELLES, Auteur ; J. ZWEIFACH, Auteur ; Joseph D. BUXBAUM, Auteur ; A. KOLEVZON, Auteur Article en page(s) : 62 p. Langues : Anglais (eng) Mots-clés : Asd  Autism spectrum disorder  Oxytocin  Pms  Phelan-McDermid syndrome  Shank3  Ovid Therapeutics. JDB has a shared patent with Mount Sinai for IGF-1 in  Phelan-McDermid syndrome. No other authors have competing interests to disclose. Index. décimale : PER Périodiques Résumé : BACKGROUND: Phelan-McDermid syndrome (PMS) is a rare neurodevelopmental disorder caused by haploinsufficiency of the SHANK3 gene and characterized by global developmental delays, deficits in speech and motor function, and autism spectrum disorder (ASD). Monogenic causes of ASD such as PMS are well suited to investigations with novel therapeutics, as interventions can be targeted based on established genetic etiology. While preclinical studies have demonstrated that the neuropeptide oxytocin can reverse electrophysiological, attentional, and social recognition memory deficits in Shank3-deficient rats, there have been no trials in individuals with PMS. The purpose of this study is to assess the efficacy and safety of intranasal oxytocin as a treatment for the core symptoms of ASD in a cohort of children with PMS. METHODS: Eighteen children aged 5-17 with PMS were enrolled. Participants were randomized to receive intranasal oxytocin or placebo (intranasal saline) and underwent treatment during a 12-week double-blind, parallel group phase, followed by a 12-week open-label extension phase during which all participants received oxytocin. Efficacy was assessed using the primary outcome of the Aberrant Behavior Checklist-Social Withdrawal (ABC-SW) subscale as well as a number of secondary outcome measures related to the core symptoms of ASD. Safety was monitored throughout the study period. RESULTS: There was no statistically significant improvement with oxytocin as compared to placebo on the ABC-SW (Mann-Whitney U?=?50, p?=?0.055), or on any secondary outcome measures, during either the double-blind or open-label phases. Oxytocin was generally well tolerated, and there were no serious adverse events. LIMITATIONS: The small sample size, potential challenges with drug administration, and expectancy bias due to relying on parent reported outcome measures may all contribute to limitations in interpreting results. CONCLUSION: Our results suggest that intranasal oxytocin is not efficacious in improving the core symptoms of ASD in children with PMS. Trial registration NCT02710084. En ligne : http://dx.doi.org/10.1186/s13229-021-00459-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459 [article] A randomized controlled trial of intranasal oxytocin in Phelan-McDermid syndrome [Texte imprimé et/ou numérique] / J. FASTMAN, Auteur ; J. FOSS-FEIG, Auteur ; Y. FRANK, Auteur ; Danielle B. HALPERN, Auteur ; Hala HARONY-NICOLAS, Auteur ; C. LAYTON, Auteur ; S. SANDIN, Auteur ; P. SIPER, Auteur ; L. TANG, Auteur ; P. TRELLES, Auteur ; J. ZWEIFACH, Auteur ; Joseph D. BUXBAUM, Auteur ; A. KOLEVZON, Auteur . - 62 p. Langues : Anglais (eng) in Molecular Autism > 12 (2021) . - 62 p. Mots-clés : Asd  Autism spectrum disorder  Oxytocin  Pms  Phelan-McDermid syndrome  Shank3  Ovid Therapeutics. JDB has a shared patent with Mount Sinai for IGF-1 in  Phelan-McDermid syndrome. No other authors have competing interests to disclose. Index. décimale : PER Périodiques Résumé : BACKGROUND: Phelan-McDermid syndrome (PMS) is a rare neurodevelopmental disorder caused by haploinsufficiency of the SHANK3 gene and characterized by global developmental delays, deficits in speech and motor function, and autism spectrum disorder (ASD). Monogenic causes of ASD such as PMS are well suited to investigations with novel therapeutics, as interventions can be targeted based on established genetic etiology. While preclinical studies have demonstrated that the neuropeptide oxytocin can reverse electrophysiological, attentional, and social recognition memory deficits in Shank3-deficient rats, there have been no trials in individuals with PMS. The purpose of this study is to assess the efficacy and safety of intranasal oxytocin as a treatment for the core symptoms of ASD in a cohort of children with PMS. METHODS: Eighteen children aged 5-17 with PMS were enrolled. Participants were randomized to receive intranasal oxytocin or placebo (intranasal saline) and underwent treatment during a 12-week double-blind, parallel group phase, followed by a 12-week open-label extension phase during which all participants received oxytocin. Efficacy was assessed using the primary outcome of the Aberrant Behavior Checklist-Social Withdrawal (ABC-SW) subscale as well as a number of secondary outcome measures related to the core symptoms of ASD. Safety was monitored throughout the study period. RESULTS: There was no statistically significant improvement with oxytocin as compared to placebo on the ABC-SW (Mann-Whitney U?=?50, p?=?0.055), or on any secondary outcome measures, during either the double-blind or open-label phases. Oxytocin was generally well tolerated, and there were no serious adverse events. LIMITATIONS: The small sample size, potential challenges with drug administration, and expectancy bias due to relying on parent reported outcome measures may all contribute to limitations in interpreting results. CONCLUSION: Our results suggest that intranasal oxytocin is not efficacious in improving the core symptoms of ASD in children with PMS. Trial registration NCT02710084. En ligne : http://dx.doi.org/10.1186/s13229-021-00459-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=459

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