Dépouillements

Neuroanatomy in mouse models of Rett syndrome is related to the severity of Mecp2 mutation and behavioral phenotypes / R. ALLEMANG-GRAND in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 32p. Titre : Neuroanatomy in mouse models of Rett syndrome is related to the severity of Mecp2 mutation and behavioral phenotypes Type de document : Texte imprimé et/ou numérique Auteurs : R. ALLEMANG-GRAND, Auteur ; J. ELLEGOOD, Auteur ; L. SPENCER NOAKES, Auteur ; J. RUSTON, Auteur ; M. JUSTICE, Auteur ; B. J. NIEMAN, Auteur ; J. P. LERCH, Auteur Article en page(s) : 32p. Langues : Anglais (eng) Mots-clés : Magnetic resonance imaging  Mecp2 mouse models  Neuroanatomy  Rett syndrome Index. décimale : PER Périodiques Résumé : BACKGROUND: Rett syndrome (RTT) is a neurodevelopmental disorder that predominantly affects girls. The majority of RTT cases are caused by de novo mutations in methyl-CpG-binding protein 2 (MECP2), and several mouse models have been created to further understand the disorder. In the current literature, many studies have focused their analyses on the behavioral abnormalities and cellular and molecular impairments that arise from Mecp2 mutations. However, limited efforts have been placed on understanding how Mecp2 mutations disrupt the neuroanatomy and networks of the brain. METHODS: In this study, we examined the neuroanatomy of male and female mice from the Mecp2(tm1Hzo), Mecp2(tm1.1Bird/J), and Mecp2(tm2Bird/J) mouse lines using high-resolution magnetic resonance imaging (MRI) paired with deformation-based morphometry to determine the brain regions susceptible to Mecp2 disruptions. RESULTS: We found that many cortical and subcortical regions were reduced in volume within the brains of mutant mice regardless of mutation type, highlighting regions that are susceptible to Mecp2 disruptions. We also found that the volume within these regions correlated with behavioral metrics. Conversely, regions of the cerebellum were differentially affected by the type of mutation, showing an increase in volume in the mutant Mecp2(tm1Hzo) brain relative to controls and a decrease in the Mecp2(tm1.1Bird/J) and Mecp2(tm2Bird/J) lines. CONCLUSIONS: Our findings demonstrate that the direction and magnitude of the neuroanatomical differences between control and mutant mice carrying Mecp2 mutations are driven by the severity of the mutation and the stage of behavioral impairments. En ligne : http://dx.doi.org/10.1186/s13229-017-0138-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=329 [article] Neuroanatomy in mouse models of Rett syndrome is related to the severity of Mecp2 mutation and behavioral phenotypes [Texte imprimé et/ou numérique] / R. ALLEMANG-GRAND, Auteur ; J. ELLEGOOD, Auteur ; L. SPENCER NOAKES, Auteur ; J. RUSTON, Auteur ; M. JUSTICE, Auteur ; B. J. NIEMAN, Auteur ; J. P. LERCH, Auteur . - 32p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 32p. Mots-clés : Magnetic resonance imaging  Mecp2 mouse models  Neuroanatomy  Rett syndrome Index. décimale : PER Périodiques Résumé : BACKGROUND: Rett syndrome (RTT) is a neurodevelopmental disorder that predominantly affects girls. The majority of RTT cases are caused by de novo mutations in methyl-CpG-binding protein 2 (MECP2), and several mouse models have been created to further understand the disorder. In the current literature, many studies have focused their analyses on the behavioral abnormalities and cellular and molecular impairments that arise from Mecp2 mutations. However, limited efforts have been placed on understanding how Mecp2 mutations disrupt the neuroanatomy and networks of the brain. METHODS: In this study, we examined the neuroanatomy of male and female mice from the Mecp2(tm1Hzo), Mecp2(tm1.1Bird/J), and Mecp2(tm2Bird/J) mouse lines using high-resolution magnetic resonance imaging (MRI) paired with deformation-based morphometry to determine the brain regions susceptible to Mecp2 disruptions. RESULTS: We found that many cortical and subcortical regions were reduced in volume within the brains of mutant mice regardless of mutation type, highlighting regions that are susceptible to Mecp2 disruptions. We also found that the volume within these regions correlated with behavioral metrics. Conversely, regions of the cerebellum were differentially affected by the type of mutation, showing an increase in volume in the mutant Mecp2(tm1Hzo) brain relative to controls and a decrease in the Mecp2(tm1.1Bird/J) and Mecp2(tm2Bird/J) lines. CONCLUSIONS: Our findings demonstrate that the direction and magnitude of the neuroanatomical differences between control and mutant mice carrying Mecp2 mutations are driven by the severity of the mutation and the stage of behavioral impairments. En ligne : http://dx.doi.org/10.1186/s13229-017-0138-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=329

Development and evaluation of a speech-generating AAC mobile app for minimally verbal children with autism spectrum disorder in Mainland China / S. AN in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 52p. Titre : Development and evaluation of a speech-generating AAC mobile app for minimally verbal children with autism spectrum disorder in Mainland China Type de document : Texte imprimé et/ou numérique Auteurs : S. AN, Auteur ; X. FENG, Auteur ; Y. DAI, Auteur ; H. BO, Auteur ; X. WANG, Auteur ; M. LI, Auteur ; J. Z. WOO, Auteur ; X. LIANG, Auteur ; C. GUO, Auteur ; C. X. LIU, Auteur ; L. WEI, Auteur Article en page(s) : 52p. Langues : Anglais (eng) Mots-clés : App  Augmentative and alternative communication  Development  Mainland China  Training effectiveness Index. décimale : PER Périodiques Résumé : BACKGROUND: Mobile touchscreen devices are currently being used as speech-generating devices (SGDs) and have been shown to promote the communication skills, particularly the requesting skills of children with autism spectrum disorders (ASD) who have limited spoken language. However, no augmentative and alternative communication (AAC) mobile app has been developed and evaluated in the Chinese language in Mainland China. METHODS: We developed an AAC mobile app, which is the first in Mainland China, to our knowledge, named Yuudee (Chinese name (xiaoyudi)). Yuudee was developed using the Objective-C and Java programming languages. A five-phase training protocol for making requests using Yuudee was developed based on the Picture Exchange Communication System. We trained ten minimally verbal children with ASD to make requests using Yuudee and evaluated the effectiveness of the training. RESULTS: Yuudee has a built-in library of over 400 pictures with corresponding spoken phrases that are divided into 39 categories ranging from making simple requests to expressing emotions. An additional important feature of Yuudee is its customization functions that allow a parent or trainer to easily select pictures and phrases to display, create new pictures and phrases, and change the layouts and orders of the pictures to fit the personal needs of each child. Yuudee is freely available in an iOS version from the iTunes App Store (https://itunes.apple.com/cn/app/xiao-yu-di/id794832934?mt=8) and in an Android version from Google Play (https://play.google.com/store/apps/details?id=com.supersuperstar.yuudee.vue) and domestic Chinese Android App stores. Three consecutive unprompted successful responses, which were defined as an initial training success, were achieved in at least three of the five phases for all ten of the evaluated children. The accuracy rate of a given phase was calculated for each child who achieved three consecutive unprompted successful responses in the phase. Seven children achieved at least 50% accuracy in at least two of the five phases. The other three children achieved at least 50% accuracy in only one phase. Two children achieved at least 50% accuracy in all of the phases in which they were trained. CONCLUSIONS: Our data suggest that Yuudee is a useful tool for helping minimally verbal children with ASD make requests. En ligne : http://dx.doi.org/10.1186/s13229-017-0165-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=329 [article] Development and evaluation of a speech-generating AAC mobile app for minimally verbal children with autism spectrum disorder in Mainland China [Texte imprimé et/ou numérique] / S. AN, Auteur ; X. FENG, Auteur ; Y. DAI, Auteur ; H. BO, Auteur ; X. WANG, Auteur ; M. LI, Auteur ; J. Z. WOO, Auteur ; X. LIANG, Auteur ; C. GUO, Auteur ; C. X. LIU, Auteur ; L. WEI, Auteur . - 52p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 52p. Mots-clés : App  Augmentative and alternative communication  Development  Mainland China  Training effectiveness Index. décimale : PER Périodiques Résumé : BACKGROUND: Mobile touchscreen devices are currently being used as speech-generating devices (SGDs) and have been shown to promote the communication skills, particularly the requesting skills of children with autism spectrum disorders (ASD) who have limited spoken language. However, no augmentative and alternative communication (AAC) mobile app has been developed and evaluated in the Chinese language in Mainland China. METHODS: We developed an AAC mobile app, which is the first in Mainland China, to our knowledge, named Yuudee (Chinese name (xiaoyudi)). Yuudee was developed using the Objective-C and Java programming languages. A five-phase training protocol for making requests using Yuudee was developed based on the Picture Exchange Communication System. We trained ten minimally verbal children with ASD to make requests using Yuudee and evaluated the effectiveness of the training. RESULTS: Yuudee has a built-in library of over 400 pictures with corresponding spoken phrases that are divided into 39 categories ranging from making simple requests to expressing emotions. An additional important feature of Yuudee is its customization functions that allow a parent or trainer to easily select pictures and phrases to display, create new pictures and phrases, and change the layouts and orders of the pictures to fit the personal needs of each child. Yuudee is freely available in an iOS version from the iTunes App Store (https://itunes.apple.com/cn/app/xiao-yu-di/id794832934?mt=8) and in an Android version from Google Play (https://play.google.com/store/apps/details?id=com.supersuperstar.yuudee.vue) and domestic Chinese Android App stores. Three consecutive unprompted successful responses, which were defined as an initial training success, were achieved in at least three of the five phases for all ten of the evaluated children. The accuracy rate of a given phase was calculated for each child who achieved three consecutive unprompted successful responses in the phase. Seven children achieved at least 50% accuracy in at least two of the five phases. The other three children achieved at least 50% accuracy in only one phase. Two children achieved at least 50% accuracy in all of the phases in which they were trained. CONCLUSIONS: Our data suggest that Yuudee is a useful tool for helping minimally verbal children with ASD make requests. En ligne : http://dx.doi.org/10.1186/s13229-017-0165-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=329

Developmental disruption of amygdala transcriptome and socioemotional behavior in rats exposed to valproic acid prenatally / C. E. BARRETT in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 42p. Titre : Developmental disruption of amygdala transcriptome and socioemotional behavior in rats exposed to valproic acid prenatally Type de document : Texte imprimé et/ou numérique Auteurs : C. E. BARRETT, Auteur ; T. M. HENNESSEY, Auteur ; K. M. GORDON, Auteur ; S. J. RYAN, Auteur ; M. L. MCNAIR, Auteur ; K. J. RESSLER, Auteur ; D. G. RAINNIE, Auteur Article en page(s) : 42p. Langues : Anglais (eng) Mots-clés : Autism  Basolateral amygdala  Protein kinase A  Proteomics  RNA sequencing  Social behavior  Transcriptomics  Valproic acid Index. décimale : PER Périodiques Résumé : BACKGROUND: The amygdala controls socioemotional behavior and has consistently been implicated in the etiology of autism spectrum disorder (ASD). Precocious amygdala development is commonly reported in ASD youth with the degree of overgrowth positively correlated to the severity of ASD symptoms. Prenatal exposure to VPA leads to an ASD phenotype in both humans and rats and has become a commonly used tool to model the complexity of ASD symptoms in the laboratory. Here, we examined abnormalities in gene expression in the amygdala and socioemotional behavior across development in the valproic acid (VPA) rat model of ASD. METHODS: Rat dams received oral gavage of VPA (500 mg/kg) or saline daily between E11 and 13. Socioemotional behavior was tracked across development in both sexes. RNA sequencing and proteomics were performed on amygdala samples from male rats across development. RESULTS: Effects of VPA on time spent in social proximity and anxiety-like behavior were sex dependent, with social abnormalities presenting in males and heightened anxiety in females. Across time VPA stunted developmental and immune, but enhanced cellular death and disorder, pathways in the amygdala relative to saline controls. At postnatal day 10, gene pathways involved in nervous system and cellular development displayed predicted activations in prenatally exposed VPA amygdala samples. By juvenile age, however, transcriptomic and proteomic pathways displayed reductions in cellular growth and neural development. Alterations in immune pathways, calcium signaling, Rho GTPases, and protein kinase A signaling were also observed. CONCLUSIONS: As behavioral, developmental, and genomic alterations are similar to those reported in ASD, these results lend support to prenatal exposure to VPA as a useful tool for understanding how developmental insults to molecular pathways in the amygdala give rise to ASD-related syndromes. En ligne : http://dx.doi.org/10.1186/s13229-017-0160-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=329 [article] Developmental disruption of amygdala transcriptome and socioemotional behavior in rats exposed to valproic acid prenatally [Texte imprimé et/ou numérique] / C. E. BARRETT, Auteur ; T. M. HENNESSEY, Auteur ; K. M. GORDON, Auteur ; S. J. RYAN, Auteur ; M. L. MCNAIR, Auteur ; K. J. RESSLER, Auteur ; D. G. RAINNIE, Auteur . - 42p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 42p. Mots-clés : Autism  Basolateral amygdala  Protein kinase A  Proteomics  RNA sequencing  Social behavior  Transcriptomics  Valproic acid Index. décimale : PER Périodiques Résumé : BACKGROUND: The amygdala controls socioemotional behavior and has consistently been implicated in the etiology of autism spectrum disorder (ASD). Precocious amygdala development is commonly reported in ASD youth with the degree of overgrowth positively correlated to the severity of ASD symptoms. Prenatal exposure to VPA leads to an ASD phenotype in both humans and rats and has become a commonly used tool to model the complexity of ASD symptoms in the laboratory. Here, we examined abnormalities in gene expression in the amygdala and socioemotional behavior across development in the valproic acid (VPA) rat model of ASD. METHODS: Rat dams received oral gavage of VPA (500 mg/kg) or saline daily between E11 and 13. Socioemotional behavior was tracked across development in both sexes. RNA sequencing and proteomics were performed on amygdala samples from male rats across development. RESULTS: Effects of VPA on time spent in social proximity and anxiety-like behavior were sex dependent, with social abnormalities presenting in males and heightened anxiety in females. Across time VPA stunted developmental and immune, but enhanced cellular death and disorder, pathways in the amygdala relative to saline controls. At postnatal day 10, gene pathways involved in nervous system and cellular development displayed predicted activations in prenatally exposed VPA amygdala samples. By juvenile age, however, transcriptomic and proteomic pathways displayed reductions in cellular growth and neural development. Alterations in immune pathways, calcium signaling, Rho GTPases, and protein kinase A signaling were also observed. CONCLUSIONS: As behavioral, developmental, and genomic alterations are similar to those reported in ASD, these results lend support to prenatal exposure to VPA as a useful tool for understanding how developmental insults to molecular pathways in the amygdala give rise to ASD-related syndromes. En ligne : http://dx.doi.org/10.1186/s13229-017-0160-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=329

Neurocognitive and observational markers: prediction of autism spectrum disorder from infancy to mid-childhood / Rachael BEDFORD in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 49p. Titre : Neurocognitive and observational markers: prediction of autism spectrum disorder from infancy to mid-childhood Type de document : Texte imprimé et/ou numérique Auteurs : Rachael BEDFORD, Auteur ; T. GLIGA, Auteur ; E. SHEPHARD, Auteur ; M. ELSABBAGH, Auteur ; A. PICKLES, Auteur ; Tony CHARMAN, Auteur ; M. H. JOHNSON, Auteur Article en page(s) : 49p. Langues : Anglais (eng) Mots-clés : Autism  Diagnosis  High risk  Infants  Neurocognitive  Prediction  Siblings Index. décimale : PER Périodiques Résumé : BACKGROUND: Prospective studies of infants at high familial risk for autism spectrum disorder (ASD) have identified a number of putative early markers that are associated with ASD outcome at 3 years of age. However, some diagnostic changes occur between toddlerhood and mid-childhood, which raises the question of whether infant markers remain associated with diagnosis into mid-childhood. METHODS: First, we tested whether infant neurocognitive markers (7-month neural response to eye gaze shifts and 14-month visual disengagement latencies) as well as an observational marker of emerging ASD behaviours (the Autism Observation Scale for Infants; AOSI) predicted ASD outcome in high-risk (HR) 7-year-olds with and without an ASD diagnosis (HR-ASD and HR-No ASD) and low risk (LR) controls. Second, we tested whether the neurocognitive markers offer predictive power over and above the AOSI. RESULTS: Both neurocognitive markers distinguished children with an ASD diagnosis at 7 years of age from those in the HR-No ASD and LR groups. Exploratory analysis suggested that neurocognitive markers may further differentiate stable versus lost/late diagnosis across the 3 to 7 year period, which will need to be tested in larger samples. At both 7 and 14 months, combining the neurocognitive marker with the AOSI offered a significantly improved model fit over the AOSI alone. CONCLUSIONS: Infant neurocognitive markers relate to ASD in mid-childhood, improving predictive power over and above an early observational marker. The findings have implications for understanding the neurodevelopmental mechanisms that lead from risk to disorder and for identification of potential targets of pre-emptive intervention. En ligne : http://dx.doi.org/10.1186/s13229-017-0167-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=329 [article] Neurocognitive and observational markers: prediction of autism spectrum disorder from infancy to mid-childhood [Texte imprimé et/ou numérique] / Rachael BEDFORD, Auteur ; T. GLIGA, Auteur ; E. SHEPHARD, Auteur ; M. ELSABBAGH, Auteur ; A. PICKLES, Auteur ; Tony CHARMAN, Auteur ; M. H. JOHNSON, Auteur . - 49p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 49p. Mots-clés : Autism  Diagnosis  High risk  Infants  Neurocognitive  Prediction  Siblings Index. décimale : PER Périodiques Résumé : BACKGROUND: Prospective studies of infants at high familial risk for autism spectrum disorder (ASD) have identified a number of putative early markers that are associated with ASD outcome at 3 years of age. However, some diagnostic changes occur between toddlerhood and mid-childhood, which raises the question of whether infant markers remain associated with diagnosis into mid-childhood. METHODS: First, we tested whether infant neurocognitive markers (7-month neural response to eye gaze shifts and 14-month visual disengagement latencies) as well as an observational marker of emerging ASD behaviours (the Autism Observation Scale for Infants; AOSI) predicted ASD outcome in high-risk (HR) 7-year-olds with and without an ASD diagnosis (HR-ASD and HR-No ASD) and low risk (LR) controls. Second, we tested whether the neurocognitive markers offer predictive power over and above the AOSI. RESULTS: Both neurocognitive markers distinguished children with an ASD diagnosis at 7 years of age from those in the HR-No ASD and LR groups. Exploratory analysis suggested that neurocognitive markers may further differentiate stable versus lost/late diagnosis across the 3 to 7 year period, which will need to be tested in larger samples. At both 7 and 14 months, combining the neurocognitive marker with the AOSI offered a significantly improved model fit over the AOSI alone. CONCLUSIONS: Infant neurocognitive markers relate to ASD in mid-childhood, improving predictive power over and above an early observational marker. The findings have implications for understanding the neurodevelopmental mechanisms that lead from risk to disorder and for identification of potential targets of pre-emptive intervention. En ligne : http://dx.doi.org/10.1186/s13229-017-0167-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=329

The EU-AIMS Longitudinal European Autism Project (LEAP): clinical characterisation / Tony CHARMAN in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 27p. Titre : The EU-AIMS Longitudinal European Autism Project (LEAP): clinical characterisation Type de document : Texte imprimé et/ou numérique Auteurs : Tony CHARMAN, Auteur ; E. LOTH, Auteur ; J. TILLMANN, Auteur ; D. CRAWLEY, Auteur ; C. WOOLDRIDGE, Auteur ; D. GOYARD, Auteur ; Jumana AHMAD, Auteur ; Bonnie AUYEUNG, Auteur ; S. AMBROSINO, Auteur ; Tobias BANASCHEWSKI, Auteur ; Simon BARON-COHEN, Auteur ; Sarah BAUMEISTER, Auteur ; C. BECKMANN, Auteur ; Sven BÖLTE, Auteur ; Thomas BOURGERON, Auteur ; Carsten BOURS, Auteur ; Michael BRAMMER, Auteur ; Daniel BRANDEIS, Auteur ; C. BROGNA, Auteur ; Y. DE BRUIJN, Auteur ; Bhismadev CHAKRABARTI, Auteur ; I. CORNELISSEN, Auteur ; F. D. ACQUA, Auteur ; G. DUMAS, Auteur ; S. DURSTON, Auteur ; C. ECKER, Auteur ; J. FAULKNER, Auteur ; V. FROUIN, Auteur ; P. GARCES, Auteur ; L. HAM, Auteur ; H. HAYWARD, Auteur ; J. HIPP, Auteur ; R. J. HOLT, Auteur ; J. ISAKSSON, Auteur ; M. H. JOHNSON, Auteur ; E. J. H. JONES, Auteur ; P. KUNDU, Auteur ; Meng-Chuan LAI, Auteur ; L. D'ARDHUY X, Auteur ; M. V. LOMBARDO, Auteur ; D. J. LYTHGOE, Auteur ; R. MANDL, Auteur ; L. MASON, Auteur ; A. MEYER-LINDENBERG, Auteur ; C. MOESSNANG, Auteur ; N. MUELLER, Auteur ; L. O'DWYER, Auteur ; M. OLDEHINKEL, Auteur ; B. ORANJE, Auteur ; Gahan PANDINA, Auteur ; A. M. PERSICO, Auteur ; B. RUGGERI, Auteur ; A. N. V. RUIGROK, Auteur ; J. SABET, Auteur ; R. SACCO, Auteur ; Antonia SAN JOSE CACERES, Auteur ; E. SIMONOFF, Auteur ; R. TORO, Auteur ; H. TOST, Auteur ; J. WALDMAN, Auteur ; S. C. R. WILLIAMS, Auteur ; M. P. ZWIERS, Auteur ; W. SPOOREN, Auteur ; D. G. M. MURPHY, Auteur ; Jan K. BUITELAAR, Auteur Article en page(s) : 27p. Langues : Anglais (eng) Mots-clés : Age  Autism  Autism spectrum disorder  Behaviours  Heterogeneity  Iq  Phenotype  Sex Index. décimale : PER Périodiques Résumé : BACKGROUND: The EU-AIMS Longitudinal European Autism Project (LEAP) is to date the largest multi-centre, multi-disciplinary observational study on biomarkers for autism spectrum disorder (ASD). The current paper describes the clinical characteristics of the LEAP cohort and examines age, sex and IQ differences in ASD core symptoms and common co-occurring psychiatric symptoms. A companion paper describes the overall design and experimental protocol and outlines the strategy to identify stratification biomarkers. METHODS: From six research centres in four European countries, we recruited 437 children and adults with ASD and 300 controls between the ages of 6 and 30 years with IQs varying between 50 and 148. We conducted in-depth clinical characterisation including a wide range of observational, interview and questionnaire measures of the ASD phenotype, as well as co-occurring psychiatric symptoms. RESULTS: The cohort showed heterogeneity in ASD symptom presentation, with only minimal to moderate site differences on core clinical and cognitive measures. On both parent-report interview and questionnaire measures, ASD symptom severity was lower in adults compared to children and adolescents. The precise pattern of differences varied across measures, but there was some evidence of both lower social symptoms and lower repetitive behaviour severity in adults. Males had higher ASD symptom scores than females on clinician-rated and parent interview diagnostic measures but not on parent-reported dimensional measures of ASD symptoms. In contrast, self-reported ASD symptom severity was higher in adults compared to adolescents, and in adult females compared to males. Higher scores on ASD symptom measures were moderately associated with lower IQ. Both inattentive and hyperactive/impulsive ADHD symptoms were lower in adults than in children and adolescents, and males with ASD had higher levels of inattentive and hyperactive/impulsive ADHD symptoms than females. CONCLUSIONS: The established phenotypic heterogeneity in ASD is well captured in the LEAP cohort. Variation both in core ASD symptom severity and in commonly co-occurring psychiatric symptoms were systematically associated with sex, age and IQ. The pattern of ASD symptom differences with age and sex also varied by whether these were clinician ratings or parent- or self-reported which has important implications for establishing stratification biomarkers and for their potential use as outcome measures in clinical trials. En ligne : http://dx.doi.org/10.1186/s13229-017-0145-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=329 [article] The EU-AIMS Longitudinal European Autism Project (LEAP): clinical characterisation [Texte imprimé et/ou numérique] / Tony CHARMAN, Auteur ; E. LOTH, Auteur ; J. TILLMANN, Auteur ; D. CRAWLEY, Auteur ; C. WOOLDRIDGE, Auteur ; D. GOYARD, Auteur ; Jumana AHMAD, Auteur ; Bonnie AUYEUNG, Auteur ; S. AMBROSINO, Auteur ; Tobias BANASCHEWSKI, Auteur ; Simon BARON-COHEN, Auteur ; Sarah BAUMEISTER, Auteur ; C. BECKMANN, Auteur ; Sven BÖLTE, Auteur ; Thomas BOURGERON, Auteur ; Carsten BOURS, Auteur ; Michael BRAMMER, Auteur ; Daniel BRANDEIS, Auteur ; C. BROGNA, Auteur ; Y. DE BRUIJN, Auteur ; Bhismadev CHAKRABARTI, Auteur ; I. CORNELISSEN, Auteur ; F. D. ACQUA, Auteur ; G. DUMAS, Auteur ; S. DURSTON, Auteur ; C. ECKER, Auteur ; J. FAULKNER, Auteur ; V. FROUIN, Auteur ; P. GARCES, Auteur ; L. HAM, Auteur ; H. HAYWARD, Auteur ; J. HIPP, Auteur ; R. J. HOLT, Auteur ; J. ISAKSSON, Auteur ; M. H. JOHNSON, Auteur ; E. J. H. JONES, Auteur ; P. KUNDU, Auteur ; Meng-Chuan LAI, Auteur ; L. D'ARDHUY X, Auteur ; M. V. LOMBARDO, Auteur ; D. J. LYTHGOE, Auteur ; R. MANDL, Auteur ; L. MASON, Auteur ; A. MEYER-LINDENBERG, Auteur ; C. MOESSNANG, Auteur ; N. MUELLER, Auteur ; L. O'DWYER, Auteur ; M. OLDEHINKEL, Auteur ; B. ORANJE, Auteur ; Gahan PANDINA, Auteur ; A. M. PERSICO, Auteur ; B. RUGGERI, Auteur ; A. N. V. RUIGROK, Auteur ; J. SABET, Auteur ; R. SACCO, Auteur ; Antonia SAN JOSE CACERES, Auteur ; E. SIMONOFF, Auteur ; R. TORO, Auteur ; H. TOST, Auteur ; J. WALDMAN, Auteur ; S. C. R. WILLIAMS, Auteur ; M. P. ZWIERS, Auteur ; W. SPOOREN, Auteur ; D. G. M. MURPHY, Auteur ; Jan K. BUITELAAR, Auteur . - 27p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 27p. Mots-clés : Age  Autism  Autism spectrum disorder  Behaviours  Heterogeneity  Iq  Phenotype  Sex Index. décimale : PER Périodiques Résumé : BACKGROUND: The EU-AIMS Longitudinal European Autism Project (LEAP) is to date the largest multi-centre, multi-disciplinary observational study on biomarkers for autism spectrum disorder (ASD). The current paper describes the clinical characteristics of the LEAP cohort and examines age, sex and IQ differences in ASD core symptoms and common co-occurring psychiatric symptoms. A companion paper describes the overall design and experimental protocol and outlines the strategy to identify stratification biomarkers. METHODS: From six research centres in four European countries, we recruited 437 children and adults with ASD and 300 controls between the ages of 6 and 30 years with IQs varying between 50 and 148. We conducted in-depth clinical characterisation including a wide range of observational, interview and questionnaire measures of the ASD phenotype, as well as co-occurring psychiatric symptoms. RESULTS: The cohort showed heterogeneity in ASD symptom presentation, with only minimal to moderate site differences on core clinical and cognitive measures. On both parent-report interview and questionnaire measures, ASD symptom severity was lower in adults compared to children and adolescents. The precise pattern of differences varied across measures, but there was some evidence of both lower social symptoms and lower repetitive behaviour severity in adults. Males had higher ASD symptom scores than females on clinician-rated and parent interview diagnostic measures but not on parent-reported dimensional measures of ASD symptoms. In contrast, self-reported ASD symptom severity was higher in adults compared to adolescents, and in adult females compared to males. Higher scores on ASD symptom measures were moderately associated with lower IQ. Both inattentive and hyperactive/impulsive ADHD symptoms were lower in adults than in children and adolescents, and males with ASD had higher levels of inattentive and hyperactive/impulsive ADHD symptoms than females. CONCLUSIONS: The established phenotypic heterogeneity in ASD is well captured in the LEAP cohort. Variation both in core ASD symptom severity and in commonly co-occurring psychiatric symptoms were systematically associated with sex, age and IQ. The pattern of ASD symptom differences with age and sex also varied by whether these were clinician ratings or parent- or self-reported which has important implications for establishing stratification biomarkers and for their potential use as outcome measures in clinical trials. En ligne : http://dx.doi.org/10.1186/s13229-017-0145-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=329

Leveraging blood serotonin as an endophenotype to identify de novo and rare variants involved in autism / R. CHEN in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 14p. Titre : Leveraging blood serotonin as an endophenotype to identify de novo and rare variants involved in autism Type de document : Texte imprimé et/ou numérique Auteurs : R. CHEN, Auteur ; L. K. DAVIS, Auteur ; S. GUTER, Auteur ; Q. WEI, Auteur ; S. JACOB, Auteur ; M. H. POTTER, Auteur ; Nancy J. COX, Auteur ; Edwin H. Jr COOK, Auteur ; J. S. SUTCLIFFE, Auteur ; B. LI, Auteur Article en page(s) : 14p. Langues : Anglais (eng) Mots-clés : Autism Spectrum Disorder/*genetics/metabolism  Endophenotypes/blood  Exome  Female  Forkhead Transcription Factors/*genetics  Genetic Predisposition to Disease  Humans  Jumonji Domain-Containing Histone Demethylases/*genetics  Male  *Mutation  Nuclear Proteins/*genetics  Repressor Proteins/*genetics  Sequence Analysis, DNA/methods  Serotonin/*blood  Signal Transduction  Ubiquitin-Specific Proteases/*genetics  *5-ht  *Autism  *Autism spectrum disorder  *Compound heterozygotes  *De novo mutation  *Endophenotype  *Group-wise transmission/disequilibrium test  *Hyperserotonemia  *Rare variants  *Serotonin  *Whole exome sequencing Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is one of the most highly heritable neuropsychiatric disorders, but underlying molecular mechanisms are still unresolved due to extreme locus heterogeneity. Leveraging meaningful endophenotypes or biomarkers may be an effective strategy to reduce heterogeneity to identify novel ASD genes. Numerous lines of evidence suggest a link between hyperserotonemia, i.e., elevated serotonin (5-hydroxytryptamine or 5-HT) in whole blood, and ASD. However, the genetic determinants of blood 5-HT level and their relationship to ASD are largely unknown. METHODS: In this study, pursuing the hypothesis that de novo variants (DNVs) and rare risk alleles acting in a recessive mode may play an important role in predisposition of hyperserotonemia in people with ASD, we carried out whole exome sequencing (WES) in 116 ASD parent-proband trios with most (107) probands having 5-HT measurements. RESULTS: Combined with published ASD DNVs, we identified USP15 as having recurrent de novo loss of function mutations and discovered evidence supporting two other known genes with recurrent DNVs (FOXP1 and KDM5B). Genes harboring functional DNVs significantly overlap with functional/disease gene sets known to be involved in ASD etiology, including FMRP targets and synaptic formation and transcriptional regulation genes. We grouped the probands into High-5HT and Normal-5HT groups based on normalized serotonin levels, and used network-based gene set enrichment analysis (NGSEA) to identify novel hyperserotonemia-related ASD genes based on LoF and missense DNVs. We found enrichment in the High-5HT group for a gene network module (DAWN-1) previously implicated in ASD, and this points to the TGF-beta pathway and cell junction processes. Through analysis of rare recessively acting variants (RAVs), we also found that rare compound heterozygotes (CHs) in the High-5HT group were enriched for loci in an ASD-associated gene set. Finally, we carried out rare variant group-wise transmission disequilibrium tests (gTDT) and observed significant association of rare variants in genes encoding a subset of the serotonin pathway with ASD. CONCLUSIONS: Our study identified USP15 as a novel gene implicated in ASD based on recurrent DNVs. It also demonstrates the potential value of 5-HT as an effective endophenotype for gene discovery in ASD, and the effectiveness of this strategy needs to be further explored in studies of larger sample sizes. En ligne : http://dx.doi.org/10.1186/s13229-017-0130-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=329 [article] Leveraging blood serotonin as an endophenotype to identify de novo and rare variants involved in autism [Texte imprimé et/ou numérique] / R. CHEN, Auteur ; L. K. DAVIS, Auteur ; S. GUTER, Auteur ; Q. WEI, Auteur ; S. JACOB, Auteur ; M. H. POTTER, Auteur ; Nancy J. COX, Auteur ; Edwin H. Jr COOK, Auteur ; J. S. SUTCLIFFE, Auteur ; B. LI, Auteur . - 14p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 14p. Mots-clés : Autism Spectrum Disorder/*genetics/metabolism  Endophenotypes/blood  Exome  Female  Forkhead Transcription Factors/*genetics  Genetic Predisposition to Disease  Humans  Jumonji Domain-Containing Histone Demethylases/*genetics  Male  *Mutation  Nuclear Proteins/*genetics  Repressor Proteins/*genetics  Sequence Analysis, DNA/methods  Serotonin/*blood  Signal Transduction  Ubiquitin-Specific Proteases/*genetics  *5-ht  *Autism  *Autism spectrum disorder  *Compound heterozygotes  *De novo mutation  *Endophenotype  *Group-wise transmission/disequilibrium test  *Hyperserotonemia  *Rare variants  *Serotonin  *Whole exome sequencing Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is one of the most highly heritable neuropsychiatric disorders, but underlying molecular mechanisms are still unresolved due to extreme locus heterogeneity. Leveraging meaningful endophenotypes or biomarkers may be an effective strategy to reduce heterogeneity to identify novel ASD genes. Numerous lines of evidence suggest a link between hyperserotonemia, i.e., elevated serotonin (5-hydroxytryptamine or 5-HT) in whole blood, and ASD. However, the genetic determinants of blood 5-HT level and their relationship to ASD are largely unknown. METHODS: In this study, pursuing the hypothesis that de novo variants (DNVs) and rare risk alleles acting in a recessive mode may play an important role in predisposition of hyperserotonemia in people with ASD, we carried out whole exome sequencing (WES) in 116 ASD parent-proband trios with most (107) probands having 5-HT measurements. RESULTS: Combined with published ASD DNVs, we identified USP15 as having recurrent de novo loss of function mutations and discovered evidence supporting two other known genes with recurrent DNVs (FOXP1 and KDM5B). Genes harboring functional DNVs significantly overlap with functional/disease gene sets known to be involved in ASD etiology, including FMRP targets and synaptic formation and transcriptional regulation genes. We grouped the probands into High-5HT and Normal-5HT groups based on normalized serotonin levels, and used network-based gene set enrichment analysis (NGSEA) to identify novel hyperserotonemia-related ASD genes based on LoF and missense DNVs. We found enrichment in the High-5HT group for a gene network module (DAWN-1) previously implicated in ASD, and this points to the TGF-beta pathway and cell junction processes. Through analysis of rare recessively acting variants (RAVs), we also found that rare compound heterozygotes (CHs) in the High-5HT group were enriched for loci in an ASD-associated gene set. Finally, we carried out rare variant group-wise transmission disequilibrium tests (gTDT) and observed significant association of rare variants in genes encoding a subset of the serotonin pathway with ASD. CONCLUSIONS: Our study identified USP15 as a novel gene implicated in ASD based on recurrent DNVs. It also demonstrates the potential value of 5-HT as an effective endophenotype for gene discovery in ASD, and the effectiveness of this strategy needs to be further explored in studies of larger sample sizes. En ligne : http://dx.doi.org/10.1186/s13229-017-0130-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=329

ADHD-related symptoms and attention profiles in the unaffected siblings of probands with autism spectrum disorder: focus on the subtypes of autism and Asperger's disorder / Yi-Ling CHIEN in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 37p. Titre : ADHD-related symptoms and attention profiles in the unaffected siblings of probands with autism spectrum disorder: focus on the subtypes of autism and Asperger's disorder Type de document : Texte imprimé et/ou numérique Auteurs : Yi-Ling CHIEN, Auteur ; Miao-Churn CHOU, Auteur ; Yen-Nan CHIU, Auteur ; W. J. CHOU, Auteur ; Y. Y. WU, Auteur ; W. C. TSAI, Auteur ; S. S. GAU, Auteur Article en page(s) : 37p. Langues : Anglais (eng) Mots-clés : Attention  Autism spectrum disorder  Continuous performance test  Endophenotype  Sibling Index. décimale : PER Périodiques Résumé : BACKGROUND: The presence of attention-deficit/hyperactive disorder (ADHD) symptoms and impaired attention performance are commonly noted in individuals with autism spectrum disorder (ASD). However, little is known about attention performance in their unaffected siblings. This study aimed to investigate the ADHD-related traits and attention performance in unaffected siblings of probands with autism and Asperger syndrome (AS), as well as the clinical correlates of ADHD-related traits. METHODS: We assessed the intention, hyperactivity-impulsivity, and oppositional symptoms, and attention profiles of 199 probands with a diagnosis of ASD (122 autism, 77 AS), their unaffected siblings, and 196 typically developing controls (TD) by their parents' reports on the ADHD-related symptoms and the Connors' Continuous Performance Test (CCPT), respectively. RESULTS: Compared to TD, unaffected siblings of ASD probands were more hyperactive/impulsive and oppositional, particularly unaffected siblings of AS probands. In CCPT, unaffected siblings of AS have intermediate levels of performance between probands with AS and TD on focused attention and sustained attention but were not statistically different from AS probands or TD in these attention profiles. In contrast, unaffected siblings of autism probands have significantly better CCPT performance when compared to autism probands but not to TD. In addition, stereotyped behaviors predicted ADHD-related traits in both sibling groups, but distinctive patterns of other correlates for ADHD-related traits were found between the two sibling groups. CONCLUSIONS: This work suggested that unaffected siblings of AS, but not autism, have more hyperactive/impulsive traits and a trend of pervasive attention deficits assessed by CCPT which might serve as potential endophenotypes for genetic studies in AS. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01582256. En ligne : http://dx.doi.org/10.1186/s13229-017-0153-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=329 [article] ADHD-related symptoms and attention profiles in the unaffected siblings of probands with autism spectrum disorder: focus on the subtypes of autism and Asperger's disorder [Texte imprimé et/ou numérique] / Yi-Ling CHIEN, Auteur ; Miao-Churn CHOU, Auteur ; Yen-Nan CHIU, Auteur ; W. J. CHOU, Auteur ; Y. Y. WU, Auteur ; W. C. TSAI, Auteur ; S. S. GAU, Auteur . - 37p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 37p. Mots-clés : Attention  Autism spectrum disorder  Continuous performance test  Endophenotype  Sibling Index. décimale : PER Périodiques Résumé : BACKGROUND: The presence of attention-deficit/hyperactive disorder (ADHD) symptoms and impaired attention performance are commonly noted in individuals with autism spectrum disorder (ASD). However, little is known about attention performance in their unaffected siblings. This study aimed to investigate the ADHD-related traits and attention performance in unaffected siblings of probands with autism and Asperger syndrome (AS), as well as the clinical correlates of ADHD-related traits. METHODS: We assessed the intention, hyperactivity-impulsivity, and oppositional symptoms, and attention profiles of 199 probands with a diagnosis of ASD (122 autism, 77 AS), their unaffected siblings, and 196 typically developing controls (TD) by their parents' reports on the ADHD-related symptoms and the Connors' Continuous Performance Test (CCPT), respectively. RESULTS: Compared to TD, unaffected siblings of ASD probands were more hyperactive/impulsive and oppositional, particularly unaffected siblings of AS probands. In CCPT, unaffected siblings of AS have intermediate levels of performance between probands with AS and TD on focused attention and sustained attention but were not statistically different from AS probands or TD in these attention profiles. In contrast, unaffected siblings of autism probands have significantly better CCPT performance when compared to autism probands but not to TD. In addition, stereotyped behaviors predicted ADHD-related traits in both sibling groups, but distinctive patterns of other correlates for ADHD-related traits were found between the two sibling groups. CONCLUSIONS: This work suggested that unaffected siblings of AS, but not autism, have more hyperactive/impulsive traits and a trend of pervasive attention deficits assessed by CCPT which might serve as potential endophenotypes for genetic studies in AS. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01582256. En ligne : http://dx.doi.org/10.1186/s13229-017-0153-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=329

Typical versus delayed speech onset influences verbal reporting of autistic interests / L. CHIODO in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 35p. Titre : Typical versus delayed speech onset influences verbal reporting of autistic interests Type de document : Texte imprimé et/ou numérique Auteurs : L. CHIODO, Auteur ; S. MAJERUS, Auteur ; Laurent MOTTRON, Auteur Article en page(s) : 35p. Langues : Anglais (eng) Mots-clés : Asperger syndrome  Autism spectrum  Heterogeneity  Restricted interests  Speech onset delay Index. décimale : PER Périodiques Résumé : BACKGROUND: The distinction between autism and Asperger syndrome has been abandoned in the DSM-5. However, this clinical categorization largely overlaps with the presence or absence of a speech onset delay which is associated with clinical, cognitive, and neural differences. It is unknown whether these different speech development pathways and associated cognitive differences are involved in the heterogeneity of the restricted interests that characterize autistic adults. METHOD: This study tested the hypothesis that speech onset delay, or conversely, early mastery of speech, orients the nature and verbal reporting of adult autistic interests. The occurrence of a priori defined descriptors for perceptual and thematic dimensions were determined, as well as the perceived function and benefits, in the response of autistic people to a semi-structured interview on their intense interests. The number of words, grammatical categories, and proportion of perceptual/thematic descriptors were computed and compared between groups by variance analyses. The participants comprised 40 autistic adults grouped according to the presence (N = 20) or absence (N = 20) of speech onset delay, as well as 20 non-autistic adults, also with intense interests, matched for non-verbal intelligence using Raven's Progressive Matrices. RESULTS: The overall nature, function, and benefit of intense interests were similar across autistic subgroups, and between autistic and non-autistic groups. However, autistic participants with a history of speech onset delay used more perceptual than thematic descriptors when talking about their interests, whereas the opposite was true for autistic individuals without speech onset delay. This finding remained significant after controlling for linguistic differences observed between the two groups. CONCLUSIONS: Verbal reporting, but not the nature or positive function, of intense interests differed between adult autistic individuals depending on their speech acquisition history: oral reporting of intense interests was characterized by perceptual dominance for autistic individuals with delayed speech onset and thematic dominance for those without. This may contribute to the heterogeneous presentation observed among autistic adults of normal intelligence. En ligne : http://dx.doi.org/10.1186/s13229-017-0155-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=329 [article] Typical versus delayed speech onset influences verbal reporting of autistic interests [Texte imprimé et/ou numérique] / L. CHIODO, Auteur ; S. MAJERUS, Auteur ; Laurent MOTTRON, Auteur . - 35p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 35p. Mots-clés : Asperger syndrome  Autism spectrum  Heterogeneity  Restricted interests  Speech onset delay Index. décimale : PER Périodiques Résumé : BACKGROUND: The distinction between autism and Asperger syndrome has been abandoned in the DSM-5. However, this clinical categorization largely overlaps with the presence or absence of a speech onset delay which is associated with clinical, cognitive, and neural differences. It is unknown whether these different speech development pathways and associated cognitive differences are involved in the heterogeneity of the restricted interests that characterize autistic adults. METHOD: This study tested the hypothesis that speech onset delay, or conversely, early mastery of speech, orients the nature and verbal reporting of adult autistic interests. The occurrence of a priori defined descriptors for perceptual and thematic dimensions were determined, as well as the perceived function and benefits, in the response of autistic people to a semi-structured interview on their intense interests. The number of words, grammatical categories, and proportion of perceptual/thematic descriptors were computed and compared between groups by variance analyses. The participants comprised 40 autistic adults grouped according to the presence (N = 20) or absence (N = 20) of speech onset delay, as well as 20 non-autistic adults, also with intense interests, matched for non-verbal intelligence using Raven's Progressive Matrices. RESULTS: The overall nature, function, and benefit of intense interests were similar across autistic subgroups, and between autistic and non-autistic groups. However, autistic participants with a history of speech onset delay used more perceptual than thematic descriptors when talking about their interests, whereas the opposite was true for autistic individuals without speech onset delay. This finding remained significant after controlling for linguistic differences observed between the two groups. CONCLUSIONS: Verbal reporting, but not the nature or positive function, of intense interests differed between adult autistic individuals depending on their speech acquisition history: oral reporting of intense interests was characterized by perceptual dominance for autistic individuals with delayed speech onset and thematic dominance for those without. This may contribute to the heterogeneous presentation observed among autistic adults of normal intelligence. En ligne : http://dx.doi.org/10.1186/s13229-017-0155-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=329

Critical region within 22q11.2 linked to higher rate of autism spectrum disorder / Caitlin C. CLEMENTS in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 58p. Titre : Critical region within 22q11.2 linked to higher rate of autism spectrum disorder Type de document : Texte imprimé et/ou numérique Auteurs : Caitlin C. CLEMENTS, Auteur ; T. L. WENGER, Auteur ; A. R. ZOLTOWSKI, Auteur ; Jennifer R. BERTOLLO, Auteur ; J. S. MILLER, Auteur ; A. B. DE MARCHENA, Auteur ; L. M. MITTEER, Auteur ; J. C. CAREY, Auteur ; B. E. YERYS, Auteur ; E. H. ZACKAI, Auteur ; B. S. EMANUEL, Auteur ; D. M. MCDONALD-MCGINN, Auteur ; Robert T. SCHULTZ, Auteur Article en page(s) : 58p. Langues : Anglais (eng) Mots-clés : 22q11.2 deletion syndrome  22q11.2 duplication syndrome  Atypical  Autism spectrum disorder  Face processing  Nested  Prosopagnosia  Ranbp1  Screening  Syndromic autism Index. décimale : PER Périodiques Résumé : BACKGROUND: Previous studies have reported no clear critical region for medical comorbidities in children with deletions or duplications of 22q11.2. The purpose of this study was to evaluate whether individuals with small nested deletions or duplications of the LCR-A to B region of 22q11.2 show an elevated rate of autism spectrum disorder (ASD) compared to individuals with deletions or duplications that do not include this region. METHODS: We recruited 46 patients with nested deletions (n = 33) or duplications (n = 13) of 22q11.2, including LCR-A to B (ndel = 11), LCR-A to C (ndel = 4), LCR-B to D (ndel = 14; ndup = 8), LCR-C to D (ndel = 4; ndup = 2), and smaller nested regions (n = 3). Parent questionnaire, record review, and, for a subset, in-person evaluation were used for ASD diagnostic classification. Rates of ASD in individuals with involvement of LCR-B to LCR-D were compared with Fisher's exact test to LCR-A to LCR-B for deletions, and to a previously published sample of LCR-A to LCR-D for duplications. The rates of medical comorbidities and psychiatric diagnoses were determined from questionnaires and chart review. We also report group mean differences on psychiatric questionnaires. RESULTS: Individuals with deletions involving LCR-A to B showed a 39-44% rate of ASD compared to 0% in individuals whose deletions did not involve LCR-A to B. We observed similar rates of medical comorbidities in individuals with involvement of LCR-A to B and LCR-B to D for both duplications and deletions, consistent with prior studies. CONCLUSIONS: Children with nested deletions of 22q11.2 may be at greater risk for autism spectrum disorder if the region includes LCR-A to LCR-B. Replication is needed. En ligne : http://dx.doi.org/10.1186/s13229-017-0171-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=329 [article] Critical region within 22q11.2 linked to higher rate of autism spectrum disorder [Texte imprimé et/ou numérique] / Caitlin C. CLEMENTS, Auteur ; T. L. WENGER, Auteur ; A. R. ZOLTOWSKI, Auteur ; Jennifer R. BERTOLLO, Auteur ; J. S. MILLER, Auteur ; A. B. DE MARCHENA, Auteur ; L. M. MITTEER, Auteur ; J. C. CAREY, Auteur ; B. E. YERYS, Auteur ; E. H. ZACKAI, Auteur ; B. S. EMANUEL, Auteur ; D. M. MCDONALD-MCGINN, Auteur ; Robert T. SCHULTZ, Auteur . - 58p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 58p. Mots-clés : 22q11.2 deletion syndrome  22q11.2 duplication syndrome  Atypical  Autism spectrum disorder  Face processing  Nested  Prosopagnosia  Ranbp1  Screening  Syndromic autism Index. décimale : PER Périodiques Résumé : BACKGROUND: Previous studies have reported no clear critical region for medical comorbidities in children with deletions or duplications of 22q11.2. The purpose of this study was to evaluate whether individuals with small nested deletions or duplications of the LCR-A to B region of 22q11.2 show an elevated rate of autism spectrum disorder (ASD) compared to individuals with deletions or duplications that do not include this region. METHODS: We recruited 46 patients with nested deletions (n = 33) or duplications (n = 13) of 22q11.2, including LCR-A to B (ndel = 11), LCR-A to C (ndel = 4), LCR-B to D (ndel = 14; ndup = 8), LCR-C to D (ndel = 4; ndup = 2), and smaller nested regions (n = 3). Parent questionnaire, record review, and, for a subset, in-person evaluation were used for ASD diagnostic classification. Rates of ASD in individuals with involvement of LCR-B to LCR-D were compared with Fisher's exact test to LCR-A to LCR-B for deletions, and to a previously published sample of LCR-A to LCR-D for duplications. The rates of medical comorbidities and psychiatric diagnoses were determined from questionnaires and chart review. We also report group mean differences on psychiatric questionnaires. RESULTS: Individuals with deletions involving LCR-A to B showed a 39-44% rate of ASD compared to 0% in individuals whose deletions did not involve LCR-A to B. We observed similar rates of medical comorbidities in individuals with involvement of LCR-A to B and LCR-B to D for both duplications and deletions, consistent with prior studies. CONCLUSIONS: Children with nested deletions of 22q11.2 may be at greater risk for autism spectrum disorder if the region includes LCR-A to LCR-B. Replication is needed. En ligne : http://dx.doi.org/10.1186/s13229-017-0171-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=329

Autistic traits affect interpersonal motor coordination by modulating strategic use of role-based behavior / A. CURIONI in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 23p. Titre : Autistic traits affect interpersonal motor coordination by modulating strategic use of role-based behavior Type de document : Texte imprimé et/ou numérique Auteurs : A. CURIONI, Auteur ; I. MINIO-PALUELLO, Auteur ; L. M. SACHELI, Auteur ; M. CANDIDI, Auteur ; S. M. AGLIOTI, Auteur Article en page(s) : 23p. Langues : Anglais (eng) Mots-clés : Autism  Cooperation  Coordination strategies  Interpersonal coordination  Joint actions  Role taking Index. décimale : PER Périodiques Résumé : BACKGROUND: Despite the fact that deficits in social communication and interaction are at the core of Autism Spectrum Conditions (ASC), no study has yet tested individuals on a continuum from neurotypical development to autism in an on-line, cooperative, joint action task. In our study, we aimed to assess whether the degree of autistic traits affects participants' ability to modulate their motor behavior while interacting in a Joint Grasping task and according to their given role. METHODS: Sixteen pairs of adult participants played a cooperative social interactive game in which they had to synchronize their reach-to-grasp movements. Pairs were comprised of one ASC and one neurotypical with no cognitive disability. In alternate experimental blocks, one participant knew what action to perform (instructed role) while the other had to infer it from his/her partner's action (adaptive role). When in the adaptive condition, participants were told to respond with an action that was either opposite or similar to their partner. Participants also played a non-social control game in which they had to synchronize with a non-biological stimulus. RESULTS: In the social interactive task, higher degree of autistic traits predicted less ability to modulate joint action according to one's interactive role. In the non-social task, autistic traits did not predict differences in movement preparation and planning, thus ruling out the possibility that social interactive task results were due to basic motor or executive function difficulties. Furthermore, when participants played the non-social game, the higher their autistic traits, the more they were interfered by the non-biological stimulus. CONCLUSIONS: Our study shows for the first time that high autistic traits predict a stereotypical interaction style when individuals are required to modulate their movements in order to coordinate with their partner according to their role in a joint action task. Specifically, the infrequent emergence of role-based motor behavior modulation during on-line motor cooperation in participants with high autistic traits sheds light on the numerous difficulties ASC have in nonverbal social interactions. En ligne : http://dx.doi.org/10.1186/s13229-017-0141-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=329 [article] Autistic traits affect interpersonal motor coordination by modulating strategic use of role-based behavior [Texte imprimé et/ou numérique] / A. CURIONI, Auteur ; I. MINIO-PALUELLO, Auteur ; L. M. SACHELI, Auteur ; M. CANDIDI, Auteur ; S. M. AGLIOTI, Auteur . - 23p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 23p. Mots-clés : Autism  Cooperation  Coordination strategies  Interpersonal coordination  Joint actions  Role taking Index. décimale : PER Périodiques Résumé : BACKGROUND: Despite the fact that deficits in social communication and interaction are at the core of Autism Spectrum Conditions (ASC), no study has yet tested individuals on a continuum from neurotypical development to autism in an on-line, cooperative, joint action task. In our study, we aimed to assess whether the degree of autistic traits affects participants' ability to modulate their motor behavior while interacting in a Joint Grasping task and according to their given role. METHODS: Sixteen pairs of adult participants played a cooperative social interactive game in which they had to synchronize their reach-to-grasp movements. Pairs were comprised of one ASC and one neurotypical with no cognitive disability. In alternate experimental blocks, one participant knew what action to perform (instructed role) while the other had to infer it from his/her partner's action (adaptive role). When in the adaptive condition, participants were told to respond with an action that was either opposite or similar to their partner. Participants also played a non-social control game in which they had to synchronize with a non-biological stimulus. RESULTS: In the social interactive task, higher degree of autistic traits predicted less ability to modulate joint action according to one's interactive role. In the non-social task, autistic traits did not predict differences in movement preparation and planning, thus ruling out the possibility that social interactive task results were due to basic motor or executive function difficulties. Furthermore, when participants played the non-social game, the higher their autistic traits, the more they were interfered by the non-biological stimulus. CONCLUSIONS: Our study shows for the first time that high autistic traits predict a stereotypical interaction style when individuals are required to modulate their movements in order to coordinate with their partner according to their role in a joint action task. Specifically, the infrequent emergence of role-based motor behavior modulation during on-line motor cooperation in participants with high autistic traits sheds light on the numerous difficulties ASC have in nonverbal social interactions. En ligne : http://dx.doi.org/10.1186/s13229-017-0141-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=329

The GapMap project: a mobile surveillance system to map diagnosed autism cases and gaps in autism services globally / J. DANIELS in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 55p. Titre : The GapMap project: a mobile surveillance system to map diagnosed autism cases and gaps in autism services globally Type de document : Texte imprimé et/ou numérique Auteurs : J. DANIELS, Auteur ; J. SCHWARTZ, Auteur ; N. ALBERT, Auteur ; M. DU, Auteur ; Dennis P. WALL, Auteur Article en page(s) : 55p. Langues : Anglais (eng) Mots-clés : Autism  Autism spectrum disorder  Crowdsourcing  Epidemiology  Prevalence  Resources Index. décimale : PER Périodiques Résumé : Although the number of autism diagnoses is on the rise, we have no evidence-based tracking of size and severity of gaps in access to autism-related resources, nor do we have methods to geographically triangulate the locations of the widest gaps in either the US or elsewhere across the globe. To combat these related issues of (1) mapping diagnosed cases of autism and (2) quantifying gaps in access to key intervention services, we have constructed a crowd-based mobile platform called "GapMap" (http://gapmap.stanford.edu) for real-time tracking of autism prevalence and autism-related resources that can be accessed from any mobile device with cellular or wireless connectivity. Now in beta, our aim is for this Android/iOS compatible mobile tool to simultaneously crowd-enroll the massive and growing community of families with autism to capture geographic, diagnostic, and resource usage information while automatically computing prevalence at granular geographical scales to yield a more complete and dynamic understanding of autism resource epidemiology. En ligne : http://dx.doi.org/10.1186/s13229-017-0163-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330 [article] The GapMap project: a mobile surveillance system to map diagnosed autism cases and gaps in autism services globally [Texte imprimé et/ou numérique] / J. DANIELS, Auteur ; J. SCHWARTZ, Auteur ; N. ALBERT, Auteur ; M. DU, Auteur ; Dennis P. WALL, Auteur . - 55p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 55p. Mots-clés : Autism  Autism spectrum disorder  Crowdsourcing  Epidemiology  Prevalence  Resources Index. décimale : PER Périodiques Résumé : Although the number of autism diagnoses is on the rise, we have no evidence-based tracking of size and severity of gaps in access to autism-related resources, nor do we have methods to geographically triangulate the locations of the widest gaps in either the US or elsewhere across the globe. To combat these related issues of (1) mapping diagnosed cases of autism and (2) quantifying gaps in access to key intervention services, we have constructed a crowd-based mobile platform called "GapMap" (http://gapmap.stanford.edu) for real-time tracking of autism prevalence and autism-related resources that can be accessed from any mobile device with cellular or wireless connectivity. Now in beta, our aim is for this Android/iOS compatible mobile tool to simultaneously crowd-enroll the massive and growing community of families with autism to capture geographic, diagnostic, and resource usage information while automatically computing prevalence at granular geographical scales to yield a more complete and dynamic understanding of autism resource epidemiology. En ligne : http://dx.doi.org/10.1186/s13229-017-0163-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330

Replicable in vivo physiological and behavioral phenotypes of the Shank3B null mutant mouse model of autism / S. C. DHAMNE in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 26p. Titre : Replicable in vivo physiological and behavioral phenotypes of the Shank3B null mutant mouse model of autism Type de document : Texte imprimé et/ou numérique Auteurs : S. C. DHAMNE, Auteur ; J. L. SILVERMAN, Auteur ; C. E. SUPER, Auteur ; S. H. T. LAMMERS, Auteur ; M. Q. HAMEED, Auteur ; M. E. MODI, Auteur ; N. A. COPPING, Auteur ; M. C. PRIDE, Auteur ; D. G. SMITH, Auteur ; A. ROTENBERG, Auteur ; J. N. CRAWLEY, Auteur ; M. SAHIN, Auteur Article en page(s) : 26p. Langues : Anglais (eng) Mots-clés : Anxiety  Autism  Gamma oscillations  Pentylenetetrazol  Repetitive behavior  Shank3B  Social behavior Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is a clinically and biologically heterogeneous condition characterized by social, repetitive, and sensory behavioral abnormalities. No treatments are approved for the core diagnostic symptoms of ASD. To enable the earliest stages of therapeutic discovery and development for ASD, robust and reproducible behavioral phenotypes and biological markers are essential to establish in preclinical animal models. The goal of this study was to identify electroencephalographic (EEG) and behavioral phenotypes that are replicable between independent cohorts in a mouse model of ASD. The larger goal of our strategy is to empower the preclinical biomedical ASD research field by generating robust and reproducible behavioral and physiological phenotypes in animal models of ASD, for the characterization of mechanistic underpinnings of ASD-relevant phenotypes, and to ensure reliability for the discovery of novel therapeutics. Genetic disruption of the SHANK3 gene, a scaffolding protein involved in the stability of the postsynaptic density in excitatory synapses, is thought to be responsible for a relatively large number of cases of ASD. Therefore, we have thoroughly characterized the robustness of ASD-relevant behavioral phenotypes in two cohorts, and for the first time quantified translational EEG activity in Shank3B null mutant mice. METHODS: In vivo physiology and behavioral assays were conducted in two independently bred and tested full cohorts of Shank3B null mutant (Shank3B KO) and wildtype littermate control (WT) mice. EEG was recorded via wireless implanted telemeters for 7 days of baseline followed by 20 min of recording following pentylenetetrazol (PTZ) challenge. Behaviors relevant to the diagnostic and associated symptoms of ASD were tested on a battery of established behavioral tests. Assays were designed to reproduce and expand on the original behavioral characterization of Shank3B KO mice. Two or more corroborative tests were conducted within each behavioral domain, including social, repetitive, cognitive, anxiety-related, sensory, and motor categories of assays. RESULTS: Relative to WT mice, Shank3B KO mice displayed a dramatic resistance to PTZ seizure induction and an enhancement of gamma band oscillatory EEG activity indicative of enhanced inhibitory tone. These findings replicated in two separate cohorts. Behaviorally, Shank3B KO mice exhibited repetitive grooming, deficits in aspects of reciprocal social interactions and vocalizations, and reduced open field activity, as well as variable deficits in sensory responses, anxiety-related behaviors, learning and memory. CONCLUSIONS: Robust animal models and quantitative, replicable biomarkers of neural dysfunction are needed to decrease risk and enable successful drug discovery and development for ASD and other neurodevelopmental disorders. Complementary to the replicated behavioral phenotypes of the Shank3B mutant mouse is the new identification of a robust, translational in vivo neurophysiological phenotype. Our findings provide strong evidence for robustness and replicability of key translational phenotypes in Shank3B mutant mice and support the usefulness of this mouse model of ASD for therapeutic discovery. En ligne : http://dx.doi.org/10.1186/s13229-017-0142-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330 [article] Replicable in vivo physiological and behavioral phenotypes of the Shank3B null mutant mouse model of autism [Texte imprimé et/ou numérique] / S. C. DHAMNE, Auteur ; J. L. SILVERMAN, Auteur ; C. E. SUPER, Auteur ; S. H. T. LAMMERS, Auteur ; M. Q. HAMEED, Auteur ; M. E. MODI, Auteur ; N. A. COPPING, Auteur ; M. C. PRIDE, Auteur ; D. G. SMITH, Auteur ; A. ROTENBERG, Auteur ; J. N. CRAWLEY, Auteur ; M. SAHIN, Auteur . - 26p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 26p. Mots-clés : Anxiety  Autism  Gamma oscillations  Pentylenetetrazol  Repetitive behavior  Shank3B  Social behavior Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is a clinically and biologically heterogeneous condition characterized by social, repetitive, and sensory behavioral abnormalities. No treatments are approved for the core diagnostic symptoms of ASD. To enable the earliest stages of therapeutic discovery and development for ASD, robust and reproducible behavioral phenotypes and biological markers are essential to establish in preclinical animal models. The goal of this study was to identify electroencephalographic (EEG) and behavioral phenotypes that are replicable between independent cohorts in a mouse model of ASD. The larger goal of our strategy is to empower the preclinical biomedical ASD research field by generating robust and reproducible behavioral and physiological phenotypes in animal models of ASD, for the characterization of mechanistic underpinnings of ASD-relevant phenotypes, and to ensure reliability for the discovery of novel therapeutics. Genetic disruption of the SHANK3 gene, a scaffolding protein involved in the stability of the postsynaptic density in excitatory synapses, is thought to be responsible for a relatively large number of cases of ASD. Therefore, we have thoroughly characterized the robustness of ASD-relevant behavioral phenotypes in two cohorts, and for the first time quantified translational EEG activity in Shank3B null mutant mice. METHODS: In vivo physiology and behavioral assays were conducted in two independently bred and tested full cohorts of Shank3B null mutant (Shank3B KO) and wildtype littermate control (WT) mice. EEG was recorded via wireless implanted telemeters for 7 days of baseline followed by 20 min of recording following pentylenetetrazol (PTZ) challenge. Behaviors relevant to the diagnostic and associated symptoms of ASD were tested on a battery of established behavioral tests. Assays were designed to reproduce and expand on the original behavioral characterization of Shank3B KO mice. Two or more corroborative tests were conducted within each behavioral domain, including social, repetitive, cognitive, anxiety-related, sensory, and motor categories of assays. RESULTS: Relative to WT mice, Shank3B KO mice displayed a dramatic resistance to PTZ seizure induction and an enhancement of gamma band oscillatory EEG activity indicative of enhanced inhibitory tone. These findings replicated in two separate cohorts. Behaviorally, Shank3B KO mice exhibited repetitive grooming, deficits in aspects of reciprocal social interactions and vocalizations, and reduced open field activity, as well as variable deficits in sensory responses, anxiety-related behaviors, learning and memory. CONCLUSIONS: Robust animal models and quantitative, replicable biomarkers of neural dysfunction are needed to decrease risk and enable successful drug discovery and development for ASD and other neurodevelopmental disorders. Complementary to the replicated behavioral phenotypes of the Shank3B mutant mouse is the new identification of a robust, translational in vivo neurophysiological phenotype. Our findings provide strong evidence for robustness and replicability of key translational phenotypes in Shank3B mutant mice and support the usefulness of this mouse model of ASD for therapeutic discovery. En ligne : http://dx.doi.org/10.1186/s13229-017-0142-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330

No evidence of early head circumference enlargements in children later diagnosed with autism in Israel / I. DINSTEIN in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 15p. Titre : No evidence of early head circumference enlargements in children later diagnosed with autism in Israel Type de document : Texte imprimé et/ou numérique Auteurs : I. DINSTEIN, Auteur ; S. HAAR, Auteur ; S. ATSMON, Auteur ; H. SCHTAERMAN, Auteur Article en page(s) : 15p. Langues : Anglais (eng) Mots-clés : Autistic Disorder/*diagnosis  Body Height  Body Weight  Cephalometry/*methods  Child, Preschool  Female  Head/*growth & development  Humans  Infant  Israel  Male  Retrospective Studies  *Autism  *Biomarker  *Early detection  *Head circumference  *Neuroanatomy Index. décimale : PER Périodiques Résumé : BACKGROUND: Large controversy exists regarding the potential existence and clinical significance of larger brain volumes in toddlers who later develop autism. Assessing this relationship is important for determining the clinical utility of early head circumference (HC) measures and for assessing the validity of the early overgrowth hypothesis of autism, which suggests that early accelerated brain development may be a hallmark of the disorder. METHODS: We performed a retrospective comparison of HC, height, and weight measurements between 66 toddlers who were later diagnosed with autism and 66 matched controls. These toddlers represent an unbiased regional sample from a single health service provider in the southern district of Israel. On average, participating toddlers had >8 measurements between birth and the age of two, which enabled us to characterize individual HC, height, and weight development with high precision and fit a negative exponential growth model to the data of each toddler with exceptional accuracy. RESULTS: The analyses revealed that HC sizes and growth rates were not significantly larger in toddlers with autism even when stratifying the autism group based on verbal capabilities at the time of diagnosis. In addition, there were no significant correlations between ADOS scores at the time of diagnosis and HC at any time-point during the first 2 years of life. CONCLUSIONS: These negative results add to accumulating evidence, which suggest that brain volume is not necessarily larger in toddlers who develop autism. We believe that conflicting results reported in other studies are due to small sample sizes, use of misleading population norms, changes in the clinical definition of autism over time, and/or inclusion of individuals with syndromic autism. While abnormally large brains may be evident in some individuals with autism and more clearly visible in MRI scans, converging evidence from this and other studies suggests that enlarged HC is not a common etiology of the entire autism population. Early HC measures, therefore, offer very limited clinical utility for assessment of autism risk in the general population. En ligne : http://dx.doi.org/10.1186/s13229-017-0129-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330 [article] No evidence of early head circumference enlargements in children later diagnosed with autism in Israel [Texte imprimé et/ou numérique] / I. DINSTEIN, Auteur ; S. HAAR, Auteur ; S. ATSMON, Auteur ; H. SCHTAERMAN, Auteur . - 15p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 15p. Mots-clés : Autistic Disorder/*diagnosis  Body Height  Body Weight  Cephalometry/*methods  Child, Preschool  Female  Head/*growth & development  Humans  Infant  Israel  Male  Retrospective Studies  *Autism  *Biomarker  *Early detection  *Head circumference  *Neuroanatomy Index. décimale : PER Périodiques Résumé : BACKGROUND: Large controversy exists regarding the potential existence and clinical significance of larger brain volumes in toddlers who later develop autism. Assessing this relationship is important for determining the clinical utility of early head circumference (HC) measures and for assessing the validity of the early overgrowth hypothesis of autism, which suggests that early accelerated brain development may be a hallmark of the disorder. METHODS: We performed a retrospective comparison of HC, height, and weight measurements between 66 toddlers who were later diagnosed with autism and 66 matched controls. These toddlers represent an unbiased regional sample from a single health service provider in the southern district of Israel. On average, participating toddlers had >8 measurements between birth and the age of two, which enabled us to characterize individual HC, height, and weight development with high precision and fit a negative exponential growth model to the data of each toddler with exceptional accuracy. RESULTS: The analyses revealed that HC sizes and growth rates were not significantly larger in toddlers with autism even when stratifying the autism group based on verbal capabilities at the time of diagnosis. In addition, there were no significant correlations between ADOS scores at the time of diagnosis and HC at any time-point during the first 2 years of life. CONCLUSIONS: These negative results add to accumulating evidence, which suggest that brain volume is not necessarily larger in toddlers who develop autism. We believe that conflicting results reported in other studies are due to small sample sizes, use of misleading population norms, changes in the clinical definition of autism over time, and/or inclusion of individuals with syndromic autism. While abnormally large brains may be evident in some individuals with autism and more clearly visible in MRI scans, converging evidence from this and other studies suggests that enlarged HC is not a common etiology of the entire autism population. Early HC measures, therefore, offer very limited clinical utility for assessment of autism risk in the general population. En ligne : http://dx.doi.org/10.1186/s13229-017-0129-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330

Clinical phenotype of ASD-associated DYRK1A haploinsufficiency / R. K. EARL in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 54p. Titre : Clinical phenotype of ASD-associated DYRK1A haploinsufficiency Type de document : Texte imprimé et/ou numérique Auteurs : R. K. EARL, Auteur ; Tychele N. TURNER, Auteur ; H. C. MEFFORD, Auteur ; C. M. HUDAC, Auteur ; J. GERDTS, Auteur ; E. E. EICHLER, Auteur ; Raphael BERNIER, Auteur Article en page(s) : 54p. Langues : Anglais (eng) Mots-clés : Autism  Clinical phenotype  Dyrk1a  Disruptive mutation  Genetic syndrome  Genetically defined subtype Index. décimale : PER Périodiques Résumé : BACKGROUND: DYRK1A is a gene recurrently disrupted in 0.1-0.5% of the ASD population. A growing number of case reports with DYRK1A haploinsufficiency exhibit common phenotypic features including microcephaly, intellectual disability, speech delay, and facial dysmorphisms. METHODS: Phenotypic information from previously published DYRK1A cases (n = 51) and participants in an ongoing study at the University of Washington (UW, n = 10) were compiled. Frequencies of recurrent phenotypic features in this population were compared to features observed in a large sample with idiopathic ASD from the Simons Simplex Collection (n = 1981). UW DYRK1A cases were further characterized quantitatively and compared to a randomly subsampled set of idiopathic ASD cases matched on age and gender (n = 10) and to cases with an ASD-associated disruptive mutation to CHD8 (n = 12). Contribution of familial genetic background to clinical heterogeneity was assessed by comparing head circumference, IQ, and ASD-related symptoms of UW DYRK1A cases to their unaffected parents. RESULTS: DYRK1A haploinsufficiency results in a common phenotypic profile including intellectual disability, speech and motor difficulties, microcephaly, feeding difficulties, and vision abnormalities. Eighty-nine percent of DYRK1A cases ascertained for ASD presented with a constellation of five or more of these symptoms. When compared quantitatively, DYRK1A cases presented with significantly lower IQ and adaptive functioning compared to idiopathic cases and significantly smaller head size compared to both idiopathic and CHD8 cases. Phenotypic variability in parental head circumference, IQ, and ASD-related symptoms corresponded to observed variability in affected child phenotype. CONCLUSIONS: Results confirm a core clinical phenotype for DYRK1A disruptions, with a combination of features that is distinct from idiopathic ASD. Cases with DYRK1A mutations are also distinguishable from disruptive mutations to CHD8 by head size. Measurable, quantitative characterization of DYRK1A haploinsufficiency illuminates clinical variability, which may be, in part, due to familial genetic background. En ligne : http://dx.doi.org/10.1186/s13229-017-0173-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330 [article] Clinical phenotype of ASD-associated DYRK1A haploinsufficiency [Texte imprimé et/ou numérique] / R. K. EARL, Auteur ; Tychele N. TURNER, Auteur ; H. C. MEFFORD, Auteur ; C. M. HUDAC, Auteur ; J. GERDTS, Auteur ; E. E. EICHLER, Auteur ; Raphael BERNIER, Auteur . - 54p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 54p. Mots-clés : Autism  Clinical phenotype  Dyrk1a  Disruptive mutation  Genetic syndrome  Genetically defined subtype Index. décimale : PER Périodiques Résumé : BACKGROUND: DYRK1A is a gene recurrently disrupted in 0.1-0.5% of the ASD population. A growing number of case reports with DYRK1A haploinsufficiency exhibit common phenotypic features including microcephaly, intellectual disability, speech delay, and facial dysmorphisms. METHODS: Phenotypic information from previously published DYRK1A cases (n = 51) and participants in an ongoing study at the University of Washington (UW, n = 10) were compiled. Frequencies of recurrent phenotypic features in this population were compared to features observed in a large sample with idiopathic ASD from the Simons Simplex Collection (n = 1981). UW DYRK1A cases were further characterized quantitatively and compared to a randomly subsampled set of idiopathic ASD cases matched on age and gender (n = 10) and to cases with an ASD-associated disruptive mutation to CHD8 (n = 12). Contribution of familial genetic background to clinical heterogeneity was assessed by comparing head circumference, IQ, and ASD-related symptoms of UW DYRK1A cases to their unaffected parents. RESULTS: DYRK1A haploinsufficiency results in a common phenotypic profile including intellectual disability, speech and motor difficulties, microcephaly, feeding difficulties, and vision abnormalities. Eighty-nine percent of DYRK1A cases ascertained for ASD presented with a constellation of five or more of these symptoms. When compared quantitatively, DYRK1A cases presented with significantly lower IQ and adaptive functioning compared to idiopathic cases and significantly smaller head size compared to both idiopathic and CHD8 cases. Phenotypic variability in parental head circumference, IQ, and ASD-related symptoms corresponded to observed variability in affected child phenotype. CONCLUSIONS: Results confirm a core clinical phenotype for DYRK1A disruptions, with a combination of features that is distinct from idiopathic ASD. Cases with DYRK1A mutations are also distinguishable from disruptive mutations to CHD8 by head size. Measurable, quantitative characterization of DYRK1A haploinsufficiency illuminates clinical variability, which may be, in part, due to familial genetic background. En ligne : http://dx.doi.org/10.1186/s13229-017-0173-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330

Exaggerated CpH methylation in the autism-affected brain / S. E. ELLIS in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 6p. Titre : Exaggerated CpH methylation in the autism-affected brain Type de document : Texte imprimé et/ou numérique Auteurs : S. E. ELLIS, Auteur ; S. GUPTA, Auteur ; A. MOES, Auteur ; A. B. WEST, Auteur ; D. E. ARKING, Auteur Article en page(s) : 6p. Langues : Anglais (eng) Mots-clés : Autistic Disorder/*genetics/pathology  Autopsy  Base Composition  Brain Chemistry  *DNA Methylation  Epigenesis, Genetic  Humans  Male  Sequence Analysis, DNA/*methods  *Autism  *Bisulfite sequencing  *Brains  *Methylation  *Rrbs Index. décimale : PER Périodiques Résumé : BACKGROUND: The etiology of autism, a complex, heritable, neurodevelopmental disorder, remains largely unexplained. Given the unexplained risk and recent evidence supporting a role for epigenetic mechanisms in the development of autism, we explored the role of CpG and CpH (H = A, C, or T) methylation within the autism-affected cortical brain tissue. METHODS: Reduced representation bisulfite sequencing (RRBS) was completed, and analysis was carried out in 63 post-mortem cortical brain samples (Brodmann area 19) from 29 autism-affected and 34 control individuals. Analyses to identify single sites that were differentially methylated and to identify any global methylation alterations at either CpG or CpH sites throughout the genome were carried out. RESULTS: We report that while no individual site or region of methylation was significantly associated with autism after multi-test correction, methylated CpH dinucleotides were markedly enriched in autism-affected brains (~2-fold enrichment at p < 0.05 cutoff, p = 0.002). CONCLUSIONS: These results further implicate epigenetic alterations in pathobiological mechanisms that underlie autism. En ligne : http://dx.doi.org/10.1186/s13229-017-0119-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330 [article] Exaggerated CpH methylation in the autism-affected brain [Texte imprimé et/ou numérique] / S. E. ELLIS, Auteur ; S. GUPTA, Auteur ; A. MOES, Auteur ; A. B. WEST, Auteur ; D. E. ARKING, Auteur . - 6p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 6p. Mots-clés : Autistic Disorder/*genetics/pathology  Autopsy  Base Composition  Brain Chemistry  *DNA Methylation  Epigenesis, Genetic  Humans  Male  Sequence Analysis, DNA/*methods  *Autism  *Bisulfite sequencing  *Brains  *Methylation  *Rrbs Index. décimale : PER Périodiques Résumé : BACKGROUND: The etiology of autism, a complex, heritable, neurodevelopmental disorder, remains largely unexplained. Given the unexplained risk and recent evidence supporting a role for epigenetic mechanisms in the development of autism, we explored the role of CpG and CpH (H = A, C, or T) methylation within the autism-affected cortical brain tissue. METHODS: Reduced representation bisulfite sequencing (RRBS) was completed, and analysis was carried out in 63 post-mortem cortical brain samples (Brodmann area 19) from 29 autism-affected and 34 control individuals. Analyses to identify single sites that were differentially methylated and to identify any global methylation alterations at either CpG or CpH sites throughout the genome were carried out. RESULTS: We report that while no individual site or region of methylation was significantly associated with autism after multi-test correction, methylated CpH dinucleotides were markedly enriched in autism-affected brains (~2-fold enrichment at p < 0.05 cutoff, p = 0.002). CONCLUSIONS: These results further implicate epigenetic alterations in pathobiological mechanisms that underlie autism. En ligne : http://dx.doi.org/10.1186/s13229-017-0119-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330

Glutathione metabolism in the prefrontal brain of adults with high-functioning autism spectrum disorder: an MRS study / D. ENDRES in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 10p. Titre : Glutathione metabolism in the prefrontal brain of adults with high-functioning autism spectrum disorder: an MRS study Type de document : Texte imprimé et/ou numérique Auteurs : D. ENDRES, Auteur ; L. TEBARTZ VAN ELST, Auteur ; S. A. MEYER, Auteur ; B. FEIGE, Auteur ; K. NICKEL, Auteur ; A. BUBL, Auteur ; A. RIEDEL, Auteur ; D. EBERT, Auteur ; T. LANGE, Auteur ; V. GLAUCHE, Auteur ; Monica BISCALDI, Auteur ; A. PHILIPSEN, Auteur ; S. J. MAIER, Auteur ; E. PERLOV, Auteur Article en page(s) : 10p. Langues : Anglais (eng) Mots-clés : Adult  Autism Spectrum Disorder/metabolism/*psychology  Female  Glutathione/*metabolism  Humans  Male  Middle Aged  Prefrontal Cortex/*metabolism  Proton Magnetic Resonance Spectroscopy/*methods  *Anterior cingulate cortex  *Asperger syndrome  *Autism spectrum disorder  *Dlpfc  *Glutathione  *MR spectroscopy Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disease characterized by difficulties in social communication, unusually restricted, repetitive behavior and interests, and specific abnormalities in language and perception. The precise etiology of ASD is still unknown and probably heterogeneous. In a subgroup of patients, toxic environmental exposure might lead to an imbalance between oxidative stress and anti-oxidant systems. Previous serum and postmortem studies measuring levels of glutathione (GSH), the main cellular free radical scavenger in the brain, have supported the hypothesis that this compound might play a role in the pathophysiology of autism. METHODS: Using the method of single-voxel proton magnetic resonance spectroscopy (MRS), we analyzed the GSH signal in the dorsal anterior cingulate cortex (dACC) and the dorsolateral prefrontal cortex (DLPFC) of 24 ASD patients with normal or above average IQs and 18 matched control subjects. We hypothesized that we would find decreased GSH concentrations in both regions. RESULTS: We did not find overall group differences in neurometabolites including GSH, neither in the dorsal ACC (Wilks' lambda test; p = 0.429) nor in the DLPFC (p = 0.288). In the dACC, we found a trend for decreased GSH signals in ASD patients (p = 0.076). CONCLUSIONS: We were unable to confirm our working hypothesis regarding decreased GSH concentrations in the ASD group. Further studies combining MRS, serum, and cerebrospinal fluid measurements of GSH metabolism including other regions of interest or even whole brain spectroscopy are needed. En ligne : http://dx.doi.org/10.1186/s13229-017-0122-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330 [article] Glutathione metabolism in the prefrontal brain of adults with high-functioning autism spectrum disorder: an MRS study [Texte imprimé et/ou numérique] / D. ENDRES, Auteur ; L. TEBARTZ VAN ELST, Auteur ; S. A. MEYER, Auteur ; B. FEIGE, Auteur ; K. NICKEL, Auteur ; A. BUBL, Auteur ; A. RIEDEL, Auteur ; D. EBERT, Auteur ; T. LANGE, Auteur ; V. GLAUCHE, Auteur ; Monica BISCALDI, Auteur ; A. PHILIPSEN, Auteur ; S. J. MAIER, Auteur ; E. PERLOV, Auteur . - 10p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 10p. Mots-clés : Adult  Autism Spectrum Disorder/metabolism/*psychology  Female  Glutathione/*metabolism  Humans  Male  Middle Aged  Prefrontal Cortex/*metabolism  Proton Magnetic Resonance Spectroscopy/*methods  *Anterior cingulate cortex  *Asperger syndrome  *Autism spectrum disorder  *Dlpfc  *Glutathione  *MR spectroscopy Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disease characterized by difficulties in social communication, unusually restricted, repetitive behavior and interests, and specific abnormalities in language and perception. The precise etiology of ASD is still unknown and probably heterogeneous. In a subgroup of patients, toxic environmental exposure might lead to an imbalance between oxidative stress and anti-oxidant systems. Previous serum and postmortem studies measuring levels of glutathione (GSH), the main cellular free radical scavenger in the brain, have supported the hypothesis that this compound might play a role in the pathophysiology of autism. METHODS: Using the method of single-voxel proton magnetic resonance spectroscopy (MRS), we analyzed the GSH signal in the dorsal anterior cingulate cortex (dACC) and the dorsolateral prefrontal cortex (DLPFC) of 24 ASD patients with normal or above average IQs and 18 matched control subjects. We hypothesized that we would find decreased GSH concentrations in both regions. RESULTS: We did not find overall group differences in neurometabolites including GSH, neither in the dorsal ACC (Wilks' lambda test; p = 0.429) nor in the DLPFC (p = 0.288). In the dACC, we found a trend for decreased GSH signals in ASD patients (p = 0.076). CONCLUSIONS: We were unable to confirm our working hypothesis regarding decreased GSH concentrations in the ASD group. Further studies combining MRS, serum, and cerebrospinal fluid measurements of GSH metabolism including other regions of interest or even whole brain spectroscopy are needed. En ligne : http://dx.doi.org/10.1186/s13229-017-0122-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330

Erratum to: Neural synchronization deficits linked to cortical hyper-excitability and auditory hypersensitivity in fragile X syndrome / L. E. ETHRIDGE in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 38p. Titre : Erratum to: Neural synchronization deficits linked to cortical hyper-excitability and auditory hypersensitivity in fragile X syndrome Type de document : Texte imprimé et/ou numérique Auteurs : L. E. ETHRIDGE, Auteur ; S. P. WHITE, Auteur ; M. W. MOSCONI, Auteur ; J. WANG, Auteur ; Ernest V. PEDAPATI, Auteur ; C. A. ERICKSON, Auteur ; M. J. BYERLY, Auteur ; J. A. SWEENEY, Auteur Article en page(s) : 38p. Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : [This corrects the article DOI: 10.1186/s13229-017-0140-1.]. En ligne : http://dx.doi.org/10.1186/s13229-017-0150-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330 [article] Erratum to: Neural synchronization deficits linked to cortical hyper-excitability and auditory hypersensitivity in fragile X syndrome [Texte imprimé et/ou numérique] / L. E. ETHRIDGE, Auteur ; S. P. WHITE, Auteur ; M. W. MOSCONI, Auteur ; J. WANG, Auteur ; Ernest V. PEDAPATI, Auteur ; C. A. ERICKSON, Auteur ; M. J. BYERLY, Auteur ; J. A. SWEENEY, Auteur . - 38p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 38p. Index. décimale : PER Périodiques Résumé : [This corrects the article DOI: 10.1186/s13229-017-0140-1.]. En ligne : http://dx.doi.org/10.1186/s13229-017-0150-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330

Neural synchronization deficits linked to cortical hyper-excitability and auditory hypersensitivity in fragile X syndrome / L. E. ETHRIDGE in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 22p. Titre : Neural synchronization deficits linked to cortical hyper-excitability and auditory hypersensitivity in fragile X syndrome Type de document : Texte imprimé et/ou numérique Auteurs : L. E. ETHRIDGE, Auteur ; S. P. WHITE, Auteur ; M. W. MOSCONI, Auteur ; J. WANG, Auteur ; Ernest V. PEDAPATI, Auteur ; C. A. ERICKSON, Auteur ; M. J. BYERLY, Auteur ; J. A. SWEENEY, Auteur Article en page(s) : 22p. Langues : Anglais (eng) Mots-clés : Chirp  Eeg  Fragile X syndrome  Gamma  Sensory Index. décimale : PER Périodiques Résumé : BACKGROUND: Studies in the fmr1 KO mouse demonstrate hyper-excitability and increased high-frequency neuronal activity in sensory cortex. These abnormalities may contribute to prominent and distressing sensory hypersensitivities in patients with fragile X syndrome (FXS). The current study investigated functional properties of auditory cortex using a sensory entrainment task in FXS. METHODS: EEG recordings were obtained from 17 adolescents and adults with FXS and 17 age- and sex-matched healthy controls. Participants heard an auditory chirp stimulus generated using a 1000-Hz tone that was amplitude modulated by a sinusoid linearly increasing in frequency from 0-100 Hz over 2 s. RESULTS: Single trial time-frequency analyses revealed decreased gamma band phase-locking to the chirp stimulus in FXS, which was strongly coupled with broadband increases in gamma power. Abnormalities in gamma phase-locking and power were also associated with theta-gamma amplitude-amplitude coupling during the pre-stimulus period and with parent reports of heightened sensory sensitivities and social communication deficits. CONCLUSIONS: This represents the first demonstration of neural entrainment alterations in FXS patients and suggests that fast-spiking interneurons regulating synchronous high-frequency neural activity have reduced functionality. This reduced ability to synchronize high-frequency neural activity was related to the total power of background gamma band activity. These observations extend findings from fmr1 KO models of FXS, characterize a core pathophysiological aspect of FXS, and may provide a translational biomarker strategy for evaluating promising therapeutics. En ligne : http://dx.doi.org/10.1186/s13229-017-0140-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330 [article] Neural synchronization deficits linked to cortical hyper-excitability and auditory hypersensitivity in fragile X syndrome [Texte imprimé et/ou numérique] / L. E. ETHRIDGE, Auteur ; S. P. WHITE, Auteur ; M. W. MOSCONI, Auteur ; J. WANG, Auteur ; Ernest V. PEDAPATI, Auteur ; C. A. ERICKSON, Auteur ; M. J. BYERLY, Auteur ; J. A. SWEENEY, Auteur . - 22p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 22p. Mots-clés : Chirp  Eeg  Fragile X syndrome  Gamma  Sensory Index. décimale : PER Périodiques Résumé : BACKGROUND: Studies in the fmr1 KO mouse demonstrate hyper-excitability and increased high-frequency neuronal activity in sensory cortex. These abnormalities may contribute to prominent and distressing sensory hypersensitivities in patients with fragile X syndrome (FXS). The current study investigated functional properties of auditory cortex using a sensory entrainment task in FXS. METHODS: EEG recordings were obtained from 17 adolescents and adults with FXS and 17 age- and sex-matched healthy controls. Participants heard an auditory chirp stimulus generated using a 1000-Hz tone that was amplitude modulated by a sinusoid linearly increasing in frequency from 0-100 Hz over 2 s. RESULTS: Single trial time-frequency analyses revealed decreased gamma band phase-locking to the chirp stimulus in FXS, which was strongly coupled with broadband increases in gamma power. Abnormalities in gamma phase-locking and power were also associated with theta-gamma amplitude-amplitude coupling during the pre-stimulus period and with parent reports of heightened sensory sensitivities and social communication deficits. CONCLUSIONS: This represents the first demonstration of neural entrainment alterations in FXS patients and suggests that fast-spiking interneurons regulating synchronous high-frequency neural activity have reduced functionality. This reduced ability to synchronize high-frequency neural activity was related to the total power of background gamma band activity. These observations extend findings from fmr1 KO models of FXS, characterize a core pathophysiological aspect of FXS, and may provide a translational biomarker strategy for evaluating promising therapeutics. En ligne : http://dx.doi.org/10.1186/s13229-017-0140-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330

Intrainsular connectivity and somatosensory responsiveness in young children with ASD / M. D. FAILLA in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 25p. Titre : Intrainsular connectivity and somatosensory responsiveness in young children with ASD Type de document : Texte imprimé et/ou numérique Auteurs : M. D. FAILLA, Auteur ; B. R. PETERS, Auteur ; H. KARBASFOROUSHAN, Auteur ; J. H. FOSS-FEIG, Auteur ; Kimberly B. SCHAUDER, Auteur ; B. H. HEFLIN, Auteur ; Carissa J. CASCIO, Auteur Article en page(s) : 25p. Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : BACKGROUND: The human somatosensory system comprises dissociable paths for discriminative and affective touch, reflected in separate peripheral afferent populations and distinct cortical targets. Differences in behavioral and neural responses to affective touch may have an important developmental role in early social experiences, which are relevant for autism spectrum disorder (ASD). METHODS: Using probabilistic tractography, we compared the structural integrity of white matter pathways for discriminative and affective touch in young children with ASD and their typically developing (TD) peers. We examined two tracts: (1) a tract linking the thalamus with the primary somatosensory cortex, which carries discriminative tactile information, and (2) a tract linking the posterior insula-the cortical projection target of unmyelinated tactile afferents mediating affective touch-with the anterior insula, which integrates sensory and visceral inputs to interpret emotional salience of sensory stimuli. We investigated associations between tract integrity and performance on a standardized observational assessment measuring tactile discrimination and affective responses to touch. RESULTS: Both the thalamocortical and intrainsular tracts showed reduced integrity (higher mean diffusivity) in the ASD group compared to those in the TD group. Consistent with the previous findings, the ASD group exhibited impaired tactile discriminative ability, more tactile defensiveness, and more sensory seeking (e.g., enthusiastic play or repetitive engagement with a specific tactile stimulus). There was a significant relation between intrainsular tract integrity and tactile seeking. The direction of this relation differed between groups: higher intrainsular mean diffusivity (MD) (reflecting decreased tract integrity) was associated with increased tactile seeking in the TD group but with decreased tactile seeking in the ASD group. In the TD group, decreased tactile defensiveness was also associated with higher intrainsular MD, but there was no relation in the ASD group. Discriminative touch was not significantly associated with integrity of either tract in either group. CONCLUSIONS: These results support previous findings suggesting a central role for the insula in affective response to touch. While both discriminative and affective touch and both somatosensory tracts are affected in ASD, the restriction of brain-behavior associations to the intrainsular tract and tactile seeking suggests more complex and perhaps higher-order influence on differences in tactile defensiveness and discrimination. En ligne : http://dx.doi.org/10.1186/s13229-017-0143-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330 [article] Intrainsular connectivity and somatosensory responsiveness in young children with ASD [Texte imprimé et/ou numérique] / M. D. FAILLA, Auteur ; B. R. PETERS, Auteur ; H. KARBASFOROUSHAN, Auteur ; J. H. FOSS-FEIG, Auteur ; Kimberly B. SCHAUDER, Auteur ; B. H. HEFLIN, Auteur ; Carissa J. CASCIO, Auteur . - 25p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 25p. Index. décimale : PER Périodiques Résumé : BACKGROUND: The human somatosensory system comprises dissociable paths for discriminative and affective touch, reflected in separate peripheral afferent populations and distinct cortical targets. Differences in behavioral and neural responses to affective touch may have an important developmental role in early social experiences, which are relevant for autism spectrum disorder (ASD). METHODS: Using probabilistic tractography, we compared the structural integrity of white matter pathways for discriminative and affective touch in young children with ASD and their typically developing (TD) peers. We examined two tracts: (1) a tract linking the thalamus with the primary somatosensory cortex, which carries discriminative tactile information, and (2) a tract linking the posterior insula-the cortical projection target of unmyelinated tactile afferents mediating affective touch-with the anterior insula, which integrates sensory and visceral inputs to interpret emotional salience of sensory stimuli. We investigated associations between tract integrity and performance on a standardized observational assessment measuring tactile discrimination and affective responses to touch. RESULTS: Both the thalamocortical and intrainsular tracts showed reduced integrity (higher mean diffusivity) in the ASD group compared to those in the TD group. Consistent with the previous findings, the ASD group exhibited impaired tactile discriminative ability, more tactile defensiveness, and more sensory seeking (e.g., enthusiastic play or repetitive engagement with a specific tactile stimulus). There was a significant relation between intrainsular tract integrity and tactile seeking. The direction of this relation differed between groups: higher intrainsular mean diffusivity (MD) (reflecting decreased tract integrity) was associated with increased tactile seeking in the TD group but with decreased tactile seeking in the ASD group. In the TD group, decreased tactile defensiveness was also associated with higher intrainsular MD, but there was no relation in the ASD group. Discriminative touch was not significantly associated with integrity of either tract in either group. CONCLUSIONS: These results support previous findings suggesting a central role for the insula in affective response to touch. While both discriminative and affective touch and both somatosensory tracts are affected in ASD, the restriction of brain-behavior associations to the intrainsular tract and tactile seeking suggests more complex and perhaps higher-order influence on differences in tactile defensiveness and discrimination. En ligne : http://dx.doi.org/10.1186/s13229-017-0143-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330

Attitudes toward risk and ambiguity in patients with autism spectrum disorder / J. FUJINO in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 45p. Titre : Attitudes toward risk and ambiguity in patients with autism spectrum disorder Type de document : Texte imprimé et/ou numérique Auteurs : J. FUJINO, Auteur ; S. TEI, Auteur ; R. I. HASHIMOTO, Auteur ; T. ITAHASHI, Auteur ; H. OHTA, Auteur ; C. KANAI, Auteur ; R. OKADA, Auteur ; M. KUBOTA, Auteur ; M. NAKAMURA, Auteur ; N. KATO, Auteur ; H. TAKAHASHI, Auteur Article en page(s) : 45p. Langues : Anglais (eng) Mots-clés : Ambiguity  Autism spectrum disorder  Decision-making  Gain  Loss  Risk  Uncertainty Index. décimale : PER Périodiques Résumé : Although the ability to make optimal decisions under uncertainty is an integral part of everyday life, individuals with autism spectrum disorder (ASD) frequently report that they experience difficulties with this skill. In behavioral economics, researchers distinguish two types of uncertainty to understand decision-making in this setting: risk (known probabilities) and ambiguity (unknown probabilities). However, it remains unclear how individuals with ASD behave under risk and ambiguity, despite growing evidence of their altered decision-making under uncertainty. We therefore extended previous research by studying the attitudes of those with ASD toward risk and ambiguity in both positive and negative contexts (i.e., gain and loss). In gain contexts, no significant difference was observed between the groups in risk attitudes, but ambiguity aversion was attenuated in ASD. In loss contexts, ambiguity attitudes did not significantly differ between the groups, but the ASD participants were less risk-seeking compared with the controls. In addition, insensitivity to the context change under risk and ambiguity in ASD was both significantly associated with poor social skills. These results improve our understanding of altered decision-making under uncertainty by disentangling the attitudes toward risk and ambiguity in ASD individuals. Applying behavioral economic tools may provide insights into the mechanisms underlying behavioral disturbances in ASD. En ligne : http://dx.doi.org/10.1186/s13229-017-0162-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330 [article] Attitudes toward risk and ambiguity in patients with autism spectrum disorder [Texte imprimé et/ou numérique] / J. FUJINO, Auteur ; S. TEI, Auteur ; R. I. HASHIMOTO, Auteur ; T. ITAHASHI, Auteur ; H. OHTA, Auteur ; C. KANAI, Auteur ; R. OKADA, Auteur ; M. KUBOTA, Auteur ; M. NAKAMURA, Auteur ; N. KATO, Auteur ; H. TAKAHASHI, Auteur . - 45p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 45p. Mots-clés : Ambiguity  Autism spectrum disorder  Decision-making  Gain  Loss  Risk  Uncertainty Index. décimale : PER Périodiques Résumé : Although the ability to make optimal decisions under uncertainty is an integral part of everyday life, individuals with autism spectrum disorder (ASD) frequently report that they experience difficulties with this skill. In behavioral economics, researchers distinguish two types of uncertainty to understand decision-making in this setting: risk (known probabilities) and ambiguity (unknown probabilities). However, it remains unclear how individuals with ASD behave under risk and ambiguity, despite growing evidence of their altered decision-making under uncertainty. We therefore extended previous research by studying the attitudes of those with ASD toward risk and ambiguity in both positive and negative contexts (i.e., gain and loss). In gain contexts, no significant difference was observed between the groups in risk attitudes, but ambiguity aversion was attenuated in ASD. In loss contexts, ambiguity attitudes did not significantly differ between the groups, but the ASD participants were less risk-seeking compared with the controls. In addition, insensitivity to the context change under risk and ambiguity in ASD was both significantly associated with poor social skills. These results improve our understanding of altered decision-making under uncertainty by disentangling the attitudes toward risk and ambiguity in ASD individuals. Applying behavioral economic tools may provide insights into the mechanisms underlying behavioral disturbances in ASD. En ligne : http://dx.doi.org/10.1186/s13229-017-0162-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330

Testing the excitation/inhibition imbalance hypothesis in a mouse model of the autism spectrum disorder: in vivo neurospectroscopy and molecular evidence for regional phenotypes / J. GONCALVES in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 47p. Titre : Testing the excitation/inhibition imbalance hypothesis in a mouse model of the autism spectrum disorder: in vivo neurospectroscopy and molecular evidence for regional phenotypes Type de document : Texte imprimé et/ou numérique Auteurs : J. GONCALVES, Auteur ; I. R. VIOLANTE, Auteur ; J. SERENO, Auteur ; R. A. LEITAO, Auteur ; Y. CAI, Auteur ; A. ABRUNHOSA, Auteur ; A. P. SILVA, Auteur ; A. J. SILVA, Auteur ; Miguel CASTELO-BRANCO, Auteur Article en page(s) : 47p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorders  Excitation/inhibition imbalance  GABA(A) receptor  Magnetic resonance spectroscopy  Neurofibromatosis type 1 Index. décimale : PER Périodiques Résumé : BACKGROUND: Excitation/inhibition (E/I) imbalance remains a widely discussed hypothesis in autism spectrum disorders (ASD). The presence of such an imbalance may potentially define a therapeutic target for the treatment of cognitive disabilities related to this pathology. Consequently, the study of monogenic disorders related to autism, such as neurofibromatosis type 1 (NF1), represents a promising approach to isolate mechanisms underlying ASD-related cognitive disabilities. However, the NF1 mouse model showed increased gamma-aminobutyric acid (GABA) neurotransmission, whereas the human disease showed reduced cortical GABA levels. It is therefore important to clarify whether the E/I imbalance hypothesis holds true. We hypothesize that E/I may depend on distinct pre- and postsynaptic push-pull mechanisms that might be are region-dependent. METHODS: In current study, we assessed two critical components of E/I regulation: the concentration of neurotransmitters and levels of GABA(A) receptors. Measurements were performed across the hippocampi, striatum, and prefrontal cortices by combined in vivo magnetic resonance spectroscopy (MRS) and molecular approaches in this ASD-related animal model, the Nf1(+/-) mouse. RESULTS: Cortical and striatal GABA/glutamate ratios were increased. At the postsynaptic level, very high receptor GABA(A) receptor expression was found in hippocampus, disproportionately to the small reduction in GABA levels. Gabaergic tone (either by receptor levels change or GABA/glutamate ratios) seemed therefore to be enhanced in all regions, although by a different mechanism. CONCLUSIONS: Our data provides support for the hypothesis of E/I imbalance in NF1 while showing that pre- and postsynaptic changes are region-specific. All these findings are consistent with our previous physiological evidence of increased inhibitory tone. Such heterogeneity suggests that therapeutic approaches to address neurochemical imbalance in ASD may need to focus on targets where convergent physiological mechanisms can be found. En ligne : http://dx.doi.org/10.1186/s13229-017-0166-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330 [article] Testing the excitation/inhibition imbalance hypothesis in a mouse model of the autism spectrum disorder: in vivo neurospectroscopy and molecular evidence for regional phenotypes [Texte imprimé et/ou numérique] / J. GONCALVES, Auteur ; I. R. VIOLANTE, Auteur ; J. SERENO, Auteur ; R. A. LEITAO, Auteur ; Y. CAI, Auteur ; A. ABRUNHOSA, Auteur ; A. P. SILVA, Auteur ; A. J. SILVA, Auteur ; Miguel CASTELO-BRANCO, Auteur . - 47p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 47p. Mots-clés : Autism spectrum disorders  Excitation/inhibition imbalance  GABA(A) receptor  Magnetic resonance spectroscopy  Neurofibromatosis type 1 Index. décimale : PER Périodiques Résumé : BACKGROUND: Excitation/inhibition (E/I) imbalance remains a widely discussed hypothesis in autism spectrum disorders (ASD). The presence of such an imbalance may potentially define a therapeutic target for the treatment of cognitive disabilities related to this pathology. Consequently, the study of monogenic disorders related to autism, such as neurofibromatosis type 1 (NF1), represents a promising approach to isolate mechanisms underlying ASD-related cognitive disabilities. However, the NF1 mouse model showed increased gamma-aminobutyric acid (GABA) neurotransmission, whereas the human disease showed reduced cortical GABA levels. It is therefore important to clarify whether the E/I imbalance hypothesis holds true. We hypothesize that E/I may depend on distinct pre- and postsynaptic push-pull mechanisms that might be are region-dependent. METHODS: In current study, we assessed two critical components of E/I regulation: the concentration of neurotransmitters and levels of GABA(A) receptors. Measurements were performed across the hippocampi, striatum, and prefrontal cortices by combined in vivo magnetic resonance spectroscopy (MRS) and molecular approaches in this ASD-related animal model, the Nf1(+/-) mouse. RESULTS: Cortical and striatal GABA/glutamate ratios were increased. At the postsynaptic level, very high receptor GABA(A) receptor expression was found in hippocampus, disproportionately to the small reduction in GABA levels. Gabaergic tone (either by receptor levels change or GABA/glutamate ratios) seemed therefore to be enhanced in all regions, although by a different mechanism. CONCLUSIONS: Our data provides support for the hypothesis of E/I imbalance in NF1 while showing that pre- and postsynaptic changes are region-specific. All these findings are consistent with our previous physiological evidence of increased inhibitory tone. Such heterogeneity suggests that therapeutic approaches to address neurochemical imbalance in ASD may need to focus on targets where convergent physiological mechanisms can be found. En ligne : http://dx.doi.org/10.1186/s13229-017-0166-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330

Neurogenetic analysis of childhood disintegrative disorder / A. R. GUPTA in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 19p. Titre : Neurogenetic analysis of childhood disintegrative disorder Type de document : Texte imprimé et/ou numérique Auteurs : A. R. GUPTA, Auteur ; A. WESTPHAL, Auteur ; D. Y. J. YANG, Auteur ; C. A. W. SULLIVAN, Auteur ; J. EILBOTT, Auteur ; S. ZAIDI, Auteur ; A. VOOS, Auteur ; B. C. VANDER WYK, Auteur ; Pamela VENTOLA, Auteur ; Z. WAQAR, Auteur ; T. V. FERNANDEZ, Auteur ; A. G. ERCAN-SENCICEK, Auteur ; M. F. WALKER, Auteur ; M. CHOI, Auteur ; A. SCHNEIDER, Auteur ; T. HEDDERLY, Auteur ; Gillian BAIRD, Auteur ; H. FRIEDMAN, Auteur ; C. CORDEAUX, Auteur ; A. RISTOW, Auteur ; F. SHIC, Auteur ; Fred R. VOLKMAR, Auteur ; Kevin A. PELPHREY, Auteur Article en page(s) : 19p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder (ASD)  Childhood disintegrative disorder (CDD)  Eye tracking  Functional magnetic resonance imaging (fMRI)  Genetics  Intellectual disability (ID)  Regression Index. décimale : PER Périodiques Résumé : BACKGROUND: Childhood disintegrative disorder (CDD) is a rare form of autism spectrum disorder (ASD) of unknown etiology. It is characterized by late-onset regression leading to significant intellectual disability (ID) and severe autism. Although there are phenotypic differences between CDD and other forms of ASD, it is unclear if there are neurobiological differences. METHODS: We pursued a multidisciplinary study of CDD (n = 17) and three comparison groups: low-functioning ASD (n = 12), high-functioning ASD (n = 50), and typically developing (n = 26) individuals. We performed whole-exome sequencing (WES), copy number variant (CNV), and gene expression analyses of CDD and, on subsets of each cohort, non-sedated functional magnetic resonance imaging (fMRI) while viewing socioemotional (faces) and non-socioemotional (houses) stimuli and eye tracking while viewing emotional faces. RESULTS: We observed potential differences between CDD and other forms of ASD. WES and CNV analyses identified one or more rare de novo, homozygous, and/or hemizygous (mother-to-son transmission on chrX) variants for most probands that were not shared by unaffected sibling controls. There were no clearly deleterious variants or highly recurrent candidate genes. Candidate genes that were found to be most conserved at variant position and most intolerant of variation, such as TRRAP, ZNF236, and KIAA2018, play a role or may be involved in transcription. Using the human BrainSpan transcriptome dataset, CDD candidate genes were found to be more highly expressed in non-neocortical regions than neocortical regions. This expression profile was similar to that of an independent cohort of ASD probands with regression. The non-neocortical regions overlapped with those identified by fMRI as abnormally hyperactive in response to viewing faces, such as the thalamus, cerebellum, caudate, and hippocampus. Eye-tracking analysis showed that, among individuals with ASD, subjects with CDD focused on eyes the most when shown pictures of faces. CONCLUSIONS: Given that cohort sizes were limited by the rarity of CDD, and the challenges of conducting non-sedated fMRI and eye tracking in subjects with ASD and significant ID, this is an exploratory study designed to investigate the neurobiological features of CDD. In addition to reporting the first multimodal analysis of CDD, a combination of fMRI and eye-tracking analyses are being presented for the first time for low-functioning individuals with ASD. Our results suggest differences between CDD and other forms of ASD on the neurobiological as well as clinical level. En ligne : http://dx.doi.org/10.1186/s13229-017-0133-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330 [article] Neurogenetic analysis of childhood disintegrative disorder [Texte imprimé et/ou numérique] / A. R. GUPTA, Auteur ; A. WESTPHAL, Auteur ; D. Y. J. YANG, Auteur ; C. A. W. SULLIVAN, Auteur ; J. EILBOTT, Auteur ; S. ZAIDI, Auteur ; A. VOOS, Auteur ; B. C. VANDER WYK, Auteur ; Pamela VENTOLA, Auteur ; Z. WAQAR, Auteur ; T. V. FERNANDEZ, Auteur ; A. G. ERCAN-SENCICEK, Auteur ; M. F. WALKER, Auteur ; M. CHOI, Auteur ; A. SCHNEIDER, Auteur ; T. HEDDERLY, Auteur ; Gillian BAIRD, Auteur ; H. FRIEDMAN, Auteur ; C. CORDEAUX, Auteur ; A. RISTOW, Auteur ; F. SHIC, Auteur ; Fred R. VOLKMAR, Auteur ; Kevin A. PELPHREY, Auteur . - 19p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 19p. Mots-clés : Autism spectrum disorder (ASD)  Childhood disintegrative disorder (CDD)  Eye tracking  Functional magnetic resonance imaging (fMRI)  Genetics  Intellectual disability (ID)  Regression Index. décimale : PER Périodiques Résumé : BACKGROUND: Childhood disintegrative disorder (CDD) is a rare form of autism spectrum disorder (ASD) of unknown etiology. It is characterized by late-onset regression leading to significant intellectual disability (ID) and severe autism. Although there are phenotypic differences between CDD and other forms of ASD, it is unclear if there are neurobiological differences. METHODS: We pursued a multidisciplinary study of CDD (n = 17) and three comparison groups: low-functioning ASD (n = 12), high-functioning ASD (n = 50), and typically developing (n = 26) individuals. We performed whole-exome sequencing (WES), copy number variant (CNV), and gene expression analyses of CDD and, on subsets of each cohort, non-sedated functional magnetic resonance imaging (fMRI) while viewing socioemotional (faces) and non-socioemotional (houses) stimuli and eye tracking while viewing emotional faces. RESULTS: We observed potential differences between CDD and other forms of ASD. WES and CNV analyses identified one or more rare de novo, homozygous, and/or hemizygous (mother-to-son transmission on chrX) variants for most probands that were not shared by unaffected sibling controls. There were no clearly deleterious variants or highly recurrent candidate genes. Candidate genes that were found to be most conserved at variant position and most intolerant of variation, such as TRRAP, ZNF236, and KIAA2018, play a role or may be involved in transcription. Using the human BrainSpan transcriptome dataset, CDD candidate genes were found to be more highly expressed in non-neocortical regions than neocortical regions. This expression profile was similar to that of an independent cohort of ASD probands with regression. The non-neocortical regions overlapped with those identified by fMRI as abnormally hyperactive in response to viewing faces, such as the thalamus, cerebellum, caudate, and hippocampus. Eye-tracking analysis showed that, among individuals with ASD, subjects with CDD focused on eyes the most when shown pictures of faces. CONCLUSIONS: Given that cohort sizes were limited by the rarity of CDD, and the challenges of conducting non-sedated fMRI and eye tracking in subjects with ASD and significant ID, this is an exploratory study designed to investigate the neurobiological features of CDD. In addition to reporting the first multimodal analysis of CDD, a combination of fMRI and eye-tracking analyses are being presented for the first time for low-functioning individuals with ASD. Our results suggest differences between CDD and other forms of ASD on the neurobiological as well as clinical level. En ligne : http://dx.doi.org/10.1186/s13229-017-0133-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330

Prenatal exposure to valproic acid increases miR-132 levels in the mouse embryonic brain / Y. HARA in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 33p. Titre : Prenatal exposure to valproic acid increases miR-132 levels in the mouse embryonic brain Type de document : Texte imprimé et/ou numérique Auteurs : Y. HARA, Auteur ; Yukio AGO, Auteur ; E. TAKANO, Auteur ; S. HASEBE, Auteur ; T. NAKAZAWA, Auteur ; H. HASHIMOTO, Auteur ; T. MATSUDA, Auteur ; K. TAKUMA, Auteur Article en page(s) : 33p. Langues : Anglais (eng) Mots-clés : Autism mouse model  Embryonic brain  MicroRNA  Valproic acid Index. décimale : PER Périodiques Résumé : BACKGROUND: MicroRNAs, small non-coding RNAs, are highly expressed in the mammalian brain, and the dysregulation of microRNA levels may be involved in neurodevelopmental disorders such as autism spectrum disorder (ASD). In the present study, we examined whether prenatal valproic acid (VPA) exposure affects levels of microRNAs, especially the brain specific and enriched microRNAs, in the mouse embryonic brain. RESULTS: Prenatal exposure to VPA at E12.5 immediately increased miR-132 levels, but not miR-9 or miR-124 levels, in the male embryonic brain. Prenatal exposure to VPA at E12.5 also increased miR-132 levels in the female embryonic brain. We further found that the prenatal exposure to VPA at E12.5 increased mRNA levels of Arc, c-Fos and brain-derived neurotrophic factor in both male and female embryonic brains, prior to miR-132 expression. In contrast, prenatal exposure to VPA at E14.5 did not affect miR-132 levels in either male or female embryonic brain. The prenatal VPA exposure at E12.5 also decreased mRNA levels of methyl-CpG-binding protein 2 and Rho GTPase-activating protein p250GAP, both of which are molecular targets of miR-132. Furthermore, RNA sequence analysis revealed that prenatal VPA exposure caused changes in several microRNA levels other than miR-132 in the embryonic whole brain. CONCLUSIONS: These findings suggest that the alterations in neuronal activity-dependent microRNAs levels, including an increased level of miR-132, in the embryonic period, at least in part, underlie the ASD-like behaviors and cortical pathology produced by prenatal VPA exposure. En ligne : http://dx.doi.org/10.1186/s13229-017-0149-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330 [article] Prenatal exposure to valproic acid increases miR-132 levels in the mouse embryonic brain [Texte imprimé et/ou numérique] / Y. HARA, Auteur ; Yukio AGO, Auteur ; E. TAKANO, Auteur ; S. HASEBE, Auteur ; T. NAKAZAWA, Auteur ; H. HASHIMOTO, Auteur ; T. MATSUDA, Auteur ; K. TAKUMA, Auteur . - 33p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 33p. Mots-clés : Autism mouse model  Embryonic brain  MicroRNA  Valproic acid Index. décimale : PER Périodiques Résumé : BACKGROUND: MicroRNAs, small non-coding RNAs, are highly expressed in the mammalian brain, and the dysregulation of microRNA levels may be involved in neurodevelopmental disorders such as autism spectrum disorder (ASD). In the present study, we examined whether prenatal valproic acid (VPA) exposure affects levels of microRNAs, especially the brain specific and enriched microRNAs, in the mouse embryonic brain. RESULTS: Prenatal exposure to VPA at E12.5 immediately increased miR-132 levels, but not miR-9 or miR-124 levels, in the male embryonic brain. Prenatal exposure to VPA at E12.5 also increased miR-132 levels in the female embryonic brain. We further found that the prenatal exposure to VPA at E12.5 increased mRNA levels of Arc, c-Fos and brain-derived neurotrophic factor in both male and female embryonic brains, prior to miR-132 expression. In contrast, prenatal exposure to VPA at E14.5 did not affect miR-132 levels in either male or female embryonic brain. The prenatal VPA exposure at E12.5 also decreased mRNA levels of methyl-CpG-binding protein 2 and Rho GTPase-activating protein p250GAP, both of which are molecular targets of miR-132. Furthermore, RNA sequence analysis revealed that prenatal VPA exposure caused changes in several microRNA levels other than miR-132 in the embryonic whole brain. CONCLUSIONS: These findings suggest that the alterations in neuronal activity-dependent microRNAs levels, including an increased level of miR-132, in the embryonic period, at least in part, underlie the ASD-like behaviors and cortical pathology produced by prenatal VPA exposure. En ligne : http://dx.doi.org/10.1186/s13229-017-0149-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330

Evaluating the quality of peer interactions in children and adolescents with autism with the Penn Interactive Peer Play Scale (PIPPS) / R. M. JONES in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 28p. Titre : Evaluating the quality of peer interactions in children and adolescents with autism with the Penn Interactive Peer Play Scale (PIPPS) Type de document : Texte imprimé et/ou numérique Auteurs : R. M. JONES, Auteur ; A. PICKLES, Auteur ; C. LORD, Auteur Article en page(s) : 28p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder (ASD)  Peer interactions  Penn Interactive Peer Play Scale (PIPPS)  Teacher ratings Index. décimale : PER Périodiques Résumé : BACKGROUND: A core difficulty for individuals with autism is making friends and successfully engaging and interacting with peers. The majority of measures to assess peer interactions are observations in a school setting or self-report. The present study examined the convergent validity of using a teacher rating scale, the Penn Interactive Peer Play Scale (PIPPS), for collecting information about the quality of peer interactions at school. METHODS: Teachers completed the PIPPS for 107 children with ASD when the child was 9 and 13 years of age. Clinicians completed diagnostic and cognitive assessments and caregivers completed the Autism Diagnostic Interview-Revised (ADI-R) when the child was 9. RESULTS: Parent report of reciprocal friendships from the ADI-R was associated with teacher report about how socially connected the child was at school on the PIPPS, indicating strong convergence between teachers and parents. Children with more severe restricted and repetitive behaviors and lower verbal abilities were less connected with peers. Children with access to typical peers had more connections with peers compared to those who were in a special education classroom. CONCLUSIONS: The findings suggest that teacher ratings from the PIPPS can accurately capture the quality of peer interactions in children and adolescents with ASD and may be useful for clinicians and researchers to evaluate peer engagement in the classroom. En ligne : http://dx.doi.org/10.1186/s13229-017-0144-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330 [article] Evaluating the quality of peer interactions in children and adolescents with autism with the Penn Interactive Peer Play Scale (PIPPS) [Texte imprimé et/ou numérique] / R. M. JONES, Auteur ; A. PICKLES, Auteur ; C. LORD, Auteur . - 28p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 28p. Mots-clés : Autism spectrum disorder (ASD)  Peer interactions  Penn Interactive Peer Play Scale (PIPPS)  Teacher ratings Index. décimale : PER Périodiques Résumé : BACKGROUND: A core difficulty for individuals with autism is making friends and successfully engaging and interacting with peers. The majority of measures to assess peer interactions are observations in a school setting or self-report. The present study examined the convergent validity of using a teacher rating scale, the Penn Interactive Peer Play Scale (PIPPS), for collecting information about the quality of peer interactions at school. METHODS: Teachers completed the PIPPS for 107 children with ASD when the child was 9 and 13 years of age. Clinicians completed diagnostic and cognitive assessments and caregivers completed the Autism Diagnostic Interview-Revised (ADI-R) when the child was 9. RESULTS: Parent report of reciprocal friendships from the ADI-R was associated with teacher report about how socially connected the child was at school on the PIPPS, indicating strong convergence between teachers and parents. Children with more severe restricted and repetitive behaviors and lower verbal abilities were less connected with peers. Children with access to typical peers had more connections with peers compared to those who were in a special education classroom. CONCLUSIONS: The findings suggest that teacher ratings from the PIPPS can accurately capture the quality of peer interactions in children and adolescents with ASD and may be useful for clinicians and researchers to evaluate peer engagement in the classroom. En ligne : http://dx.doi.org/10.1186/s13229-017-0144-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330

Zebrafish knockout of Down syndrome gene, DYRK1A, shows social impairments relevant to autism / O. H. KIM in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 50p. Titre : Zebrafish knockout of Down syndrome gene, DYRK1A, shows social impairments relevant to autism Type de document : Texte imprimé et/ou numérique Auteurs : O. H. KIM, Auteur ; H. J. CHO, Auteur ; E. HAN, Auteur ; T. I. HONG, Auteur ; K. ARIYASIRI, Auteur ; J. H. CHOI, Auteur ; K. S. HWANG, Auteur ; Y. M. JEONG, Auteur ; S. Y. YANG, Auteur ; K. YU, Auteur ; D. S. PARK, Auteur ; H. W. OH, Auteur ; E. E. DAVIS, Auteur ; C. E. SCHWARTZ, Auteur ; J. S. LEE, Auteur ; H. G. KIM, Auteur ; C. H. KIM, Auteur Article en page(s) : 50p. Langues : Anglais (eng) Mots-clés : Autism  Dyrk1a  Down syndrome  Group behavior  Knockout  Shoaling  Social interaction  Zebrafish Index. décimale : PER Périodiques Résumé : BACKGROUND: DYRK1A maps to the Down syndrome critical region at 21q22. Mutations in this kinase-encoding gene have been reported to cause microcephaly associated with either intellectual disability or autism in humans. Intellectual disability accompanied by microcephaly was recapitulated in a murine model by overexpressing Dyrk1a which mimicked Down syndrome phenotypes. However, given embryonic lethality in homozygous knockout (KO) mice, no murine model studies could present sufficient evidence to link Dyrk1a dysfunction with autism. To understand the molecular mechanisms underlying microcephaly and autism spectrum disorders (ASD), we established an in vivo dyrk1aa KO model using zebrafish. METHODS: We identified a patient with a mutation in the DYRK1A gene using microarray analysis. Circumventing the barrier of murine model studies, we generated a dyrk1aa KO zebrafish using transcription activator-like effector nuclease (TALEN)-mediated genome editing. For social behavioral tests, we have established a social interaction test, shoaling assay, and group behavior assay. For molecular analysis, we examined the neuronal activity in specific brain regions of dyrk1aa KO zebrafish through in situ hybridization with various probes including c-fos and crh which are the molecular markers for stress response. RESULTS: Microarray detected an intragenic microdeletion of DYRK1A in an individual with microcephaly and autism. From behavioral tests of social interaction and group behavior, dyrk1aa KO zebrafish exhibited social impairments that reproduce human phenotypes of autism in a vertebrate animal model. Social impairment in dyrk1aa KO zebrafish was further confirmed by molecular analysis of c-fos and crh expression. Transcriptional expression of c-fos and crh was lower than that of wild type fish in specific hypothalamic regions, suggesting that KO fish brains are less activated by social context. CONCLUSIONS: In this study, we established a zebrafish model to validate a candidate gene for autism in a vertebrate animal. These results illustrate the functional deficiency of DYRK1A as an underlying disease mechanism for autism. We also propose simple social behavioral assays as a tool for the broader study of autism candidate genes. En ligne : http://dx.doi.org/10.1186/s13229-017-0168-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330 [article] Zebrafish knockout of Down syndrome gene, DYRK1A, shows social impairments relevant to autism [Texte imprimé et/ou numérique] / O. H. KIM, Auteur ; H. J. CHO, Auteur ; E. HAN, Auteur ; T. I. HONG, Auteur ; K. ARIYASIRI, Auteur ; J. H. CHOI, Auteur ; K. S. HWANG, Auteur ; Y. M. JEONG, Auteur ; S. Y. YANG, Auteur ; K. YU, Auteur ; D. S. PARK, Auteur ; H. W. OH, Auteur ; E. E. DAVIS, Auteur ; C. E. SCHWARTZ, Auteur ; J. S. LEE, Auteur ; H. G. KIM, Auteur ; C. H. KIM, Auteur . - 50p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 50p. Mots-clés : Autism  Dyrk1a  Down syndrome  Group behavior  Knockout  Shoaling  Social interaction  Zebrafish Index. décimale : PER Périodiques Résumé : BACKGROUND: DYRK1A maps to the Down syndrome critical region at 21q22. Mutations in this kinase-encoding gene have been reported to cause microcephaly associated with either intellectual disability or autism in humans. Intellectual disability accompanied by microcephaly was recapitulated in a murine model by overexpressing Dyrk1a which mimicked Down syndrome phenotypes. However, given embryonic lethality in homozygous knockout (KO) mice, no murine model studies could present sufficient evidence to link Dyrk1a dysfunction with autism. To understand the molecular mechanisms underlying microcephaly and autism spectrum disorders (ASD), we established an in vivo dyrk1aa KO model using zebrafish. METHODS: We identified a patient with a mutation in the DYRK1A gene using microarray analysis. Circumventing the barrier of murine model studies, we generated a dyrk1aa KO zebrafish using transcription activator-like effector nuclease (TALEN)-mediated genome editing. For social behavioral tests, we have established a social interaction test, shoaling assay, and group behavior assay. For molecular analysis, we examined the neuronal activity in specific brain regions of dyrk1aa KO zebrafish through in situ hybridization with various probes including c-fos and crh which are the molecular markers for stress response. RESULTS: Microarray detected an intragenic microdeletion of DYRK1A in an individual with microcephaly and autism. From behavioral tests of social interaction and group behavior, dyrk1aa KO zebrafish exhibited social impairments that reproduce human phenotypes of autism in a vertebrate animal model. Social impairment in dyrk1aa KO zebrafish was further confirmed by molecular analysis of c-fos and crh expression. Transcriptional expression of c-fos and crh was lower than that of wild type fish in specific hypothalamic regions, suggesting that KO fish brains are less activated by social context. CONCLUSIONS: In this study, we established a zebrafish model to validate a candidate gene for autism in a vertebrate animal. These results illustrate the functional deficiency of DYRK1A as an underlying disease mechanism for autism. We also propose simple social behavioral assays as a tool for the broader study of autism candidate genes. En ligne : http://dx.doi.org/10.1186/s13229-017-0168-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330

Early development of infants with neurofibromatosis type 1: a case series / A. M. KOLESNIK in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 62p. Titre : Early development of infants with neurofibromatosis type 1: a case series Type de document : Texte imprimé et/ou numérique Auteurs : A. M. KOLESNIK, Auteur ; E. J. H. JONES, Auteur ; S. GARG, Auteur ; J. GREEN, Auteur ; Tony CHARMAN, Auteur ; M. H. JOHNSON, Auteur Article en page(s) : 62p. Langues : Anglais (eng) Mots-clés : Adaptive functioning  Autism  Cognition  Development  Infant  Nf1  Prospective longitudinal  Sensory processing  Social engagement  Translational neurodevelopment Index. décimale : PER Périodiques Résumé : Background: Prospective studies of infants at familial risk for autism spectrum disorder (ASD) have yielded insights into the earliest signs of the disorder but represent heterogeneous samples of unclear aetiology. Complementing this approach by studying cohorts of infants with monogenic syndromes associated with high rates of ASD offers the opportunity to elucidate the factors that lead to ASD. Methods: We present the first report from a prospective study of ten 10-month-old infants with neurofibromatosis type 1 (NF1), a monogenic disorder with high prevalence of ASD or ASD symptomatology. We compared data from infants with NF1 to a large cohort of infants at familial risk for ASD, separated by outcome at age 3 of ASD (n = 34), atypical development (n = 44), or typical development (n = 89), and low-risk controls (n = 75). Domains assessed at 10 months by parent report and examiner observation include cognitive and adaptive function, sensory processing, social engagement, and temperament. Results: Infants with NF1 showed striking impairments in motor functioning relative to low-risk infants; this pattern was seen in infants with later ASD from the familial cohort (HR-ASD). Both infants with NF1 and the HR-ASD group showed communication delays relative to low-risk infants. Conclusions: Ten-month-old infants with NF1 show a range of developmental difficulties that were particularly striking in motor and communication domains. As with HR-ASD infants, social skills at this age were not notably impaired. This is some of the first information on early neurodevelopment in NF1. Strong inferences are limited by the sample size, but the findings suggest implications for early comparative developmental science and highlight motor functioning as an important domain to inform the development of relevant animal models. The findings have clinical implications in indicating an important focus for early surveillance and remediation in this early diagnosed genetic disorder. En ligne : http://dx.doi.org/10.1186/s13229-017-0178-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330 [article] Early development of infants with neurofibromatosis type 1: a case series [Texte imprimé et/ou numérique] / A. M. KOLESNIK, Auteur ; E. J. H. JONES, Auteur ; S. GARG, Auteur ; J. GREEN, Auteur ; Tony CHARMAN, Auteur ; M. H. JOHNSON, Auteur . - 62p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 62p. Mots-clés : Adaptive functioning  Autism  Cognition  Development  Infant  Nf1  Prospective longitudinal  Sensory processing  Social engagement  Translational neurodevelopment Index. décimale : PER Périodiques Résumé : Background: Prospective studies of infants at familial risk for autism spectrum disorder (ASD) have yielded insights into the earliest signs of the disorder but represent heterogeneous samples of unclear aetiology. Complementing this approach by studying cohorts of infants with monogenic syndromes associated with high rates of ASD offers the opportunity to elucidate the factors that lead to ASD. Methods: We present the first report from a prospective study of ten 10-month-old infants with neurofibromatosis type 1 (NF1), a monogenic disorder with high prevalence of ASD or ASD symptomatology. We compared data from infants with NF1 to a large cohort of infants at familial risk for ASD, separated by outcome at age 3 of ASD (n = 34), atypical development (n = 44), or typical development (n = 89), and low-risk controls (n = 75). Domains assessed at 10 months by parent report and examiner observation include cognitive and adaptive function, sensory processing, social engagement, and temperament. Results: Infants with NF1 showed striking impairments in motor functioning relative to low-risk infants; this pattern was seen in infants with later ASD from the familial cohort (HR-ASD). Both infants with NF1 and the HR-ASD group showed communication delays relative to low-risk infants. Conclusions: Ten-month-old infants with NF1 show a range of developmental difficulties that were particularly striking in motor and communication domains. As with HR-ASD infants, social skills at this age were not notably impaired. This is some of the first information on early neurodevelopment in NF1. Strong inferences are limited by the sample size, but the findings suggest implications for early comparative developmental science and highlight motor functioning as an important domain to inform the development of relevant animal models. The findings have clinical implications in indicating an important focus for early surveillance and remediation in this early diagnosed genetic disorder. En ligne : http://dx.doi.org/10.1186/s13229-017-0178-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330

No preliminary evidence of differences in astrocyte density within the white matter of the dorsolateral prefrontal cortex in autism / T. T. LEE in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 64p. Titre : No preliminary evidence of differences in astrocyte density within the white matter of the dorsolateral prefrontal cortex in autism Type de document : Texte imprimé et/ou numérique Auteurs : T. T. LEE, Auteur ; E. SKAFIDAS, Auteur ; M. DOTTORI, Auteur ; D. ZANTOMIO, Auteur ; Christos PANTELIS, Auteur ; I. EVERALL, Auteur ; G. CHANA, Auteur Article en page(s) : 64p. Langues : Anglais (eng) Mots-clés : Astrocytes  Autism  Cell density  Dorsolateral prefrontal cortex (DLPFC)  Glia  White matter Index. décimale : PER Périodiques Résumé : Background: While evidence for white matter and astrocytic abnormalities exist in autism, a detailed investigation of astrocytes has not been conducted. Such an investigation is further warranted by an increasing role for neuroinflammation in autism pathogenesis, with astrocytes being key players in this process. We present the first study of astrocyte density and morphology within the white matter of the dorsolateral prefrontal cortex (DLPFC) in individuals with autism. Methods: DLPFC formalin-fixed sections containing white matter from individuals with autism (n = 8, age = 4-51 years) and age-matched controls (n = 7, age = 4-46 years) were immunostained for glial fibrillary acidic protein (GFAP). Density of astrocytes and other glia were estimated via the optical fractionator, astrocyte somal size estimated via the nucleator, and astrocyte process length via the spaceballs probe. Results: We found no evidence for alteration in astrocyte density within DLPFC white matter of individuals with autism versus controls, together with no differences in astrocyte somal size and process length. Conclusion: Our results suggest that astrocyte abnormalities within the white matter in the DLPFC in autism may be less pronounced than previously thought. However, astrocytic dysregulation may still exist in autism, even in the absence of gross morphological changes. Our lack of evidence for astrocyte abnormalities could have been confounded to an extent by having a small sample size and wide age range, with pathological features potentially restricted to early stages of autism. Nonetheless, future investigations would benefit from assessing functional markers of astrocytes in light of the underlying pathophysiology of autism. En ligne : http://dx.doi.org/10.1186/s13229-017-0181-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330 [article] No preliminary evidence of differences in astrocyte density within the white matter of the dorsolateral prefrontal cortex in autism [Texte imprimé et/ou numérique] / T. T. LEE, Auteur ; E. SKAFIDAS, Auteur ; M. DOTTORI, Auteur ; D. ZANTOMIO, Auteur ; Christos PANTELIS, Auteur ; I. EVERALL, Auteur ; G. CHANA, Auteur . - 64p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 64p. Mots-clés : Astrocytes  Autism  Cell density  Dorsolateral prefrontal cortex (DLPFC)  Glia  White matter Index. décimale : PER Périodiques Résumé : Background: While evidence for white matter and astrocytic abnormalities exist in autism, a detailed investigation of astrocytes has not been conducted. Such an investigation is further warranted by an increasing role for neuroinflammation in autism pathogenesis, with astrocytes being key players in this process. We present the first study of astrocyte density and morphology within the white matter of the dorsolateral prefrontal cortex (DLPFC) in individuals with autism. Methods: DLPFC formalin-fixed sections containing white matter from individuals with autism (n = 8, age = 4-51 years) and age-matched controls (n = 7, age = 4-46 years) were immunostained for glial fibrillary acidic protein (GFAP). Density of astrocytes and other glia were estimated via the optical fractionator, astrocyte somal size estimated via the nucleator, and astrocyte process length via the spaceballs probe. Results: We found no evidence for alteration in astrocyte density within DLPFC white matter of individuals with autism versus controls, together with no differences in astrocyte somal size and process length. Conclusion: Our results suggest that astrocyte abnormalities within the white matter in the DLPFC in autism may be less pronounced than previously thought. However, astrocytic dysregulation may still exist in autism, even in the absence of gross morphological changes. Our lack of evidence for astrocyte abnormalities could have been confounded to an extent by having a small sample size and wide age range, with pathological features potentially restricted to early stages of autism. Nonetheless, future investigations would benefit from assessing functional markers of astrocytes in light of the underlying pathophysiology of autism. En ligne : http://dx.doi.org/10.1186/s13229-017-0181-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330

Sparsifying machine learning models identify stable subsets of predictive features for behavioral detection of autism / S. LEVY in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 65p. Titre : Sparsifying machine learning models identify stable subsets of predictive features for behavioral detection of autism Type de document : Texte imprimé et/ou numérique Auteurs : S. LEVY, Auteur ; M. DUDA, Auteur ; N. HABER, Auteur ; Dennis P. WALL, Auteur Article en page(s) : 65p. Langues : Anglais (eng) Mots-clés : Asd  Autism  Autism diagnosis  Autism screening  Autism spectrum disorder  Machine learning  Sparse machine learning  company focused on building digital solutions for child health.Springer Nature  remains neutral with regard to jurisdictional claims in published maps and  institutional affiliations. Index. décimale : PER Périodiques Résumé : Background: Autism spectrum disorder (ASD) diagnosis can be delayed due in part to the time required for administration of standard exams, such as the Autism Diagnostic Observation Schedule (ADOS). Shorter and potentially mobilized approaches would help to alleviate bottlenecks in the healthcare system. Previous work using machine learning suggested that a subset of the behaviors measured by ADOS can achieve clinically acceptable levels of accuracy. Here we expand on this initial work to build sparse models that have higher potential to generalize to the clinical population. Methods: We assembled a collection of score sheets for two ADOS modules, one for children with phrased speech (Module 2; 1319 ASD cases, 70 controls) and the other for children with verbal fluency (Module 3; 2870 ASD cases, 273 controls). We used sparsity/parsimony enforcing regularization techniques in a nested cross validation grid search to select features for 17 unique supervised learning models, encoding missing values as additional indicator features. We augmented our feature sets with gender and age to train minimal and interpretable classifiers capable of robust detection of ASD from non-ASD. Results: By applying 17 unique supervised learning methods across 5 classification families tuned for sparse use of features and to be within 1 standard error of the optimal model, we find reduced sets of 10 and 5 features used in a majority of models. We tested the performance of the most interpretable of these sparse models, including Logistic Regression with L2 regularization or Linear SVM with L1 regularization. We obtained an area under the ROC curve of 0.95 for ADOS Module 3 and 0.93 for ADOS Module 2 with less than or equal to 10 features. Conclusions: The resulting models provide improved stability over previous machine learning efforts to minimize the time complexity of autism detection due to regularization and a small parameter space. These robustness techniques yield classifiers that are sparse, interpretable and that have potential to generalize to alternative modes of autism screening, diagnosis and monitoring, possibly including analysis of short home videos. En ligne : http://dx.doi.org/10.1186/s13229-017-0180-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330 [article] Sparsifying machine learning models identify stable subsets of predictive features for behavioral detection of autism [Texte imprimé et/ou numérique] / S. LEVY, Auteur ; M. DUDA, Auteur ; N. HABER, Auteur ; Dennis P. WALL, Auteur . - 65p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 65p. Mots-clés : Asd  Autism  Autism diagnosis  Autism screening  Autism spectrum disorder  Machine learning  Sparse machine learning  company focused on building digital solutions for child health.Springer Nature  remains neutral with regard to jurisdictional claims in published maps and  institutional affiliations. Index. décimale : PER Périodiques Résumé : Background: Autism spectrum disorder (ASD) diagnosis can be delayed due in part to the time required for administration of standard exams, such as the Autism Diagnostic Observation Schedule (ADOS). Shorter and potentially mobilized approaches would help to alleviate bottlenecks in the healthcare system. Previous work using machine learning suggested that a subset of the behaviors measured by ADOS can achieve clinically acceptable levels of accuracy. Here we expand on this initial work to build sparse models that have higher potential to generalize to the clinical population. Methods: We assembled a collection of score sheets for two ADOS modules, one for children with phrased speech (Module 2; 1319 ASD cases, 70 controls) and the other for children with verbal fluency (Module 3; 2870 ASD cases, 273 controls). We used sparsity/parsimony enforcing regularization techniques in a nested cross validation grid search to select features for 17 unique supervised learning models, encoding missing values as additional indicator features. We augmented our feature sets with gender and age to train minimal and interpretable classifiers capable of robust detection of ASD from non-ASD. Results: By applying 17 unique supervised learning methods across 5 classification families tuned for sparse use of features and to be within 1 standard error of the optimal model, we find reduced sets of 10 and 5 features used in a majority of models. We tested the performance of the most interpretable of these sparse models, including Logistic Regression with L2 regularization or Linear SVM with L1 regularization. We obtained an area under the ROC curve of 0.95 for ADOS Module 3 and 0.93 for ADOS Module 2 with less than or equal to 10 features. Conclusions: The resulting models provide improved stability over previous machine learning efforts to minimize the time complexity of autism detection due to regularization and a small parameter space. These robustness techniques yield classifiers that are sparse, interpretable and that have potential to generalize to alternative modes of autism screening, diagnosis and monitoring, possibly including analysis of short home videos. En ligne : http://dx.doi.org/10.1186/s13229-017-0180-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330

Hierarchical cortical transcriptome disorganization in autism / M. V. LOMBARDO in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 29p. Titre : Hierarchical cortical transcriptome disorganization in autism Type de document : Texte imprimé et/ou numérique Auteurs : M. V. LOMBARDO, Auteur ; E. COURCHESNE, Auteur ; N. E. LEWIS, Auteur ; T. PRAMPARO, Auteur Article en page(s) : 29p. Langues : Anglais (eng) Mots-clés : Autism  Gene co-expression networks  Immune  Synapse  Systems biology  Transcriptome  Translation Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorders (ASD) are etiologically heterogeneous and complex. Functional genomics work has begun to identify a diverse array of dysregulated transcriptomic programs (e.g., synaptic, immune, cell cycle, DNA damage, WNT signaling, cortical patterning and differentiation) potentially involved in ASD brain abnormalities during childhood and adulthood. However, it remains unclear whether such diverse dysregulated pathways are independent of each other or instead reflect coordinated hierarchical systems-level pathology. METHODS: Two ASD cortical transcriptome datasets were re-analyzed using consensus weighted gene co-expression network analysis (WGCNA) to identify common co-expression modules across datasets. Linear mixed-effect models and Bayesian replication statistics were used to identify replicable differentially expressed modules. Eigengene network analysis was then utilized to identify between-group differences in how co-expression modules interact and cluster into hierarchical meta-modular organization. Protein-protein interaction analyses were also used to determine whether dysregulated co-expression modules show enhanced interactions. RESULTS: We find replicable evidence for 10 gene co-expression modules that are differentially expressed in ASD cortex. Rather than being independent non-interacting sources of pathology, these dysregulated co-expression modules work in synergy and physically interact at the protein level. These systems-level transcriptional signals are characterized by downregulation of synaptic processes coordinated with upregulation of immune/inflammation, response to other organism, catabolism, viral processes, translation, protein targeting and localization, cell proliferation, and vasculature development. Hierarchical organization of meta-modules (clusters of highly correlated modules) is also highly affected in ASD. CONCLUSIONS: These findings highlight that dysregulation of the ASD cortical transcriptome is characterized by the dysregulation of multiple coordinated transcriptional programs producing synergistic systems-level effects that cannot be fully appreciated by studying the individual component biological processes in isolation. En ligne : http://dx.doi.org/10.1186/s13229-017-0147-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330 [article] Hierarchical cortical transcriptome disorganization in autism [Texte imprimé et/ou numérique] / M. V. LOMBARDO, Auteur ; E. COURCHESNE, Auteur ; N. E. LEWIS, Auteur ; T. PRAMPARO, Auteur . - 29p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 29p. Mots-clés : Autism  Gene co-expression networks  Immune  Synapse  Systems biology  Transcriptome  Translation Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorders (ASD) are etiologically heterogeneous and complex. Functional genomics work has begun to identify a diverse array of dysregulated transcriptomic programs (e.g., synaptic, immune, cell cycle, DNA damage, WNT signaling, cortical patterning and differentiation) potentially involved in ASD brain abnormalities during childhood and adulthood. However, it remains unclear whether such diverse dysregulated pathways are independent of each other or instead reflect coordinated hierarchical systems-level pathology. METHODS: Two ASD cortical transcriptome datasets were re-analyzed using consensus weighted gene co-expression network analysis (WGCNA) to identify common co-expression modules across datasets. Linear mixed-effect models and Bayesian replication statistics were used to identify replicable differentially expressed modules. Eigengene network analysis was then utilized to identify between-group differences in how co-expression modules interact and cluster into hierarchical meta-modular organization. Protein-protein interaction analyses were also used to determine whether dysregulated co-expression modules show enhanced interactions. RESULTS: We find replicable evidence for 10 gene co-expression modules that are differentially expressed in ASD cortex. Rather than being independent non-interacting sources of pathology, these dysregulated co-expression modules work in synergy and physically interact at the protein level. These systems-level transcriptional signals are characterized by downregulation of synaptic processes coordinated with upregulation of immune/inflammation, response to other organism, catabolism, viral processes, translation, protein targeting and localization, cell proliferation, and vasculature development. Hierarchical organization of meta-modules (clusters of highly correlated modules) is also highly affected in ASD. CONCLUSIONS: These findings highlight that dysregulation of the ASD cortical transcriptome is characterized by the dysregulation of multiple coordinated transcriptional programs producing synergistic systems-level effects that cannot be fully appreciated by studying the individual component biological processes in isolation. En ligne : http://dx.doi.org/10.1186/s13229-017-0147-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330

The EU-AIMS Longitudinal European Autism Project (LEAP): design and methodologies to identify and validate stratification biomarkers for autism spectrum disorders / E. LOTH in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 24p. Titre : The EU-AIMS Longitudinal European Autism Project (LEAP): design and methodologies to identify and validate stratification biomarkers for autism spectrum disorders Type de document : Texte imprimé et/ou numérique Auteurs : E. LOTH, Auteur ; Tony CHARMAN, Auteur ; L. MASON, Auteur ; J. TILLMANN, Auteur ; E. J. H. JONES, Auteur ; C. WOOLDRIDGE, Auteur ; Jumana AHMAD, Auteur ; Bonnie AUYEUNG, Auteur ; C. BROGNA, Auteur ; S. AMBROSINO, Auteur ; Tobias BANASCHEWSKI, Auteur ; Simon BARON-COHEN, Auteur ; Sarah BAUMEISTER, Auteur ; C. BECKMANN, Auteur ; Michael BRAMMER, Auteur ; Daniel BRANDEIS, Auteur ; Sven BÖLTE, Auteur ; Thomas BOURGERON, Auteur ; Carsten BOURS, Auteur ; Y. DE BRUIJN, Auteur ; Bhismadev CHAKRABARTI, Auteur ; D. CRAWLEY, Auteur ; I. CORNELISSEN, Auteur ; F. D. ACQUA, Auteur ; G. DUMAS, Auteur ; S. DURSTON, Auteur ; C. ECKER, Auteur ; J. FAULKNER, Auteur ; V. FROUIN, Auteur ; P. GARCES, Auteur ; D. GOYARD, Auteur ; H. HAYWARD, Auteur ; L. M. HAM, Auteur ; J. HIPP, Auteur ; R. J. HOLT, Auteur ; M. H. JOHNSON, Auteur ; J. ISAKSSON, Auteur ; P. KUNDU, Auteur ; Meng-Chuan LAI, Auteur ; L. D'ARDHUY X, Auteur ; M. V. LOMBARDO, Auteur ; D. J. LYTHGOE, Auteur ; R. MANDL, Auteur ; A. MEYER-LINDENBERG, Auteur ; C. MOESSNANG, Auteur ; N. MUELLER, Auteur ; L. O'DWYER, Auteur ; M. OLDEHINKEL, Auteur ; B. ORANJE, Auteur ; Gahan PANDINA, Auteur ; A. M. PERSICO, Auteur ; A. N. V. RUIGROK, Auteur ; B. RUGGERI, Auteur ; J. SABET, Auteur ; R. SACCO, Auteur ; Antonia SAN JOSE CACERES, Auteur ; E. SIMONOFF, Auteur ; R. TORO, Auteur ; H. TOST, Auteur ; J. WALDMAN, Auteur ; S. C. R. WILLIAMS, Auteur ; M. P. ZWIERS, Auteur ; W. SPOOREN, Auteur ; D. G. M. MURPHY, Auteur ; Jan K. BUITELAAR, Auteur Article en page(s) : 24p. Langues : Anglais (eng) Mots-clés : Biomarkers  Cognition  Eeg  Eye-tracking  Genetics  Mri  Neuroimaging Index. décimale : PER Périodiques Résumé : BACKGROUND: The tremendous clinical and aetiological diversity among individuals with autism spectrum disorder (ASD) has been a major obstacle to the development of new treatments, as many may only be effective in particular subgroups. Precision medicine approaches aim to overcome this challenge by combining pathophysiologically based treatments with stratification biomarkers that predict which treatment may be most beneficial for particular individuals. However, so far, we have no single validated stratification biomarker for ASD. This may be due to the fact that most research studies primarily have focused on the identification of mean case-control differences, rather than within-group variability, and included small samples that were underpowered for stratification approaches. The EU-AIMS Longitudinal European Autism Project (LEAP) is to date the largest multi-centre, multi-disciplinary observational study worldwide that aims to identify and validate stratification biomarkers for ASD. METHODS: LEAP includes 437 children and adults with ASD and 300 individuals with typical development or mild intellectual disability. Using an accelerated longitudinal design, each participant is comprehensively characterised in terms of clinical symptoms, comorbidities, functional outcomes, neurocognitive profile, brain structure and function, biochemical markers and genomics. In addition, 51 twin-pairs (of which 36 had one sibling with ASD) are included to identify genetic and environmental factors in phenotypic variability. RESULTS: Here, we describe the demographic characteristics of the cohort, planned analytic stratification approaches, criteria and steps to validate candidate stratification markers, pre-registration procedures to increase transparency, standardisation and data robustness across all analyses, and share some 'lessons learnt'. A clinical characterisation of the cohort is given in the companion paper (Charman et al., accepted). CONCLUSION: We expect that LEAP will enable us to confirm, reject and refine current hypotheses of neurocognitive/neurobiological abnormalities, identify biologically and clinically meaningful ASD subgroups, and help us map phenotypic heterogeneity to different aetiologies. En ligne : http://dx.doi.org/10.1186/s13229-017-0146-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330 [article] The EU-AIMS Longitudinal European Autism Project (LEAP): design and methodologies to identify and validate stratification biomarkers for autism spectrum disorders [Texte imprimé et/ou numérique] / E. LOTH, Auteur ; Tony CHARMAN, Auteur ; L. MASON, Auteur ; J. TILLMANN, Auteur ; E. J. H. JONES, Auteur ; C. WOOLDRIDGE, Auteur ; Jumana AHMAD, Auteur ; Bonnie AUYEUNG, Auteur ; C. BROGNA, Auteur ; S. AMBROSINO, Auteur ; Tobias BANASCHEWSKI, Auteur ; Simon BARON-COHEN, Auteur ; Sarah BAUMEISTER, Auteur ; C. BECKMANN, Auteur ; Michael BRAMMER, Auteur ; Daniel BRANDEIS, Auteur ; Sven BÖLTE, Auteur ; Thomas BOURGERON, Auteur ; Carsten BOURS, Auteur ; Y. DE BRUIJN, Auteur ; Bhismadev CHAKRABARTI, Auteur ; D. CRAWLEY, Auteur ; I. CORNELISSEN, Auteur ; F. D. ACQUA, Auteur ; G. DUMAS, Auteur ; S. DURSTON, Auteur ; C. ECKER, Auteur ; J. FAULKNER, Auteur ; V. FROUIN, Auteur ; P. GARCES, Auteur ; D. GOYARD, Auteur ; H. HAYWARD, Auteur ; L. M. HAM, Auteur ; J. HIPP, Auteur ; R. J. HOLT, Auteur ; M. H. JOHNSON, Auteur ; J. ISAKSSON, Auteur ; P. KUNDU, Auteur ; Meng-Chuan LAI, Auteur ; L. D'ARDHUY X, Auteur ; M. V. LOMBARDO, Auteur ; D. J. LYTHGOE, Auteur ; R. MANDL, Auteur ; A. MEYER-LINDENBERG, Auteur ; C. MOESSNANG, Auteur ; N. MUELLER, Auteur ; L. O'DWYER, Auteur ; M. OLDEHINKEL, Auteur ; B. ORANJE, Auteur ; Gahan PANDINA, Auteur ; A. M. PERSICO, Auteur ; A. N. V. RUIGROK, Auteur ; B. RUGGERI, Auteur ; J. SABET, Auteur ; R. SACCO, Auteur ; Antonia SAN JOSE CACERES, Auteur ; E. SIMONOFF, Auteur ; R. TORO, Auteur ; H. TOST, Auteur ; J. WALDMAN, Auteur ; S. C. R. WILLIAMS, Auteur ; M. P. ZWIERS, Auteur ; W. SPOOREN, Auteur ; D. G. M. MURPHY, Auteur ; Jan K. BUITELAAR, Auteur . - 24p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 24p. Mots-clés : Biomarkers  Cognition  Eeg  Eye-tracking  Genetics  Mri  Neuroimaging Index. décimale : PER Périodiques Résumé : BACKGROUND: The tremendous clinical and aetiological diversity among individuals with autism spectrum disorder (ASD) has been a major obstacle to the development of new treatments, as many may only be effective in particular subgroups. Precision medicine approaches aim to overcome this challenge by combining pathophysiologically based treatments with stratification biomarkers that predict which treatment may be most beneficial for particular individuals. However, so far, we have no single validated stratification biomarker for ASD. This may be due to the fact that most research studies primarily have focused on the identification of mean case-control differences, rather than within-group variability, and included small samples that were underpowered for stratification approaches. The EU-AIMS Longitudinal European Autism Project (LEAP) is to date the largest multi-centre, multi-disciplinary observational study worldwide that aims to identify and validate stratification biomarkers for ASD. METHODS: LEAP includes 437 children and adults with ASD and 300 individuals with typical development or mild intellectual disability. Using an accelerated longitudinal design, each participant is comprehensively characterised in terms of clinical symptoms, comorbidities, functional outcomes, neurocognitive profile, brain structure and function, biochemical markers and genomics. In addition, 51 twin-pairs (of which 36 had one sibling with ASD) are included to identify genetic and environmental factors in phenotypic variability. RESULTS: Here, we describe the demographic characteristics of the cohort, planned analytic stratification approaches, criteria and steps to validate candidate stratification markers, pre-registration procedures to increase transparency, standardisation and data robustness across all analyses, and share some 'lessons learnt'. A clinical characterisation of the cohort is given in the companion paper (Charman et al., accepted). CONCLUSION: We expect that LEAP will enable us to confirm, reject and refine current hypotheses of neurocognitive/neurobiological abnormalities, identify biologically and clinically meaningful ASD subgroups, and help us map phenotypic heterogeneity to different aetiologies. En ligne : http://dx.doi.org/10.1186/s13229-017-0146-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330

Specificity of executive function and theory of mind performance in relation to attention-deficit/hyperactivity symptoms in autism spectrum disorders / S. LUKITO in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 60p. Titre : Specificity of executive function and theory of mind performance in relation to attention-deficit/hyperactivity symptoms in autism spectrum disorders Type de document : Texte imprimé et/ou numérique Auteurs : S. LUKITO, Auteur ; Catherine R. G. JONES, Auteur ; A. PICKLES, Auteur ; Gillian BAIRD, Auteur ; Francesca HAPPE, Auteur ; Tony CHARMAN, Auteur ; E. SIMONOFF, Auteur Article en page(s) : 60p. Langues : Anglais (eng) Mots-clés : Attention-deficit/hyperactivity disorder  Autism spectrum disorder  Comorbidity  Executive function  Snap  Theory of mind Index. décimale : PER Périodiques Résumé : Background: Individuals with autism spectrum disorder (ASD) frequently demonstrate symptoms of attention-deficit/hyperactivity disorder (ADHD). Previous findings in children with ASD have suggested that these symptoms are associated with an impairment in executive function (EF) abilities. However, studies rarely considered this association within a single framework that controls for other related factors such as Theory of Mind (ToM) abilities and ASD symptoms. Methods: We used structural equation modeling to explore the relations among EF, ToM, and symptoms of ASD and ADHD, using data from a population-based sample of 100 adolescents with ASD and full-scale IQ >/= 50 (the Special Needs and Autism Project (SNAP) cohort). The study used a multi-measure and multi-informant approach, where performance of inhibition, planning, switching, and working memory tasks indexed EF and performance on tasks involving mentalizing indexed ToM. Measures of ASD and ADHD symptoms included parent and teacher reports and direct observation of the children. Shared source of symptom reporting was accounted for with a parental rating latent factor indexed by symptom measures reported by parents. Results: Impairments in EF abilities were specifically associated with ADHD symptoms while impaired ToM was specifically associated with ASD symptoms, when accounting for the associations of each cognitive domain with the other factors. ASD and ADHD symptom latent factors were also correlated, but this association became nonsignificant once the shared source of reporting from parents was accounted for and within a model that also controlled for the correlated pathway between EF and ToM factors. The specific relations between the cognitive domains and behavioral symptoms remained even after controlling for IQ. Conclusions: In this ASD sample, symptoms of ADHD and ASD are underpinned by separate cognitive domains. The association between EF and ToM impairments is a likely partial explanation for the co-occurrence of ADHD symptoms in ASD, but the role of shared reporting effects is also important and supports the inclusion of independent informants and objective measures in future research. En ligne : http://dx.doi.org/10.1186/s13229-017-0177-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330 [article] Specificity of executive function and theory of mind performance in relation to attention-deficit/hyperactivity symptoms in autism spectrum disorders [Texte imprimé et/ou numérique] / S. LUKITO, Auteur ; Catherine R. G. JONES, Auteur ; A. PICKLES, Auteur ; Gillian BAIRD, Auteur ; Francesca HAPPE, Auteur ; Tony CHARMAN, Auteur ; E. SIMONOFF, Auteur . - 60p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 60p. Mots-clés : Attention-deficit/hyperactivity disorder  Autism spectrum disorder  Comorbidity  Executive function  Snap  Theory of mind Index. décimale : PER Périodiques Résumé : Background: Individuals with autism spectrum disorder (ASD) frequently demonstrate symptoms of attention-deficit/hyperactivity disorder (ADHD). Previous findings in children with ASD have suggested that these symptoms are associated with an impairment in executive function (EF) abilities. However, studies rarely considered this association within a single framework that controls for other related factors such as Theory of Mind (ToM) abilities and ASD symptoms. Methods: We used structural equation modeling to explore the relations among EF, ToM, and symptoms of ASD and ADHD, using data from a population-based sample of 100 adolescents with ASD and full-scale IQ >/= 50 (the Special Needs and Autism Project (SNAP) cohort). The study used a multi-measure and multi-informant approach, where performance of inhibition, planning, switching, and working memory tasks indexed EF and performance on tasks involving mentalizing indexed ToM. Measures of ASD and ADHD symptoms included parent and teacher reports and direct observation of the children. Shared source of symptom reporting was accounted for with a parental rating latent factor indexed by symptom measures reported by parents. Results: Impairments in EF abilities were specifically associated with ADHD symptoms while impaired ToM was specifically associated with ASD symptoms, when accounting for the associations of each cognitive domain with the other factors. ASD and ADHD symptom latent factors were also correlated, but this association became nonsignificant once the shared source of reporting from parents was accounted for and within a model that also controlled for the correlated pathway between EF and ToM factors. The specific relations between the cognitive domains and behavioral symptoms remained even after controlling for IQ. Conclusions: In this ASD sample, symptoms of ADHD and ASD are underpinned by separate cognitive domains. The association between EF and ToM impairments is a likely partial explanation for the co-occurrence of ADHD symptoms in ASD, but the role of shared reporting effects is also important and supports the inclusion of independent informants and objective measures in future research. En ligne : http://dx.doi.org/10.1186/s13229-017-0177-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330

Use of clinical chromosomal microarray in Chinese patients with autism spectrum disorder-implications of a copy number variation involving DPP10 / A. S. L. MAK in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 31p. Titre : Use of clinical chromosomal microarray in Chinese patients with autism spectrum disorder-implications of a copy number variation involving DPP10 Type de document : Texte imprimé et/ou numérique Auteurs : A. S. L. MAK, Auteur ; A. T. G. CHIU, Auteur ; G. K. C. LEUNG, Auteur ; C. C. Y. MAK, Auteur ; Y. W. Y. CHU, Auteur ; G. T. K. MOK, Auteur ; W. F. TANG, Auteur ; K. Y. K. CHAN, Auteur ; M. H. Y. TANG, Auteur ; E. T. LAU YIM, Auteur ; K. W. SO, Auteur ; V. Q. TAO, Auteur ; C. W. FUNG, Auteur ; Virginia C.N. WONG, Auteur ; M. UDDIN, Auteur ; S. L. LEE, Auteur ; C. R. MARSHALL, Auteur ; Stephen SCHERER, Auteur ; A. S. Y. KAN, Auteur ; B. H. Y. CHUNG, Auteur Article en page(s) : 31p. Langues : Anglais (eng) Mots-clés : Array comparative genomic hybridization (aCGH)  Autism spectrum disorder (ASD)  Chinese  Copy number variations (CNVs)  Dpp10 Index. décimale : PER Périodiques Résumé : BACKGROUND: Array comparative genomic hybridization (aCGH) is recommended as a first-tier genetic test for children with autism spectrum disorder (ASD). However, interpretation of results can often be challenging partly due to the fact that copy number variants (CNVs) in non-European ASD patients are not well studied. To address this literature gap, we report the CNV findings in a cohort of Chinese children with ASD. METHODS: DNA samples were obtained from 258 Chinese ASD patients recruited from a child assessment center between January 2011 and August 2014. aCGH was performed using NimbleGen-CGX-135k or Agilent-CGX 60k oligonucleotide array. Results were classified based on existing guidelines and literature. RESULTS: Ten pathogenic CNVs and one likely pathogenic CNV were found in nine patients, with an overall diagnostic yield of 3.5%. A 138 kb duplication involving 3' exons of DPP10 (arr[GRCh37] 2q14.1(116534689_116672358)x3), reported to be associated with ASD, was identified in one patient (0.39%). The same CNV was reported as variant of uncertain significance (VUS) in DECIPHER database. Multiple individuals of typical development carrying a similar duplication were identified among our ancestry-matched control with a frequency of 6/653 (0.92%) as well as from literature and genomic databases. CONCLUSIONS: The DPP10 duplication is likely a benign CNV polymorphism enriched in Southern Chinese with a population frequency of ~1%. This highlights the importance of using ancestry-matched controls in interpretation of aCGH findings. En ligne : http://dx.doi.org/10.1186/s13229-017-0136-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330 [article] Use of clinical chromosomal microarray in Chinese patients with autism spectrum disorder-implications of a copy number variation involving DPP10 [Texte imprimé et/ou numérique] / A. S. L. MAK, Auteur ; A. T. G. CHIU, Auteur ; G. K. C. LEUNG, Auteur ; C. C. Y. MAK, Auteur ; Y. W. Y. CHU, Auteur ; G. T. K. MOK, Auteur ; W. F. TANG, Auteur ; K. Y. K. CHAN, Auteur ; M. H. Y. TANG, Auteur ; E. T. LAU YIM, Auteur ; K. W. SO, Auteur ; V. Q. TAO, Auteur ; C. W. FUNG, Auteur ; Virginia C.N. WONG, Auteur ; M. UDDIN, Auteur ; S. L. LEE, Auteur ; C. R. MARSHALL, Auteur ; Stephen SCHERER, Auteur ; A. S. Y. KAN, Auteur ; B. H. Y. CHUNG, Auteur . - 31p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 31p. Mots-clés : Array comparative genomic hybridization (aCGH)  Autism spectrum disorder (ASD)  Chinese  Copy number variations (CNVs)  Dpp10 Index. décimale : PER Périodiques Résumé : BACKGROUND: Array comparative genomic hybridization (aCGH) is recommended as a first-tier genetic test for children with autism spectrum disorder (ASD). However, interpretation of results can often be challenging partly due to the fact that copy number variants (CNVs) in non-European ASD patients are not well studied. To address this literature gap, we report the CNV findings in a cohort of Chinese children with ASD. METHODS: DNA samples were obtained from 258 Chinese ASD patients recruited from a child assessment center between January 2011 and August 2014. aCGH was performed using NimbleGen-CGX-135k or Agilent-CGX 60k oligonucleotide array. Results were classified based on existing guidelines and literature. RESULTS: Ten pathogenic CNVs and one likely pathogenic CNV were found in nine patients, with an overall diagnostic yield of 3.5%. A 138 kb duplication involving 3' exons of DPP10 (arr[GRCh37] 2q14.1(116534689_116672358)x3), reported to be associated with ASD, was identified in one patient (0.39%). The same CNV was reported as variant of uncertain significance (VUS) in DECIPHER database. Multiple individuals of typical development carrying a similar duplication were identified among our ancestry-matched control with a frequency of 6/653 (0.92%) as well as from literature and genomic databases. CONCLUSIONS: The DPP10 duplication is likely a benign CNV polymorphism enriched in Southern Chinese with a population frequency of ~1%. This highlights the importance of using ancestry-matched controls in interpretation of aCGH findings. En ligne : http://dx.doi.org/10.1186/s13229-017-0136-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330

Susceptibility to Ebbinghaus and Muller-Lyer illusions in autistic children: a comparison of three different methods / C. MANNING in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 16p. Titre : Susceptibility to Ebbinghaus and Muller-Lyer illusions in autistic children: a comparison of three different methods Type de document : Texte imprimé et/ou numérique Auteurs : C. MANNING, Auteur ; M. J. MORGAN, Auteur ; C. T. W. ALLEN, Auteur ; E. PELLICANO, Auteur Article en page(s) : 16p. Langues : Anglais (eng) Mots-clés : Adolescent  Autistic Disorder/*psychology  Child  Female  Humans  Male  Optical Illusions/*physiology  Pattern Recognition, Visual  Photic Stimulation/*methods  Size Perception  *Autism  *Cognitive bias  *Context  *Global processing  *Perception  *Response bias  *Vision  *Visual illusions Index. décimale : PER Périodiques Résumé : BACKGROUND: Studies reporting altered susceptibility to visual illusions in autistic individuals compared to that typically developing individuals have been taken to reflect differences in perception (e.g. reduced global processing), but could instead reflect differences in higher-level decision-making strategies. METHODS: We measured susceptibility to two contextual illusions (Ebbinghaus, Muller-Lyer) in autistic children aged 6-14 years and typically developing children matched in age and non-verbal ability using three methods. In experiment 1, we used a new two-alternative-forced-choice method with a roving pedestal designed to minimise cognitive biases. Here, children judged which of two comparison stimuli was most similar in size to a reference stimulus. In experiments 2 and 3, we used methods previously used with autistic populations. In experiment 2, children judged whether stimuli were the 'same' or 'different', and in experiment 3, we used a method-of-adjustment task. RESULTS: Across all tasks, autistic children were equally susceptible to the Ebbinghaus illusion as typically developing children. Autistic children showed a heightened susceptibility to the Muller-Lyer illusion, but only in the method-of-adjustment task. This result may reflect differences in decisional criteria. CONCLUSIONS: Our results are inconsistent with theories proposing reduced contextual integration in autism and suggest that previous reports of altered susceptibility to illusions may arise from differences in decision-making, rather than differences in perception per se. Our findings help to elucidate the underlying reasons for atypical responses to perceptual illusions in autism and call for the use of methods that reduce cognitive bias when measuring illusion susceptibility. En ligne : http://dx.doi.org/10.1186/s13229-017-0127-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330 [article] Susceptibility to Ebbinghaus and Muller-Lyer illusions in autistic children: a comparison of three different methods [Texte imprimé et/ou numérique] / C. MANNING, Auteur ; M. J. MORGAN, Auteur ; C. T. W. ALLEN, Auteur ; E. PELLICANO, Auteur . - 16p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 16p. Mots-clés : Adolescent  Autistic Disorder/*psychology  Child  Female  Humans  Male  Optical Illusions/*physiology  Pattern Recognition, Visual  Photic Stimulation/*methods  Size Perception  *Autism  *Cognitive bias  *Context  *Global processing  *Perception  *Response bias  *Vision  *Visual illusions Index. décimale : PER Périodiques Résumé : BACKGROUND: Studies reporting altered susceptibility to visual illusions in autistic individuals compared to that typically developing individuals have been taken to reflect differences in perception (e.g. reduced global processing), but could instead reflect differences in higher-level decision-making strategies. METHODS: We measured susceptibility to two contextual illusions (Ebbinghaus, Muller-Lyer) in autistic children aged 6-14 years and typically developing children matched in age and non-verbal ability using three methods. In experiment 1, we used a new two-alternative-forced-choice method with a roving pedestal designed to minimise cognitive biases. Here, children judged which of two comparison stimuli was most similar in size to a reference stimulus. In experiments 2 and 3, we used methods previously used with autistic populations. In experiment 2, children judged whether stimuli were the 'same' or 'different', and in experiment 3, we used a method-of-adjustment task. RESULTS: Across all tasks, autistic children were equally susceptible to the Ebbinghaus illusion as typically developing children. Autistic children showed a heightened susceptibility to the Muller-Lyer illusion, but only in the method-of-adjustment task. This result may reflect differences in decisional criteria. CONCLUSIONS: Our results are inconsistent with theories proposing reduced contextual integration in autism and suggest that previous reports of altered susceptibility to illusions may arise from differences in decision-making, rather than differences in perception per se. Our findings help to elucidate the underlying reasons for atypical responses to perceptual illusions in autism and call for the use of methods that reduce cognitive bias when measuring illusion susceptibility. En ligne : http://dx.doi.org/10.1186/s13229-017-0127-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330

Cytokine levels and associations with symptom severity in male and female children with autism spectrum disorder / A. MASI in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 63p. Titre : Cytokine levels and associations with symptom severity in male and female children with autism spectrum disorder Type de document : Texte imprimé et/ou numérique Auteurs : A. MASI, Auteur ; E. J. BREEN, Auteur ; Gail A. ALVARES, Auteur ; N. GLOZIER, Auteur ; I. B. HICKIE, Auteur ; A. HUNT, Auteur ; J. HUI, Auteur ; J. BEILBY, Auteur ; D. RAVINE, Auteur ; J. WRAY, Auteur ; Andrew J. O. WHITEHOUSE, Auteur ; A. J. GUASTELLA, Auteur Article en page(s) : 63p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  Behavior  Cytokine  Pediatric  Severity Index. décimale : PER Périodiques Résumé : Background: Autism spectrum disorders (ASDs) are complex, pervasive, and heterogeneous neurodevelopmental conditions with varying trajectories, significant male bias and largely unknown etiology. However, an understanding of the biological mechanisms driving pathophysiology is evolving. Immune system aberrations, as identified through cytokine profiles, are believed to have a role in ASD. Altered cytokine levels may facilitate identification of ASD subtypes as well as provide biological markers of response to effective treatments. Research exploring the relationship between cytokine profiles and ASD symptoms is, however, in its infancy. The objective of this study was to explore relationships between cytokine levels and the severity of ASD and other clinical traits. Methods: Multiplex assay techniques were used to measure levels of 27 cytokines in plasma samples from a cohort of 144 children diagnosed with ASD. Results: Overall, results showed a significant negative association between platelet-derived growth factor (PDGF)-BB, and the severity of ASD symptoms. Furthermore, a significant interaction with sex suggested a different immune profile for females compared to males. ASD symptom severity was negatively associated with levels of 4 cytokines, IL-1beta, IL-8, MIP-1beta, and VEGF, in females, but not in males. Conclusions: Results of the present study suggest that an altered cytokine response or profile is associated with the severity of ASD-related symptoms, with sex a potential modifier of this relationship. Further research in larger populations which recognizes the importance of sex comparisons and longitudinal assessments are now required to extend and further describe the role of the immune system in ASD. En ligne : http://dx.doi.org/10.1186/s13229-017-0176-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330 [article] Cytokine levels and associations with symptom severity in male and female children with autism spectrum disorder [Texte imprimé et/ou numérique] / A. MASI, Auteur ; E. J. BREEN, Auteur ; Gail A. ALVARES, Auteur ; N. GLOZIER, Auteur ; I. B. HICKIE, Auteur ; A. HUNT, Auteur ; J. HUI, Auteur ; J. BEILBY, Auteur ; D. RAVINE, Auteur ; J. WRAY, Auteur ; Andrew J. O. WHITEHOUSE, Auteur ; A. J. GUASTELLA, Auteur . - 63p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 63p. Mots-clés : Autism spectrum disorder  Behavior  Cytokine  Pediatric  Severity Index. décimale : PER Périodiques Résumé : Background: Autism spectrum disorders (ASDs) are complex, pervasive, and heterogeneous neurodevelopmental conditions with varying trajectories, significant male bias and largely unknown etiology. However, an understanding of the biological mechanisms driving pathophysiology is evolving. Immune system aberrations, as identified through cytokine profiles, are believed to have a role in ASD. Altered cytokine levels may facilitate identification of ASD subtypes as well as provide biological markers of response to effective treatments. Research exploring the relationship between cytokine profiles and ASD symptoms is, however, in its infancy. The objective of this study was to explore relationships between cytokine levels and the severity of ASD and other clinical traits. Methods: Multiplex assay techniques were used to measure levels of 27 cytokines in plasma samples from a cohort of 144 children diagnosed with ASD. Results: Overall, results showed a significant negative association between platelet-derived growth factor (PDGF)-BB, and the severity of ASD symptoms. Furthermore, a significant interaction with sex suggested a different immune profile for females compared to males. ASD symptom severity was negatively associated with levels of 4 cytokines, IL-1beta, IL-8, MIP-1beta, and VEGF, in females, but not in males. Conclusions: Results of the present study suggest that an altered cytokine response or profile is associated with the severity of ASD-related symptoms, with sex a potential modifier of this relationship. Further research in larger populations which recognizes the importance of sex comparisons and longitudinal assessments are now required to extend and further describe the role of the immune system in ASD. En ligne : http://dx.doi.org/10.1186/s13229-017-0176-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330

Disconnection from others in autism is more than just a feeling: whole-brain neural synchrony in adults during implicit processing of emotional faces / R. MENNELLA in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 7p. Titre : Disconnection from others in autism is more than just a feeling: whole-brain neural synchrony in adults during implicit processing of emotional faces Type de document : Texte imprimé et/ou numérique Auteurs : R. MENNELLA, Auteur ; R. C. LEUNG, Auteur ; M. J. TAYLOR, Auteur ; B. T. DUNKLEY, Auteur Article en page(s) : 7p. Langues : Anglais (eng) Mots-clés : Adult  Autism Spectrum Disorder/*psychology  Brain/*physiology  Brain Mapping/*methods  Facial Expression  Female  Humans  Image Processing, Computer-Assisted  Magnetoencephalography/*methods  Male  Social Perception  Young Adult  *Autism  *Emotional faces  *Functional connectivity  *Magnetoencephalography  *Social brain  *Young adults Index. décimale : PER Périodiques Résumé : BACKGROUND: Socio-emotional difficulties in autism spectrum disorder (ASD) are thought to reflect impaired functional connectivity within the "social brain". Nonetheless, a whole-brain characterization of the fast responses in functional connectivity during implicit processing of emotional faces in adults with ASD is lacking. METHODS: The present study used magnetoencephalography to investigate early responses in functional connectivity, as measured by interregional phase synchronization, during implicit processing of angry, neutral and happy faces. The sample (n = 44) consisted of 22 young adults with ASD and 22 age- and sex-matched typically developed (TD) controls. RESULTS: Reduced phase-synchrony in the beta band around 300 ms emerged during processing of angry faces in the ASD compared to TD group, involving key areas of the social brain. In the same time window, de-synchronization in the beta band in the amygdala was reduced in the ASD group across conditions. CONCLUSIONS: This is the first demonstration of atypical global and local synchrony patterns in the social brain in adults with ASD during implicit processing of emotional faces. The present results replicate and substantially extend previous findings on adolescents, highlighting that atypical brain synchrony during processing of socio-emotional stimuli is a hallmark of clinical sequelae in autism. En ligne : http://dx.doi.org/10.1186/s13229-017-0123-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330 [article] Disconnection from others in autism is more than just a feeling: whole-brain neural synchrony in adults during implicit processing of emotional faces [Texte imprimé et/ou numérique] / R. MENNELLA, Auteur ; R. C. LEUNG, Auteur ; M. J. TAYLOR, Auteur ; B. T. DUNKLEY, Auteur . - 7p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 7p. Mots-clés : Adult  Autism Spectrum Disorder/*psychology  Brain/*physiology  Brain Mapping/*methods  Facial Expression  Female  Humans  Image Processing, Computer-Assisted  Magnetoencephalography/*methods  Male  Social Perception  Young Adult  *Autism  *Emotional faces  *Functional connectivity  *Magnetoencephalography  *Social brain  *Young adults Index. décimale : PER Périodiques Résumé : BACKGROUND: Socio-emotional difficulties in autism spectrum disorder (ASD) are thought to reflect impaired functional connectivity within the "social brain". Nonetheless, a whole-brain characterization of the fast responses in functional connectivity during implicit processing of emotional faces in adults with ASD is lacking. METHODS: The present study used magnetoencephalography to investigate early responses in functional connectivity, as measured by interregional phase synchronization, during implicit processing of angry, neutral and happy faces. The sample (n = 44) consisted of 22 young adults with ASD and 22 age- and sex-matched typically developed (TD) controls. RESULTS: Reduced phase-synchrony in the beta band around 300 ms emerged during processing of angry faces in the ASD compared to TD group, involving key areas of the social brain. In the same time window, de-synchronization in the beta band in the amygdala was reduced in the ASD group across conditions. CONCLUSIONS: This is the first demonstration of atypical global and local synchrony patterns in the social brain in adults with ASD during implicit processing of emotional faces. The present results replicate and substantially extend previous findings on adolescents, highlighting that atypical brain synchrony during processing of socio-emotional stimuli is a hallmark of clinical sequelae in autism. En ligne : http://dx.doi.org/10.1186/s13229-017-0123-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330

Environmental risk factors for autism: an evidence-based review of systematic reviews and meta-analyses / A. MODABBERNIA in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 13p. Titre : Environmental risk factors for autism: an evidence-based review of systematic reviews and meta-analyses Type de document : Texte imprimé et/ou numérique Auteurs : A. MODABBERNIA, Auteur ; E. VELTHORST, Auteur ; A. REICHENBERG, Auteur Article en page(s) : 13p. Langues : Anglais (eng) Mots-clés : Autism Spectrum Disorder/*etiology  Delivery, Obstetric/*adverse effects  Environmental Exposure/*adverse effects  Female  Humans  Metals, Heavy/*toxicity  Parents  Pregnancy  Prospective Studies  Risk Factors  *Autism spectrum disorders  *Environment  *Epigenetics  *Gene-environment interaction  *Metals  *Nutrition  *Pregnancy prenatal  *Toxin  *Vaccine Index. décimale : PER Périodiques Résumé : BACKGROUND: According to recent evidence, up to 40-50% of variance in autism spectrum disorder (ASD) liability might be determined by environmental factors. In the present paper, we conducted a review of systematic reviews and meta-analyses of environmental risk factors for ASD. We assessed each review for quality of evidence and provided a brief overview of putative mechanisms of environmental risk factors for ASD. FINDINGS: Current evidence suggests that several environmental factors including vaccination, maternal smoking, thimerosal exposure, and most likely assisted reproductive technologies are unrelated to risk of ASD. On the contrary, advanced parental age is associated with higher risk of ASD. Birth complications that are associated with trauma or ischemia and hypoxia have also shown strong links to ASD, whereas other pregnancy-related factors such as maternal obesity, maternal diabetes, and caesarian section have shown a less strong (but significant) association with risk of ASD. The reviews on nutritional elements have been inconclusive about the detrimental effects of deficiency in folic acid and omega 3, but vitamin D seems to be deficient in patients with ASD. The studies on toxic elements have been largely limited by their design, but there is enough evidence for the association between some heavy metals (most important inorganic mercury and lead) and ASD that warrants further investigation. Mechanisms of the association between environmental factors and ASD are debated but might include non-causative association (including confounding), gene-related effect, oxidative stress, inflammation, hypoxia/ischemia, endocrine disruption, neurotransmitter alterations, and interference with signaling pathways. CONCLUSIONS: Compared to genetic studies of ASD, studies of environmental risk factors are in their infancy and have significant methodological limitations. Future studies of ASD risk factors would benefit from a developmental psychopathology approach, prospective design, precise exposure measurement, reliable timing of exposure in relation to critical developmental periods and should take into account the dynamic interplay between gene and environment by using genetically informed designs. En ligne : http://dx.doi.org/10.1186/s13229-017-0121-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330 [article] Environmental risk factors for autism: an evidence-based review of systematic reviews and meta-analyses [Texte imprimé et/ou numérique] / A. MODABBERNIA, Auteur ; E. VELTHORST, Auteur ; A. REICHENBERG, Auteur . - 13p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 13p. Mots-clés : Autism Spectrum Disorder/*etiology  Delivery, Obstetric/*adverse effects  Environmental Exposure/*adverse effects  Female  Humans  Metals, Heavy/*toxicity  Parents  Pregnancy  Prospective Studies  Risk Factors  *Autism spectrum disorders  *Environment  *Epigenetics  *Gene-environment interaction  *Metals  *Nutrition  *Pregnancy prenatal  *Toxin  *Vaccine Index. décimale : PER Périodiques Résumé : BACKGROUND: According to recent evidence, up to 40-50% of variance in autism spectrum disorder (ASD) liability might be determined by environmental factors. In the present paper, we conducted a review of systematic reviews and meta-analyses of environmental risk factors for ASD. We assessed each review for quality of evidence and provided a brief overview of putative mechanisms of environmental risk factors for ASD. FINDINGS: Current evidence suggests that several environmental factors including vaccination, maternal smoking, thimerosal exposure, and most likely assisted reproductive technologies are unrelated to risk of ASD. On the contrary, advanced parental age is associated with higher risk of ASD. Birth complications that are associated with trauma or ischemia and hypoxia have also shown strong links to ASD, whereas other pregnancy-related factors such as maternal obesity, maternal diabetes, and caesarian section have shown a less strong (but significant) association with risk of ASD. The reviews on nutritional elements have been inconclusive about the detrimental effects of deficiency in folic acid and omega 3, but vitamin D seems to be deficient in patients with ASD. The studies on toxic elements have been largely limited by their design, but there is enough evidence for the association between some heavy metals (most important inorganic mercury and lead) and ASD that warrants further investigation. Mechanisms of the association between environmental factors and ASD are debated but might include non-causative association (including confounding), gene-related effect, oxidative stress, inflammation, hypoxia/ischemia, endocrine disruption, neurotransmitter alterations, and interference with signaling pathways. CONCLUSIONS: Compared to genetic studies of ASD, studies of environmental risk factors are in their infancy and have significant methodological limitations. Future studies of ASD risk factors would benefit from a developmental psychopathology approach, prospective design, precise exposure measurement, reliable timing of exposure in relation to critical developmental periods and should take into account the dynamic interplay between gene and environment by using genetically informed designs. En ligne : http://dx.doi.org/10.1186/s13229-017-0121-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330

A novel system for tracking social preference dynamics in mice reveals sex- and strain-specific characteristics / S. NETSER in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 53p. Titre : A novel system for tracking social preference dynamics in mice reveals sex- and strain-specific characteristics Type de document : Texte imprimé et/ou numérique Auteurs : S. NETSER, Auteur ; S. HASKAL, Auteur ; H. MAGALNIK, Auteur ; S. WAGNER, Auteur Article en page(s) : 53p. Langues : Anglais (eng) Mots-clés : Social investigation  Social preference  Three-chamber test Index. décimale : PER Périodiques Résumé : BACKGROUND: Deciphering the biological mechanisms underlying social behavior in animal models requires standard behavioral paradigms that can be unbiasedly employed in an observer- and laboratory-independent manner. During the past decade, the three-chamber test has become such a standard paradigm used to evaluate social preference (sociability) and social novelty preference in mice. This test suffers from several caveats, including its reliance on spatial navigation skills and negligence of behavioral dynamics. METHODS: Here, we present a novel experimental apparatus and an automated analysis system which offer an alternative to the three-chamber test while solving the aforementioned caveats. The custom-made apparatus is simple for production, and the analysis system is publically available as an open-source software, enabling its free use. We used this system to compare the dynamics of social behavior during the social preference and social novelty preference tests between male and female C57BL/6J mice. RESULTS: We found that in both tests, male mice keep their preference towards one of the stimuli for longer periods than females. We then employed our system to define several new parameters of social behavioral dynamics in mice and revealed that social preference behavior is segregated in time into two distinct phases. An early exploration phase, characterized by high rate of transitions between stimuli and short bouts of stimulus investigation, is followed by an interaction phase with low transition rate and prolonged interactions, mainly with the preferred stimulus. Finally, we compared the dynamics of social behavior between C57BL/6J and BTBR male mice, the latter of which are considered as asocial strain serving as a model for autism spectrum disorder. We found that BTBR mice (n = 8) showed a specific deficit in transition from the exploration phase to the interaction phase in the social preference test, suggesting a reduced tendency towards social interaction. CONCLUSIONS: We successfully employed our new experimental system to unravel previously unidentified sex- and strain-specific differences in the dynamics of social behavior in mice. Thus, the system presented here facilitates a more thorough and detailed analysis of social behavior in small rodent models, enabling a better comparison between strains and treatments. En ligne : http://dx.doi.org/10.1186/s13229-017-0169-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330 [article] A novel system for tracking social preference dynamics in mice reveals sex- and strain-specific characteristics [Texte imprimé et/ou numérique] / S. NETSER, Auteur ; S. HASKAL, Auteur ; H. MAGALNIK, Auteur ; S. WAGNER, Auteur . - 53p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 53p. Mots-clés : Social investigation  Social preference  Three-chamber test Index. décimale : PER Périodiques Résumé : BACKGROUND: Deciphering the biological mechanisms underlying social behavior in animal models requires standard behavioral paradigms that can be unbiasedly employed in an observer- and laboratory-independent manner. During the past decade, the three-chamber test has become such a standard paradigm used to evaluate social preference (sociability) and social novelty preference in mice. This test suffers from several caveats, including its reliance on spatial navigation skills and negligence of behavioral dynamics. METHODS: Here, we present a novel experimental apparatus and an automated analysis system which offer an alternative to the three-chamber test while solving the aforementioned caveats. The custom-made apparatus is simple for production, and the analysis system is publically available as an open-source software, enabling its free use. We used this system to compare the dynamics of social behavior during the social preference and social novelty preference tests between male and female C57BL/6J mice. RESULTS: We found that in both tests, male mice keep their preference towards one of the stimuli for longer periods than females. We then employed our system to define several new parameters of social behavioral dynamics in mice and revealed that social preference behavior is segregated in time into two distinct phases. An early exploration phase, characterized by high rate of transitions between stimuli and short bouts of stimulus investigation, is followed by an interaction phase with low transition rate and prolonged interactions, mainly with the preferred stimulus. Finally, we compared the dynamics of social behavior between C57BL/6J and BTBR male mice, the latter of which are considered as asocial strain serving as a model for autism spectrum disorder. We found that BTBR mice (n = 8) showed a specific deficit in transition from the exploration phase to the interaction phase in the social preference test, suggesting a reduced tendency towards social interaction. CONCLUSIONS: We successfully employed our new experimental system to unravel previously unidentified sex- and strain-specific differences in the dynamics of social behavior in mice. Thus, the system presented here facilitates a more thorough and detailed analysis of social behavior in small rodent models, enabling a better comparison between strains and treatments. En ligne : http://dx.doi.org/10.1186/s13229-017-0169-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330

RNA sequencing and proteomics approaches reveal novel deficits in the cortex of Mecp2-deficient mice, a model for Rett syndrome / N. L. PACHECO in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 56p. Titre : RNA sequencing and proteomics approaches reveal novel deficits in the cortex of Mecp2-deficient mice, a model for Rett syndrome Type de document : Texte imprimé et/ou numérique Auteurs : N. L. PACHECO, Auteur ; M. R. HEAVEN, Auteur ; L. M. HOLT, Auteur ; D. K. CROSSMAN, Auteur ; K. J. BOGGIO, Auteur ; S. A. SHAFFER, Auteur ; D. L. FLINT, Auteur ; M. L. OLSEN, Auteur Article en page(s) : 56p. Langues : Anglais (eng) Mots-clés : Multi-cellular deficits  Proteome  Rett syndrome  Transcriptome Index. décimale : PER Périodiques Résumé : BACKGROUND: Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused by mutations in the transcriptional regulator MeCP2. Much of our understanding of MeCP2 function is derived from transcriptomic studies with the general assumption that alterations in the transcriptome correlate with proteomic changes. Advances in mass spectrometry-based proteomics have facilitated recent interest in the examination of global protein expression to better understand the biology between transcriptional and translational regulation. METHODS: We therefore performed the first comprehensive transcriptome-proteome comparison in a RTT mouse model to elucidate RTT pathophysiology, identify potential therapeutic targets, and further our understanding of MeCP2 function. The whole cortex of wild-type and symptomatic RTT male littermates (n = 4 per genotype) were analyzed using RNA-sequencing and data-independent acquisition liquid chromatography tandem mass spectrometry. Ingenuity(R) Pathway Analysis was used to identify significantly affected pathways in the transcriptomic and proteomic data sets. RESULTS: Our results indicate these two "omics" data sets supplement one another. In addition to confirming previous works regarding mRNA expression in Mecp2-deficient animals, the current study identified hundreds of novel protein targets. Several selected protein targets were validated by Western blot analysis. These data indicate RNA metabolism, proteostasis, monoamine metabolism, and cholesterol synthesis are disrupted in the RTT proteome. Hits common to both data sets indicate disrupted cellular metabolism, calcium signaling, protein stability, DNA binding, and cytoskeletal cell structure. Finally, in addition to confirming disrupted pathways and identifying novel hits in neuronal structure and synaptic transmission, our data indicate aberrant myelination, inflammation, and vascular disruption. Intriguingly, there is no evidence of reactive gliosis, but instead, gene, protein, and pathway analysis suggest astrocytic maturation and morphological deficits. CONCLUSIONS: This comparative omics analysis supports previous works indicating widespread CNS dysfunction and may serve as a valuable resource for those interested in cellular dysfunction in RTT. En ligne : http://dx.doi.org/10.1186/s13229-017-0174-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330 [article] RNA sequencing and proteomics approaches reveal novel deficits in the cortex of Mecp2-deficient mice, a model for Rett syndrome [Texte imprimé et/ou numérique] / N. L. PACHECO, Auteur ; M. R. HEAVEN, Auteur ; L. M. HOLT, Auteur ; D. K. CROSSMAN, Auteur ; K. J. BOGGIO, Auteur ; S. A. SHAFFER, Auteur ; D. L. FLINT, Auteur ; M. L. OLSEN, Auteur . - 56p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 56p. Mots-clés : Multi-cellular deficits  Proteome  Rett syndrome  Transcriptome Index. décimale : PER Périodiques Résumé : BACKGROUND: Rett syndrome (RTT) is an X-linked neurodevelopmental disorder caused by mutations in the transcriptional regulator MeCP2. Much of our understanding of MeCP2 function is derived from transcriptomic studies with the general assumption that alterations in the transcriptome correlate with proteomic changes. Advances in mass spectrometry-based proteomics have facilitated recent interest in the examination of global protein expression to better understand the biology between transcriptional and translational regulation. METHODS: We therefore performed the first comprehensive transcriptome-proteome comparison in a RTT mouse model to elucidate RTT pathophysiology, identify potential therapeutic targets, and further our understanding of MeCP2 function. The whole cortex of wild-type and symptomatic RTT male littermates (n = 4 per genotype) were analyzed using RNA-sequencing and data-independent acquisition liquid chromatography tandem mass spectrometry. Ingenuity(R) Pathway Analysis was used to identify significantly affected pathways in the transcriptomic and proteomic data sets. RESULTS: Our results indicate these two "omics" data sets supplement one another. In addition to confirming previous works regarding mRNA expression in Mecp2-deficient animals, the current study identified hundreds of novel protein targets. Several selected protein targets were validated by Western blot analysis. These data indicate RNA metabolism, proteostasis, monoamine metabolism, and cholesterol synthesis are disrupted in the RTT proteome. Hits common to both data sets indicate disrupted cellular metabolism, calcium signaling, protein stability, DNA binding, and cytoskeletal cell structure. Finally, in addition to confirming disrupted pathways and identifying novel hits in neuronal structure and synaptic transmission, our data indicate aberrant myelination, inflammation, and vascular disruption. Intriguingly, there is no evidence of reactive gliosis, but instead, gene, protein, and pathway analysis suggest astrocytic maturation and morphological deficits. CONCLUSIONS: This comparative omics analysis supports previous works indicating widespread CNS dysfunction and may serve as a valuable resource for those interested in cellular dysfunction in RTT. En ligne : http://dx.doi.org/10.1186/s13229-017-0174-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330

Serum and cerebrospinal fluid immune mediators in children with autistic disorder: a longitudinal study / Carlos A. PARDO in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 1p. Titre : Serum and cerebrospinal fluid immune mediators in children with autistic disorder: a longitudinal study Type de document : Texte imprimé et/ou numérique Auteurs : Carlos A. PARDO, Auteur ; C. A. FARMER, Auteur ; A. THURM, Auteur ; F. M. SHEBL, Auteur ; J. ILIEVA, Auteur ; S. KALRA, Auteur ; Susan E. SWEDO, Auteur Article en page(s) : 1p. Langues : Anglais (eng) Mots-clés : Autistic Disorder/*immunology/metabolism  Chemokines/*blood/*cerebrospinal fluid  Child  Child, Preschool  Cytokines/*blood/*cerebrospinal fluid  Female  Humans  Intercellular Signaling Peptides and Proteins/blood/cerebrospinal fluid  Longitudinal Studies  Male  Prospective Studies  *Autism  *Csf  *Chemokine  *Cytokine  *Growth factor  *Immune Index. décimale : PER Périodiques Résumé : BACKGROUND: The causes of autism likely involve genetic and environmental factors that influence neurobiological changes and the neurological and behavioral features of the disorder. Immune factors and inflammation are hypothesized pathogenic influences, but have not been examined longitudinally. METHODS: In a cohort of 104 participants with autism, we performed an assessment of immune mediators such as cytokines, chemokines, or growth factors in serum and cerebrospinal fluid (n = 67) to determine potential influences of such mediators in autism. RESULTS: As compared with 54 typically developing controls, we found no evidence of differences in the blood profile of immune mediators supportive of active systemic inflammation mechanisms in participants with autism. Some modulators of immune function (e.g., EGF and soluble CD40 ligand) were increased in the autism group; however, no evidence of group differences in traditional markers of active inflammation (e.g., IL-6, TNFalpha, IL-1beta) were observed in the serum. Further, within-subject stability (measured by estimated intraclass correlations) of most analytes was low, indicating that a single measurement is not a reliable prospective indicator of concentration for most analytes. Additionally, in participants with autism, there was little correspondence between the blood and CSF profiles of cytokines, chemokines, and growth factors, suggesting that peripheral markers may not optimally reflect the immune status of the central nervous system. Although the relatively high fraction of intrathecal production of selected chemokines involved in monocyte/microglia function may suggest a possible relationship with the homeostatic role of microglia, control data are needed for further interpretation of its relevance in autism. CONCLUSIONS: These longitudinal observations fail to provide support for the hypothesized role of disturbances in the expression of circulating cytokines and chemokines as an indicator of systemic inflammation in autism. ClinicalTrials.gov, NCT00298246. En ligne : http://dx.doi.org/10.1186/s13229-016-0115-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330 [article] Serum and cerebrospinal fluid immune mediators in children with autistic disorder: a longitudinal study [Texte imprimé et/ou numérique] / Carlos A. PARDO, Auteur ; C. A. FARMER, Auteur ; A. THURM, Auteur ; F. M. SHEBL, Auteur ; J. ILIEVA, Auteur ; S. KALRA, Auteur ; Susan E. SWEDO, Auteur . - 1p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 1p. Mots-clés : Autistic Disorder/*immunology/metabolism  Chemokines/*blood/*cerebrospinal fluid  Child  Child, Preschool  Cytokines/*blood/*cerebrospinal fluid  Female  Humans  Intercellular Signaling Peptides and Proteins/blood/cerebrospinal fluid  Longitudinal Studies  Male  Prospective Studies  *Autism  *Csf  *Chemokine  *Cytokine  *Growth factor  *Immune Index. décimale : PER Périodiques Résumé : BACKGROUND: The causes of autism likely involve genetic and environmental factors that influence neurobiological changes and the neurological and behavioral features of the disorder. Immune factors and inflammation are hypothesized pathogenic influences, but have not been examined longitudinally. METHODS: In a cohort of 104 participants with autism, we performed an assessment of immune mediators such as cytokines, chemokines, or growth factors in serum and cerebrospinal fluid (n = 67) to determine potential influences of such mediators in autism. RESULTS: As compared with 54 typically developing controls, we found no evidence of differences in the blood profile of immune mediators supportive of active systemic inflammation mechanisms in participants with autism. Some modulators of immune function (e.g., EGF and soluble CD40 ligand) were increased in the autism group; however, no evidence of group differences in traditional markers of active inflammation (e.g., IL-6, TNFalpha, IL-1beta) were observed in the serum. Further, within-subject stability (measured by estimated intraclass correlations) of most analytes was low, indicating that a single measurement is not a reliable prospective indicator of concentration for most analytes. Additionally, in participants with autism, there was little correspondence between the blood and CSF profiles of cytokines, chemokines, and growth factors, suggesting that peripheral markers may not optimally reflect the immune status of the central nervous system. Although the relatively high fraction of intrathecal production of selected chemokines involved in monocyte/microglia function may suggest a possible relationship with the homeostatic role of microglia, control data are needed for further interpretation of its relevance in autism. CONCLUSIONS: These longitudinal observations fail to provide support for the hypothesized role of disturbances in the expression of circulating cytokines and chemokines as an indicator of systemic inflammation in autism. ClinicalTrials.gov, NCT00298246. En ligne : http://dx.doi.org/10.1186/s13229-016-0115-7 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330

Linguistic camouflage in girls with autism spectrum disorder / Julia PARISH-MORRIS in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 48p. Titre : Linguistic camouflage in girls with autism spectrum disorder Type de document : Texte imprimé et/ou numérique Auteurs : Julia PARISH-MORRIS, Auteur ; M. Y. LIBERMAN, Auteur ; C. CIERI, Auteur ; J. D. HERRINGTON, Auteur ; B. E. YERYS, Auteur ; Leila BATEMAN, Auteur ; J. DONAHER, Auteur ; E. FERGUSON, Auteur ; J. PANDEY, Auteur ; Robert T. SCHULTZ, Auteur Article en page(s) : 48p. Langues : Anglais (eng) Mots-clés : Autism  Disfluency  Filled pauses  Gender differences  Language  Linguistic camouflage  Pragmatic communication  Sex differences Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is diagnosed more frequently in boys than girls, even when girls are equally symptomatic. Cutting-edge behavioral imaging has detected "camouflaging" in girls with ASD, wherein social behaviors appear superficially typical, complicating diagnosis. The present study explores a new kind of camouflage based on language differences. Pauses during conversation can be filled with words like UM or UH, but research suggests that these two words are pragmatically distinct (e.g., UM is used to signal longer pauses, and may correlate with greater social communicative sophistication than UH). Large-scale research suggests that women and younger people produce higher rates of UM during conversational pauses than do men and older people, who produce relatively more UH. Although it has been argued that children and adolescents with ASD use UM less often than typical peers, prior research has not included sufficient numbers of girls to examine whether sex explains this effect. Here, we explore UM vs. UH in school-aged boys and girls with ASD, and ask whether filled pauses relate to dimensional measures of autism symptom severity. METHODS: Sixty-five verbal school-aged participants with ASD (49 boys, 16 girls, IQ estimates in the average range) participated, along with a small comparison group of typically developing children (8 boys, 9 girls). Speech samples from the Autism Diagnostic Observation Schedule were orthographically transcribed and time-aligned, with filled pauses marked. Parents completed the Social Communication Questionnaire and the Vineland Adaptive Behavior Scales. RESULTS: Girls used UH less often than boys across both diagnostic groups. UH suppression resulted in higher UM ratios for girls than boys, and overall filled pause rates were higher for typical children than for children with ASD. Higher UM ratios correlated with better socialization in boys with ASD, but this effect was driven by increased use of UH by boys with greater symptoms. CONCLUSIONS: Pragmatic language markers distinguish girls and boys with ASD, mirroring sex differences in the general population. One implication of this finding is that typical-sounding disfluency patterns (i.e., reduced relative UH production leading to higher UM ratios) may normalize the way girls with ASD sound relative to other children, serving as "linguistic camouflage" for a naive listener and distinguishing them from boys with ASD. This first-of-its-kind study highlights the importance of continued commitment to understanding how sex and gender change the way that ASD manifests, and illustrates the potential of natural language to contribute to objective "behavioral imaging" diagnostics for ASD. En ligne : http://dx.doi.org/10.1186/s13229-017-0164-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330 [article] Linguistic camouflage in girls with autism spectrum disorder [Texte imprimé et/ou numérique] / Julia PARISH-MORRIS, Auteur ; M. Y. LIBERMAN, Auteur ; C. CIERI, Auteur ; J. D. HERRINGTON, Auteur ; B. E. YERYS, Auteur ; Leila BATEMAN, Auteur ; J. DONAHER, Auteur ; E. FERGUSON, Auteur ; J. PANDEY, Auteur ; Robert T. SCHULTZ, Auteur . - 48p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 48p. Mots-clés : Autism  Disfluency  Filled pauses  Gender differences  Language  Linguistic camouflage  Pragmatic communication  Sex differences Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is diagnosed more frequently in boys than girls, even when girls are equally symptomatic. Cutting-edge behavioral imaging has detected "camouflaging" in girls with ASD, wherein social behaviors appear superficially typical, complicating diagnosis. The present study explores a new kind of camouflage based on language differences. Pauses during conversation can be filled with words like UM or UH, but research suggests that these two words are pragmatically distinct (e.g., UM is used to signal longer pauses, and may correlate with greater social communicative sophistication than UH). Large-scale research suggests that women and younger people produce higher rates of UM during conversational pauses than do men and older people, who produce relatively more UH. Although it has been argued that children and adolescents with ASD use UM less often than typical peers, prior research has not included sufficient numbers of girls to examine whether sex explains this effect. Here, we explore UM vs. UH in school-aged boys and girls with ASD, and ask whether filled pauses relate to dimensional measures of autism symptom severity. METHODS: Sixty-five verbal school-aged participants with ASD (49 boys, 16 girls, IQ estimates in the average range) participated, along with a small comparison group of typically developing children (8 boys, 9 girls). Speech samples from the Autism Diagnostic Observation Schedule were orthographically transcribed and time-aligned, with filled pauses marked. Parents completed the Social Communication Questionnaire and the Vineland Adaptive Behavior Scales. RESULTS: Girls used UH less often than boys across both diagnostic groups. UH suppression resulted in higher UM ratios for girls than boys, and overall filled pause rates were higher for typical children than for children with ASD. Higher UM ratios correlated with better socialization in boys with ASD, but this effect was driven by increased use of UH by boys with greater symptoms. CONCLUSIONS: Pragmatic language markers distinguish girls and boys with ASD, mirroring sex differences in the general population. One implication of this finding is that typical-sounding disfluency patterns (i.e., reduced relative UH production leading to higher UM ratios) may normalize the way girls with ASD sound relative to other children, serving as "linguistic camouflage" for a naive listener and distinguishing them from boys with ASD. This first-of-its-kind study highlights the importance of continued commitment to understanding how sex and gender change the way that ASD manifests, and illustrates the potential of natural language to contribute to objective "behavioral imaging" diagnostics for ASD. En ligne : http://dx.doi.org/10.1186/s13229-017-0164-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330

Umbilical cord blood androgen levels and ASD-related phenotypes at 12 and 36 months in an enriched risk cohort study / B. Y. PARK in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 3p. Titre : Umbilical cord blood androgen levels and ASD-related phenotypes at 12 and 36 months in an enriched risk cohort study Type de document : Texte imprimé et/ou numérique Auteurs : B. Y. PARK, Auteur ; Brian K. LEE, Auteur ; Igor BURSTYN, Auteur ; Loni P. TABB, Auteur ; J. A. KEELAN, Auteur ; Andrew J. O. WHITEHOUSE, Auteur ; Lisa A. CROEN, Auteur ; M. D. FALLIN, Auteur ; I. HERTZ-PICCIOTTO, Auteur ; O. MONTGOMERY, Auteur ; C. J. NEWSCHAFFER, Auteur Article en page(s) : 3p. Langues : Anglais (eng) Mots-clés : Adult  Androstenedione/*metabolism  Autism Spectrum Disorder/metabolism/*psychology  Chromatography, Liquid  Cohort Studies  Dehydroepiandrosterone/*metabolism  Female  Fetal Blood/*metabolism  Humans  Infant  Linear Models  Longitudinal Studies  Male  Pregnancy  Prospective Studies  Risk Assessment  Severity of Illness Index  Siblings/*psychology  Tandem Mass Spectrometry  Testosterone/*metabolism  *Autism  *Sex difference  *Sibling  *Testosterone  *Umbilical cord blood Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) affects more than 1% of children in the USA. The male-to-female prevalence ratio of roughly 4:1 in ASD is a well-recognized but poorly understood phenomenon. An explicit focus on potential etiologic pathways consistent with this sex difference, such as those involving prenatal androgen exposure, may help elucidate causes of ASD. Furthermore, the multi-threshold liability model suggests that the genetic mechanisms in females with ASD may be distinct and may modulate ASD risk in families with female ASD in the pedigree. METHODS: We examined umbilical cord blood from 137 children in the Early Autism Risk Longitudinal Investigation (EARLI) cohort. EARLI is an ASD-enriched risk cohort with all children having an older sibling already diagnosed with ASD. Fetal testosterone (T), androstenedione (A4), and dehyroepiandrosterone (DHEA) levels were measured in cord blood using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Robust linear regression models were used to determine associations between cord blood androgen levels and 12-month Autism Observation Scales for Infants (AOSI) scores and 36-month Social Responsiveness Scale (SRS) scores adjusting for potential confounders. RESULTS: Increasing androgens were not associated with increasing 12-month AOSI score or 36-month total SRS score in either boys or girls. However, the association between T and autistic traits among subjects with a female older affected sibling was greater at 12 months (test of interaction, P = 0.008) and deficits in reciprocal social behavior at 36 months were also greater (test of interaction, P = 0.006) than in subjects whose older affected sibling was male. CONCLUSIONS: While increased prenatal testosterone levels were not associated with autistic traits at 12 or 36 months, our findings of a positive association in infants whose older ASD-affected siblings were female suggests an androgen-related mechanism that may be dependent on, or related to, genetic liability factors present more often in families containing female ASD cases. However, this initial finding, based on a small subgroup of our sample, should be interpreted with considerable caution. En ligne : http://dx.doi.org/10.1186/s13229-017-0118-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330 [article] Umbilical cord blood androgen levels and ASD-related phenotypes at 12 and 36 months in an enriched risk cohort study [Texte imprimé et/ou numérique] / B. Y. PARK, Auteur ; Brian K. LEE, Auteur ; Igor BURSTYN, Auteur ; Loni P. TABB, Auteur ; J. A. KEELAN, Auteur ; Andrew J. O. WHITEHOUSE, Auteur ; Lisa A. CROEN, Auteur ; M. D. FALLIN, Auteur ; I. HERTZ-PICCIOTTO, Auteur ; O. MONTGOMERY, Auteur ; C. J. NEWSCHAFFER, Auteur . - 3p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 3p. Mots-clés : Adult  Androstenedione/*metabolism  Autism Spectrum Disorder/metabolism/*psychology  Chromatography, Liquid  Cohort Studies  Dehydroepiandrosterone/*metabolism  Female  Fetal Blood/*metabolism  Humans  Infant  Linear Models  Longitudinal Studies  Male  Pregnancy  Prospective Studies  Risk Assessment  Severity of Illness Index  Siblings/*psychology  Tandem Mass Spectrometry  Testosterone/*metabolism  *Autism  *Sex difference  *Sibling  *Testosterone  *Umbilical cord blood Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) affects more than 1% of children in the USA. The male-to-female prevalence ratio of roughly 4:1 in ASD is a well-recognized but poorly understood phenomenon. An explicit focus on potential etiologic pathways consistent with this sex difference, such as those involving prenatal androgen exposure, may help elucidate causes of ASD. Furthermore, the multi-threshold liability model suggests that the genetic mechanisms in females with ASD may be distinct and may modulate ASD risk in families with female ASD in the pedigree. METHODS: We examined umbilical cord blood from 137 children in the Early Autism Risk Longitudinal Investigation (EARLI) cohort. EARLI is an ASD-enriched risk cohort with all children having an older sibling already diagnosed with ASD. Fetal testosterone (T), androstenedione (A4), and dehyroepiandrosterone (DHEA) levels were measured in cord blood using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Robust linear regression models were used to determine associations between cord blood androgen levels and 12-month Autism Observation Scales for Infants (AOSI) scores and 36-month Social Responsiveness Scale (SRS) scores adjusting for potential confounders. RESULTS: Increasing androgens were not associated with increasing 12-month AOSI score or 36-month total SRS score in either boys or girls. However, the association between T and autistic traits among subjects with a female older affected sibling was greater at 12 months (test of interaction, P = 0.008) and deficits in reciprocal social behavior at 36 months were also greater (test of interaction, P = 0.006) than in subjects whose older affected sibling was male. CONCLUSIONS: While increased prenatal testosterone levels were not associated with autistic traits at 12 or 36 months, our findings of a positive association in infants whose older ASD-affected siblings were female suggests an androgen-related mechanism that may be dependent on, or related to, genetic liability factors present more often in families containing female ASD cases. However, this initial finding, based on a small subgroup of our sample, should be interpreted with considerable caution. En ligne : http://dx.doi.org/10.1186/s13229-017-0118-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330

A few of my favorite things: circumscribed interests in autism are not accompanied by increased attentional salience on a personalized selective attention task / O. E. PARSONS in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 20p. Titre : A few of my favorite things: circumscribed interests in autism are not accompanied by increased attentional salience on a personalized selective attention task Type de document : Texte imprimé et/ou numérique Auteurs : O. E. PARSONS, Auteur ; Andrew P. BAYLISS, Auteur ; A. REMINGTON, Auteur Article en page(s) : 20p. Langues : Anglais (eng) Mots-clés : Adolescent  Adult  Attention/*physiology  Autistic Disorder/*psychology  Humans  Photic Stimulation/*methods  Reaction Time  Visual Perception  Young Adult  *Attention  *Autism  *Circumscribed interests  *Perception  *Special interests Index. décimale : PER Périodiques Résumé : BACKGROUND: Autistic individuals commonly show circumscribed or "special" interests: areas of obsessive interest in a specific category. The present study investigated what impact these interests have on attention, an aspect of autistic cognition often reported as altered. In neurotypical individuals, interest and expertise have been shown to result in an automatic attentional priority for related items. Here, we examine whether this change in salience is also seen in autism. METHODS: Adolescents and young adults with and without autism performed a personalized selective attention task assessing the level of attentional priority afforded to images related to the participant's specific interests. In addition, participants performed a similar task with generic images in order to isolate any effects of interest and expertise. Crucially, all autistic and non-autistic individuals recruited for this study held a strong passion or interest. As such, any differences in attention could not be solely attributed to differing prevalence of interests in the two groups. In both tasks, participants were asked to perform a central target-detection task while ignoring irrelevant distractors (related or unrelated to their interests). The level of distractor interference under various task conditions was taken as an indication of attentional priority. RESULTS: Neurotypical individuals showed the predicted attentional priority for the circumscribed interest images but not generic items, reflecting the impact of their interest and expertise. Contrary to predictions, autistic individuals did not show this priority: processing the interest-related stimuli only when task demands were low. Attention to images unrelated to circumscribed interests was equivalent in the two groups. CONCLUSIONS: These results suggest that despite autistic individuals holding an intense interest in a particular class of stimuli, there may be a reduced impact of this prior experience and expertise on attentional processing. The implications of this absence of automatic priority are discussed in terms of the behaviors associated with the condition. En ligne : http://dx.doi.org/10.1186/s13229-017-0132-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330 [article] A few of my favorite things: circumscribed interests in autism are not accompanied by increased attentional salience on a personalized selective attention task [Texte imprimé et/ou numérique] / O. E. PARSONS, Auteur ; Andrew P. BAYLISS, Auteur ; A. REMINGTON, Auteur . - 20p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 20p. Mots-clés : Adolescent  Adult  Attention/*physiology  Autistic Disorder/*psychology  Humans  Photic Stimulation/*methods  Reaction Time  Visual Perception  Young Adult  *Attention  *Autism  *Circumscribed interests  *Perception  *Special interests Index. décimale : PER Périodiques Résumé : BACKGROUND: Autistic individuals commonly show circumscribed or "special" interests: areas of obsessive interest in a specific category. The present study investigated what impact these interests have on attention, an aspect of autistic cognition often reported as altered. In neurotypical individuals, interest and expertise have been shown to result in an automatic attentional priority for related items. Here, we examine whether this change in salience is also seen in autism. METHODS: Adolescents and young adults with and without autism performed a personalized selective attention task assessing the level of attentional priority afforded to images related to the participant's specific interests. In addition, participants performed a similar task with generic images in order to isolate any effects of interest and expertise. Crucially, all autistic and non-autistic individuals recruited for this study held a strong passion or interest. As such, any differences in attention could not be solely attributed to differing prevalence of interests in the two groups. In both tasks, participants were asked to perform a central target-detection task while ignoring irrelevant distractors (related or unrelated to their interests). The level of distractor interference under various task conditions was taken as an indication of attentional priority. RESULTS: Neurotypical individuals showed the predicted attentional priority for the circumscribed interest images but not generic items, reflecting the impact of their interest and expertise. Contrary to predictions, autistic individuals did not show this priority: processing the interest-related stimuli only when task demands were low. Attention to images unrelated to circumscribed interests was equivalent in the two groups. CONCLUSIONS: These results suggest that despite autistic individuals holding an intense interest in a particular class of stimuli, there may be a reduced impact of this prior experience and expertise on attentional processing. The implications of this absence of automatic priority are discussed in terms of the behaviors associated with the condition. En ligne : http://dx.doi.org/10.1186/s13229-017-0132-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330

Bio-collections in autism research / J. REILLY in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 34p. Titre : Bio-collections in autism research Type de document : Texte imprimé et/ou numérique Auteurs : J. REILLY, Auteur ; L. GALLAGHER, Auteur ; J. L. CHEN, Auteur ; G. LEADER, Auteur ; S. SHEN, Auteur Article en page(s) : 34p. Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) is a group of complex neurodevelopmental disorders with diverse clinical manifestations and symptoms. In the last 10 years, there have been significant advances in understanding the genetic basis for ASD, critically supported through the establishment of ASD bio-collections and application in research. Here, we summarise a selection of major ASD bio-collections and their associated findings. Collectively, these include mapping ASD candidate genes, assessing the nature and frequency of gene mutations and their association with ASD clinical subgroups, insights into related molecular pathways such as the synapses, chromatin remodelling, transcription and ASD-related brain regions. We also briefly review emerging studies on the use of induced pluripotent stem cells (iPSCs) to potentially model ASD in culture. These provide deeper insight into ASD progression during development and could generate human cell models for drug screening. Finally, we provide perspectives concerning the utilities of ASD bio-collections and limitations, and highlight considerations in setting up a new bio-collection for ASD research. En ligne : http://dx.doi.org/10.1186/s13229-017-0154-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330 [article] Bio-collections in autism research [Texte imprimé et/ou numérique] / J. REILLY, Auteur ; L. GALLAGHER, Auteur ; J. L. CHEN, Auteur ; G. LEADER, Auteur ; S. SHEN, Auteur . - 34p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 34p. Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) is a group of complex neurodevelopmental disorders with diverse clinical manifestations and symptoms. In the last 10 years, there have been significant advances in understanding the genetic basis for ASD, critically supported through the establishment of ASD bio-collections and application in research. Here, we summarise a selection of major ASD bio-collections and their associated findings. Collectively, these include mapping ASD candidate genes, assessing the nature and frequency of gene mutations and their association with ASD clinical subgroups, insights into related molecular pathways such as the synapses, chromatin remodelling, transcription and ASD-related brain regions. We also briefly review emerging studies on the use of induced pluripotent stem cells (iPSCs) to potentially model ASD in culture. These provide deeper insight into ASD progression during development and could generate human cell models for drug screening. Finally, we provide perspectives concerning the utilities of ASD bio-collections and limitations, and highlight considerations in setting up a new bio-collection for ASD research. En ligne : http://dx.doi.org/10.1186/s13229-017-0154-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330

Effects of a social stimulus on gene expression in a mouse model of fragile X syndrome / T. D. ROGERS in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 30p. Titre : Effects of a social stimulus on gene expression in a mouse model of fragile X syndrome Type de document : Texte imprimé et/ou numérique Auteurs : T. D. ROGERS, Auteur ; A. M. J. ANACKER, Auteur ; T. M. KERR, Auteur ; C. G. FORSBERG, Auteur ; J. WANG, Auteur ; B. ZHANG, Auteur ; J. VEENSTRA-VANDERWEELE, Auteur Article en page(s) : 30p. Langues : Anglais (eng) Mots-clés : Amygdala  Autism spectrum disorder  Fragile X syndrome  Prefrontal cortex  RNA sequencing  Social behavior Index. décimale : PER Périodiques Résumé : BACKGROUND: People with fragile X syndrome (FXS) often have deficits in social behavior, and a substantial portion meet criteria for autism spectrum disorder. Though the genetic cause of FXS is known to be due to the silencing of FMR1, and the Fmr1 null mouse model representing this lesion has been extensively studied, the contributions of this gene and its protein product, FMRP, to social behavior are not well understood. METHODS: Fmr1 null mice and wildtype littermates were exposed to a social or non-social stimulus. In one experiment, subjects were assessed for expression of the inducible transcription factor c-Fos in response to the stimulus, to detect brain regions with social-specific activity. In a separate experiment, tissue was taken from those brain regions showing differential activity, and RNA sequencing was performed. RESULTS: Immunohistochemistry revealed a significantly greater number of c-Fos-positive cells in the lateral amygdala and medial amygdala in the brains of mice exposed to a social stimulus, compared to a non-social stimulus. In the prelimbic cortex, there was no significant effect of social stimulus; although the number of c-Fos-positive cells was lower in the social condition compared to the non-social condition, and negatively correlated with c-Fos in the amygdala. RNA sequencing revealed differentially expressed genes enriched for molecules known to interact with FMRP and also for autism-related genes identified in the Simons Foundation Autism Research Initiative gene database. Ingenuity Pathway Analysis detected enrichment of differentially expressed genes in networks and pathways related to neuronal development, intracellular signaling, and inflammatory response. CONCLUSIONS: Using the Fmr1 null mouse model of fragile X syndrome, we have identified brain regions, gene networks, and molecular pathways responsive to a social stimulus. These findings, and future experiments following up on the role of specific gene networks, may shed light on the neural mechanisms underlying dysregulated social behaviors in fragile X syndrome and more broadly. En ligne : http://dx.doi.org/10.1186/s13229-017-0148-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330 [article] Effects of a social stimulus on gene expression in a mouse model of fragile X syndrome [Texte imprimé et/ou numérique] / T. D. ROGERS, Auteur ; A. M. J. ANACKER, Auteur ; T. M. KERR, Auteur ; C. G. FORSBERG, Auteur ; J. WANG, Auteur ; B. ZHANG, Auteur ; J. VEENSTRA-VANDERWEELE, Auteur . - 30p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 30p. Mots-clés : Amygdala  Autism spectrum disorder  Fragile X syndrome  Prefrontal cortex  RNA sequencing  Social behavior Index. décimale : PER Périodiques Résumé : BACKGROUND: People with fragile X syndrome (FXS) often have deficits in social behavior, and a substantial portion meet criteria for autism spectrum disorder. Though the genetic cause of FXS is known to be due to the silencing of FMR1, and the Fmr1 null mouse model representing this lesion has been extensively studied, the contributions of this gene and its protein product, FMRP, to social behavior are not well understood. METHODS: Fmr1 null mice and wildtype littermates were exposed to a social or non-social stimulus. In one experiment, subjects were assessed for expression of the inducible transcription factor c-Fos in response to the stimulus, to detect brain regions with social-specific activity. In a separate experiment, tissue was taken from those brain regions showing differential activity, and RNA sequencing was performed. RESULTS: Immunohistochemistry revealed a significantly greater number of c-Fos-positive cells in the lateral amygdala and medial amygdala in the brains of mice exposed to a social stimulus, compared to a non-social stimulus. In the prelimbic cortex, there was no significant effect of social stimulus; although the number of c-Fos-positive cells was lower in the social condition compared to the non-social condition, and negatively correlated with c-Fos in the amygdala. RNA sequencing revealed differentially expressed genes enriched for molecules known to interact with FMRP and also for autism-related genes identified in the Simons Foundation Autism Research Initiative gene database. Ingenuity Pathway Analysis detected enrichment of differentially expressed genes in networks and pathways related to neuronal development, intracellular signaling, and inflammatory response. CONCLUSIONS: Using the Fmr1 null mouse model of fragile X syndrome, we have identified brain regions, gene networks, and molecular pathways responsive to a social stimulus. These findings, and future experiments following up on the role of specific gene networks, may shed light on the neural mechanisms underlying dysregulated social behaviors in fragile X syndrome and more broadly. En ligne : http://dx.doi.org/10.1186/s13229-017-0148-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=330

Possible sexually dimorphic role of miRNA and other sncRNA in ASD brain / C. M. SCHUMANN in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 4p. Titre : Possible sexually dimorphic role of miRNA and other sncRNA in ASD brain Type de document : Texte imprimé et/ou numérique Auteurs : C. M. SCHUMANN, Auteur ; F. R. SHARP, Auteur ; Bradley P. ANDER, Auteur ; B. STAMOVA, Auteur Article en page(s) : 4p. Langues : Anglais (eng) Mots-clés : Adolescent  Adult  Autism Spectrum Disorder/*genetics  Child  Child, Preschool  Female  Gene Expression Profiling/*methods  Gene Expression Regulation  Humans  Male  MicroRNAs/*genetics  Middle Aged  Oligonucleotide Array Sequence Analysis/*methods  RNA, Small Untranslated/*genetics  Sex Characteristics  Young Adult  *Auditory cortex  *Autism  *Myelin  *Oligodendrocytes  *Postmortem human brain  *Sex  *Sexual dimorphism  *Superior Temporal Sulcus  *miR-125  *miR-181  *miR-219  *miR-338  *miR-448  *microRNA  *small noncoding RNA Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is sexually dimorphic in brain structure, genetics, and behaviors. In studies of brain tissue, the age of the population is clearly a factor in interpreting study outcome, yet sex is rarely considered. To begin to address this issue, we extend our previously published microarray analyses to examine expression of small noncoding RNAs (sncRNAs), including microRNAs (miRNAs), in ASD and in the control temporal cortex in males and females. Predicted miRNA targets were identified as well as the pathways they overpopulate. FINDINGS: After considering age, sexual dimorphism in ASD sncRNA expression persists in the temporal cortex and in the patterning that distinguishes regions. Among the sexually dimorphic miRNAs are miR-219 and miR-338, which promote oligodendrocyte differentiation, miR-125, implicated in neuronal differentiation, and miR-488, implicated in anxiety. Putative miRNA targets are significantly over-represented in immune and nervous system pathways in both sexes, consistent with previous mRNA studies. Even for common pathways, the specific target mRNAs are often sexually dimorphic. For example, both male and female target genes significantly populate the Axonal Guidance Signaling pathway, yet less than a third of the targets are common to both sexes. CONCLUSIONS: Our findings of sexual dimorphism in sncRNA levels underscore the importance of considering sex, in addition to age, when interpreting molecular findings on ASD brain. En ligne : http://dx.doi.org/10.1186/s13229-017-0117-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331 [article] Possible sexually dimorphic role of miRNA and other sncRNA in ASD brain [Texte imprimé et/ou numérique] / C. M. SCHUMANN, Auteur ; F. R. SHARP, Auteur ; Bradley P. ANDER, Auteur ; B. STAMOVA, Auteur . - 4p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 4p. Mots-clés : Adolescent  Adult  Autism Spectrum Disorder/*genetics  Child  Child, Preschool  Female  Gene Expression Profiling/*methods  Gene Expression Regulation  Humans  Male  MicroRNAs/*genetics  Middle Aged  Oligonucleotide Array Sequence Analysis/*methods  RNA, Small Untranslated/*genetics  Sex Characteristics  Young Adult  *Auditory cortex  *Autism  *Myelin  *Oligodendrocytes  *Postmortem human brain  *Sex  *Sexual dimorphism  *Superior Temporal Sulcus  *miR-125  *miR-181  *miR-219  *miR-338  *miR-448  *microRNA  *small noncoding RNA Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is sexually dimorphic in brain structure, genetics, and behaviors. In studies of brain tissue, the age of the population is clearly a factor in interpreting study outcome, yet sex is rarely considered. To begin to address this issue, we extend our previously published microarray analyses to examine expression of small noncoding RNAs (sncRNAs), including microRNAs (miRNAs), in ASD and in the control temporal cortex in males and females. Predicted miRNA targets were identified as well as the pathways they overpopulate. FINDINGS: After considering age, sexual dimorphism in ASD sncRNA expression persists in the temporal cortex and in the patterning that distinguishes regions. Among the sexually dimorphic miRNAs are miR-219 and miR-338, which promote oligodendrocyte differentiation, miR-125, implicated in neuronal differentiation, and miR-488, implicated in anxiety. Putative miRNA targets are significantly over-represented in immune and nervous system pathways in both sexes, consistent with previous mRNA studies. Even for common pathways, the specific target mRNAs are often sexually dimorphic. For example, both male and female target genes significantly populate the Axonal Guidance Signaling pathway, yet less than a third of the targets are common to both sexes. CONCLUSIONS: Our findings of sexual dimorphism in sncRNA levels underscore the importance of considering sex, in addition to age, when interpreting molecular findings on ASD brain. En ligne : http://dx.doi.org/10.1186/s13229-017-0117-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331

Prospective investigation of FOXP1 syndrome / P. M. SIPER in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 57p. Titre : Prospective investigation of FOXP1 syndrome Type de document : Texte imprimé et/ou numérique Auteurs : P. M. SIPER, Auteur ; S. DE RUBEIS, Auteur ; M. D. P. TRELLES, Auteur ; A. DURKIN, Auteur ; D. DI MARINO, Auteur ; F. MURATET, Auteur ; Y. FRANK, Auteur ; R. LOZANO, Auteur ; E. E. EICHLER, Auteur ; M. KELLY, Auteur ; Jennifer BEIGHLEY, Auteur ; J. GERDTS, Auteur ; Arianne S. WALLACE, Auteur ; H. C. MEFFORD, Auteur ; Raphael BERNIER, Auteur ; A. KOLEVZON, Auteur ; Joseph D. BUXBAUM, Auteur Article en page(s) : 57p. Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : BACKGROUND: Haploinsufficiency of the forkhead-box protein P1 (FOXP1) gene leads to a neurodevelopmental disorder termed FOXP1 syndrome. Previous studies in individuals carrying FOXP1 mutations and deletions have described the presence of autism spectrum disorder (ASD) traits, intellectual disability, language impairment, and psychiatric features. The goal of the present study was to comprehensively characterize the genetic and clinical spectrum of FOXP1 syndrome. This is the first study to prospectively examine the genotype-phenotype relationship in multiple individuals with FOXP1 syndrome, using a battery of standardized clinical assessments. METHODS: Genetic and clinical data was obtained and analyzed from nine children and adolescents between the ages of 5-17 with mutations in FOXP1. Phenotypic characterization included gold standard ASD testing and norm-referenced measures of cognition, adaptive behavior, language, motor, and visual-motor integration skills. In addition, psychiatric, medical, neurological, and dysmorphology examinations were completed by a multidisciplinary team of clinicians. A comprehensive review of reported cases was also performed. All missense and in-frame mutations were mapped onto the three-dimensional structure of DNA-bound FOXP1. RESULTS: We have identified nine de novo mutations, including three frameshift, one nonsense, one mutation in an essential splice site resulting in frameshift and insertion of a premature stop codon, three missense, and one in-frame deletion. Reviewing prior literature, we found seven instances of recurrent mutations and another 34 private mutations. The majority of pathogenic missense and in-frame mutations, including all four missense mutations in our cohort, lie in the DNA-binding domain. Through structural analyses, we show that the mutations perturb amino acids necessary for binding to the DNA or interfere with the domain swapping that mediates FOXP1 dimerization. Individuals with FOXP1 syndrome presented with delays in early motor and language milestones, language impairment (expressive language > receptive language), ASD symptoms, visual-motor integration deficits, and complex psychiatric presentations characterized by anxiety, obsessive-compulsive traits, attention deficits, and externalizing symptoms. Medical features included non-specific structural brain abnormalities and dysmorphic features, endocrine and gastrointestinal problems, sleep disturbances, and sinopulmonary infections. CONCLUSIONS: This study identifies novel FOXP1 mutations associated with FOXP1 syndrome, identifies recurrent mutations, and demonstrates significant clustering of missense mutations in the DNA-binding domain. Clinical findings confirm the role FOXP1 plays in development across multiple domains of functioning. The genetic findings can be incorporated into clinical genetics practice to improve accurate genetic diagnosis of FOXP1 syndrome and the clinical findings can inform monitoring and treatment of individuals with FOXP1 syndrome. En ligne : http://dx.doi.org/10.1186/s13229-017-0172-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331 [article] Prospective investigation of FOXP1 syndrome [Texte imprimé et/ou numérique] / P. M. SIPER, Auteur ; S. DE RUBEIS, Auteur ; M. D. P. TRELLES, Auteur ; A. DURKIN, Auteur ; D. DI MARINO, Auteur ; F. MURATET, Auteur ; Y. FRANK, Auteur ; R. LOZANO, Auteur ; E. E. EICHLER, Auteur ; M. KELLY, Auteur ; Jennifer BEIGHLEY, Auteur ; J. GERDTS, Auteur ; Arianne S. WALLACE, Auteur ; H. C. MEFFORD, Auteur ; Raphael BERNIER, Auteur ; A. KOLEVZON, Auteur ; Joseph D. BUXBAUM, Auteur . - 57p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 57p. Index. décimale : PER Périodiques Résumé : BACKGROUND: Haploinsufficiency of the forkhead-box protein P1 (FOXP1) gene leads to a neurodevelopmental disorder termed FOXP1 syndrome. Previous studies in individuals carrying FOXP1 mutations and deletions have described the presence of autism spectrum disorder (ASD) traits, intellectual disability, language impairment, and psychiatric features. The goal of the present study was to comprehensively characterize the genetic and clinical spectrum of FOXP1 syndrome. This is the first study to prospectively examine the genotype-phenotype relationship in multiple individuals with FOXP1 syndrome, using a battery of standardized clinical assessments. METHODS: Genetic and clinical data was obtained and analyzed from nine children and adolescents between the ages of 5-17 with mutations in FOXP1. Phenotypic characterization included gold standard ASD testing and norm-referenced measures of cognition, adaptive behavior, language, motor, and visual-motor integration skills. In addition, psychiatric, medical, neurological, and dysmorphology examinations were completed by a multidisciplinary team of clinicians. A comprehensive review of reported cases was also performed. All missense and in-frame mutations were mapped onto the three-dimensional structure of DNA-bound FOXP1. RESULTS: We have identified nine de novo mutations, including three frameshift, one nonsense, one mutation in an essential splice site resulting in frameshift and insertion of a premature stop codon, three missense, and one in-frame deletion. Reviewing prior literature, we found seven instances of recurrent mutations and another 34 private mutations. The majority of pathogenic missense and in-frame mutations, including all four missense mutations in our cohort, lie in the DNA-binding domain. Through structural analyses, we show that the mutations perturb amino acids necessary for binding to the DNA or interfere with the domain swapping that mediates FOXP1 dimerization. Individuals with FOXP1 syndrome presented with delays in early motor and language milestones, language impairment (expressive language > receptive language), ASD symptoms, visual-motor integration deficits, and complex psychiatric presentations characterized by anxiety, obsessive-compulsive traits, attention deficits, and externalizing symptoms. Medical features included non-specific structural brain abnormalities and dysmorphic features, endocrine and gastrointestinal problems, sleep disturbances, and sinopulmonary infections. CONCLUSIONS: This study identifies novel FOXP1 mutations associated with FOXP1 syndrome, identifies recurrent mutations, and demonstrates significant clustering of missense mutations in the DNA-binding domain. Clinical findings confirm the role FOXP1 plays in development across multiple domains of functioning. The genetic findings can be incorporated into clinical genetics practice to improve accurate genetic diagnosis of FOXP1 syndrome and the clinical findings can inform monitoring and treatment of individuals with FOXP1 syndrome. En ligne : http://dx.doi.org/10.1186/s13229-017-0172-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331

Initial evidence that non-clinical autistic traits are associated with lower income / W. J. SKYLARK in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 61p. Titre : Initial evidence that non-clinical autistic traits are associated with lower income Type de document : Texte imprimé et/ou numérique Auteurs : W. J. SKYLARK, Auteur ; Simon BARON-COHEN, Auteur Article en page(s) : 61p. Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Among non-clinical samples, autistic traits correlate with a range of educational and social outcomes. However, previous work has not investigated the relationship between autistic traits and income, a key determinant of socio-economic status and well-being. In five studies (total N = 2491), we recruited participants without a diagnosis of autism from the general US population via an online platform and administered the short-form Autism Spectrum Quotient (AQ) as well as asked a range of demographic questions. We found a negative association between AQ and household income, which remained robust after controlling for age, gender, education, employment status, ethnicity, and socially desirable responding. The effect was primarily driven by the participant's own income and was mainly due to the social subscale of the AQ. These results provide initial evidence that income is negatively related to autistic traits among the general population, with potential implications for a range of social, psychological, and health outcomes. En ligne : http://dx.doi.org/10.1186/s13229-017-0179-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331 [article] Initial evidence that non-clinical autistic traits are associated with lower income [Texte imprimé et/ou numérique] / W. J. SKYLARK, Auteur ; Simon BARON-COHEN, Auteur . - 61p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 61p. Index. décimale : PER Périodiques Résumé : Among non-clinical samples, autistic traits correlate with a range of educational and social outcomes. However, previous work has not investigated the relationship between autistic traits and income, a key determinant of socio-economic status and well-being. In five studies (total N = 2491), we recruited participants without a diagnosis of autism from the general US population via an online platform and administered the short-form Autism Spectrum Quotient (AQ) as well as asked a range of demographic questions. We found a negative association between AQ and household income, which remained robust after controlling for age, gender, education, employment status, ethnicity, and socially desirable responding. The effect was primarily driven by the participant's own income and was mainly due to the social subscale of the AQ. These results provide initial evidence that income is negatively related to autistic traits among the general population, with potential implications for a range of social, psychological, and health outcomes. En ligne : http://dx.doi.org/10.1186/s13229-017-0179-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331

Shared genetic influences between dimensional ASD and ADHD symptoms during child and adolescent development / E. STERGIAKOULI in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 18p. Titre : Shared genetic influences between dimensional ASD and ADHD symptoms during child and adolescent development Type de document : Texte imprimé et/ou numérique Auteurs : E. STERGIAKOULI, Auteur ; George DAVEY SMITH, Auteur ; J. MARTIN, Auteur ; D. H. SKUSE, Auteur ; W. VIECHTBAUER, Auteur ; S. M. RING, Auteur ; A. RONALD, Auteur ; D. E. EVANS, Auteur ; S. E. FISHER, Auteur ; A. THAPAR, Auteur ; B. ST POURCAIN, Auteur Article en page(s) : 18p. Langues : Anglais (eng) Mots-clés : ADHD symptoms  Alspac  Clinical ADHD  Genetic overlap  Social communication Index. décimale : PER Périodiques Résumé : BACKGROUND: Shared genetic influences between attention-deficit/hyperactivity disorder (ADHD) symptoms and autism spectrum disorder (ASD) symptoms have been reported. Cross-trait genetic relationships are, however, subject to dynamic changes during development. We investigated the continuity of genetic overlap between ASD and ADHD symptoms in a general population sample during childhood and adolescence. We also studied uni- and cross-dimensional trait-disorder links with respect to genetic ADHD and ASD risk. METHODS: Social-communication difficulties (N En ligne : http://dx.doi.org/10.1186/s13229-017-0131-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331 [article] Shared genetic influences between dimensional ASD and ADHD symptoms during child and adolescent development [Texte imprimé et/ou numérique] / E. STERGIAKOULI, Auteur ; George DAVEY SMITH, Auteur ; J. MARTIN, Auteur ; D. H. SKUSE, Auteur ; W. VIECHTBAUER, Auteur ; S. M. RING, Auteur ; A. RONALD, Auteur ; D. E. EVANS, Auteur ; S. E. FISHER, Auteur ; A. THAPAR, Auteur ; B. ST POURCAIN, Auteur . - 18p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 18p. Mots-clés : ADHD symptoms  Alspac  Clinical ADHD  Genetic overlap  Social communication Index. décimale : PER Périodiques Résumé : BACKGROUND: Shared genetic influences between attention-deficit/hyperactivity disorder (ADHD) symptoms and autism spectrum disorder (ASD) symptoms have been reported. Cross-trait genetic relationships are, however, subject to dynamic changes during development. We investigated the continuity of genetic overlap between ASD and ADHD symptoms in a general population sample during childhood and adolescence. We also studied uni- and cross-dimensional trait-disorder links with respect to genetic ADHD and ASD risk. METHODS: Social-communication difficulties (N En ligne : http://dx.doi.org/10.1186/s13229-017-0131-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331

Etiological influences on the stability of autistic traits from childhood to early adulthood: evidence from a twin study / M. J. TAYLOR in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 5p. Titre : Etiological influences on the stability of autistic traits from childhood to early adulthood: evidence from a twin study Type de document : Texte imprimé et/ou numérique Auteurs : M. J. TAYLOR, Auteur ; C. GILLBERG, Auteur ; P. LICHTENSTEIN, Auteur ; S. LUNDSTRÖM, Auteur Article en page(s) : 5p. Langues : Anglais (eng) Mots-clés : Adolescent  Autistic Disorder/*genetics/*psychology  Child  Diseases in Twins  Female  Humans  Longitudinal Studies  Male  Phenotype  Surveys and Questionnaires  Twins/*genetics  *Adulthood  *Autism  *Genetics  *Stability  *Twin study Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorders (ASD) are persistent and lifelong conditions. Despite this, almost all twin studies focus on childhood. This twin study investigated the stability of autistic traits from childhood to early adulthood and explored the degree to which any stability could be explained by genetic or environmental factors. METHODS: Parents of over 2500 twin pairs completed questionnaires assessing autistic traits when twins were aged either 9 or 12 years and again when twins were aged 18. Bivariate twin analysis assessed the degree of phenotypic and etiological stability in autistic traits across this period. Genetic overlap in autistic traits across development was also tested in individuals displaying a broad ASD phenotype, defined as scoring within the highest 5% of the sample. RESULTS: Autistic traits displayed moderate phenotypic stability (r = .39). The heritability of autistic traits was 76-77% in childhood and 60-62% in adulthood. A moderate degree of genetic influences on childhood autistic traits were carried across into adulthood (genetic correlation = .49). The majority (85%) of the stability in autistic traits was attributable to genetic factors. Genetic influences on autistic traits were moderately stable from childhood to early adulthood at the extremes (genetic correlation = .64). CONCLUSIONS: Broad autistic traits display moderate phenotypic and etiological stability from childhood to early adulthood. Genetic factors accounted for almost all phenotypic stability, although there was some phenotypic and etiological instability in autistic traits. Thus, autistic traits in adulthood are influenced by a combination of enduring and unique genetic factors. En ligne : http://dx.doi.org/10.1186/s13229-017-0120-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331 [article] Etiological influences on the stability of autistic traits from childhood to early adulthood: evidence from a twin study [Texte imprimé et/ou numérique] / M. J. TAYLOR, Auteur ; C. GILLBERG, Auteur ; P. LICHTENSTEIN, Auteur ; S. LUNDSTRÖM, Auteur . - 5p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 5p. Mots-clés : Adolescent  Autistic Disorder/*genetics/*psychology  Child  Diseases in Twins  Female  Humans  Longitudinal Studies  Male  Phenotype  Surveys and Questionnaires  Twins/*genetics  *Adulthood  *Autism  *Genetics  *Stability  *Twin study Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorders (ASD) are persistent and lifelong conditions. Despite this, almost all twin studies focus on childhood. This twin study investigated the stability of autistic traits from childhood to early adulthood and explored the degree to which any stability could be explained by genetic or environmental factors. METHODS: Parents of over 2500 twin pairs completed questionnaires assessing autistic traits when twins were aged either 9 or 12 years and again when twins were aged 18. Bivariate twin analysis assessed the degree of phenotypic and etiological stability in autistic traits across this period. Genetic overlap in autistic traits across development was also tested in individuals displaying a broad ASD phenotype, defined as scoring within the highest 5% of the sample. RESULTS: Autistic traits displayed moderate phenotypic stability (r = .39). The heritability of autistic traits was 76-77% in childhood and 60-62% in adulthood. A moderate degree of genetic influences on childhood autistic traits were carried across into adulthood (genetic correlation = .49). The majority (85%) of the stability in autistic traits was attributable to genetic factors. Genetic influences on autistic traits were moderately stable from childhood to early adulthood at the extremes (genetic correlation = .64). CONCLUSIONS: Broad autistic traits display moderate phenotypic and etiological stability from childhood to early adulthood. Genetic factors accounted for almost all phenotypic stability, although there was some phenotypic and etiological instability in autistic traits. Thus, autistic traits in adulthood are influenced by a combination of enduring and unique genetic factors. En ligne : http://dx.doi.org/10.1186/s13229-017-0120-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331

Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia / THE AUTISM SPECTRUM DISORDERS WORKING GROUP OF THE PSYCHIATRIC GENOMICS CONSORTIUM in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 21p. Titre : Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia Type de document : Texte imprimé et/ou numérique Auteurs : THE AUTISM SPECTRUM DISORDERS WORKING GROUP OF THE PSYCHIATRIC GENOMICS CONSORTIUM, Auteur Article en page(s) : 21p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  Gene-set analysis  Genetic correlation  Genome-wide association study  Heritability  Meta-analysis  Neurodevelopment  Schizophrenia Index. décimale : PER Périodiques Résumé : BACKGROUND: Over the past decade genome-wide association studies (GWAS) have been applied to aid in the understanding of the biology of traits. The success of this approach is governed by the underlying effect sizes carried by the true risk variants and the corresponding statistical power to observe such effects given the study design and sample size under investigation. Previous ASD GWAS have identified genome-wide significant (GWS) risk loci; however, these studies were of only of low statistical power to identify GWS loci at the lower effect sizes (odds ratio (OR) <1.15). METHODS: We conducted a large-scale coordinated international collaboration to combine independent genotyping data to improve the statistical power and aid in robust discovery of GWS loci. This study uses genome-wide genotyping data from a discovery sample (7387 ASD cases and 8567 controls) followed by meta-analysis of summary statistics from two replication sets (7783 ASD cases and 11359 controls; and 1369 ASD cases and 137308 controls). RESULTS: We observe a GWS locus at 10q24.32 that overlaps several genes including PITX3, which encodes a transcription factor identified as playing a role in neuronal differentiation and CUEDC2 previously reported to be associated with social skills in an independent population cohort. We also observe overlap with regions previously implicated in schizophrenia which was further supported by a strong genetic correlation between these disorders (Rg = 0.23; P = 9 x 10(-6)). We further combined these Psychiatric Genomics Consortium (PGC) ASD GWAS data with the recent PGC schizophrenia GWAS to identify additional regions which may be important in a common neurodevelopmental phenotype and identified 12 novel GWS loci. These include loci previously implicated in ASD such as FOXP1 at 3p13, ATP2B2 at 3p25.3, and a 'neurodevelopmental hub' on chromosome 8p11.23. CONCLUSIONS: This study is an important step in the ongoing endeavour to identify the loci which underpin the common variant signal in ASD. In addition to novel GWS loci, we have identified a significant genetic correlation with schizophrenia and association of ASD with several neurodevelopmental-related genes such as EXT1, ASTN2, MACROD2, and HDAC4. En ligne : http://dx.doi.org/10.1186/s13229-017-0137-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331 [article] Meta-analysis of GWAS of over 16,000 individuals with autism spectrum disorder highlights a novel locus at 10q24.32 and a significant overlap with schizophrenia [Texte imprimé et/ou numérique] / THE AUTISM SPECTRUM DISORDERS WORKING GROUP OF THE PSYCHIATRIC GENOMICS CONSORTIUM, Auteur . - 21p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 21p. Mots-clés : Autism spectrum disorder  Gene-set analysis  Genetic correlation  Genome-wide association study  Heritability  Meta-analysis  Neurodevelopment  Schizophrenia Index. décimale : PER Périodiques Résumé : BACKGROUND: Over the past decade genome-wide association studies (GWAS) have been applied to aid in the understanding of the biology of traits. The success of this approach is governed by the underlying effect sizes carried by the true risk variants and the corresponding statistical power to observe such effects given the study design and sample size under investigation. Previous ASD GWAS have identified genome-wide significant (GWS) risk loci; however, these studies were of only of low statistical power to identify GWS loci at the lower effect sizes (odds ratio (OR) <1.15). METHODS: We conducted a large-scale coordinated international collaboration to combine independent genotyping data to improve the statistical power and aid in robust discovery of GWS loci. This study uses genome-wide genotyping data from a discovery sample (7387 ASD cases and 8567 controls) followed by meta-analysis of summary statistics from two replication sets (7783 ASD cases and 11359 controls; and 1369 ASD cases and 137308 controls). RESULTS: We observe a GWS locus at 10q24.32 that overlaps several genes including PITX3, which encodes a transcription factor identified as playing a role in neuronal differentiation and CUEDC2 previously reported to be associated with social skills in an independent population cohort. We also observe overlap with regions previously implicated in schizophrenia which was further supported by a strong genetic correlation between these disorders (Rg = 0.23; P = 9 x 10(-6)). We further combined these Psychiatric Genomics Consortium (PGC) ASD GWAS data with the recent PGC schizophrenia GWAS to identify additional regions which may be important in a common neurodevelopmental phenotype and identified 12 novel GWS loci. These include loci previously implicated in ASD such as FOXP1 at 3p13, ATP2B2 at 3p25.3, and a 'neurodevelopmental hub' on chromosome 8p11.23. CONCLUSIONS: This study is an important step in the ongoing endeavour to identify the loci which underpin the common variant signal in ASD. In addition to novel GWS loci, we have identified a significant genetic correlation with schizophrenia and association of ASD with several neurodevelopmental-related genes such as EXT1, ASTN2, MACROD2, and HDAC4. En ligne : http://dx.doi.org/10.1186/s13229-017-0137-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331

Interrelationship between insistence on sameness, effortful control and anxiety in adolescents and young adults with autism spectrum disorder (ASD) / M. ULJAREVIC in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 36p. Titre : Interrelationship between insistence on sameness, effortful control and anxiety in adolescents and young adults with autism spectrum disorder (ASD) Type de document : Texte imprimé et/ou numérique Auteurs : M. ULJAREVIC, Auteur ; A. L. RICHDALE, Auteur ; D. W. EVANS, Auteur ; Ru Ying CAI, Auteur ; S. R. LEEKAM, Auteur Article en page(s) : 36p. Langues : Anglais (eng) Mots-clés : Anxiety  Autism  Effortful control  Insistence on sameness  Self-regulation Index. décimale : PER Périodiques Résumé : BACKGROUND: Both self-regulation and insistence on sameness (IS) are related to anxiety, which is a common feature of individuals with autism spectrum disorder (ASD). Here, we aimed to characterise the IS-self-regulation-anxiety interrelationship by investigating the potential contribution made by self-regulation, assessed via effortful control (EC), to the IS-anxiety relationship in a sample of adolescents and young adults with ASD. METHOD: Seventy-one older adolescents and younger adults with ASD (49 males, 22 females; Mage = 18.71 years, SD = 2.51, range 14.42-24.81) completed the Adult Repetitive Behaviour Questionnaire-2, Effortful Control Scale of the Adult Temperament Questionnaire and the DSM-5 Dimensional Anxiety Scales. RESULTS: IS was associated with both EC (r = -.39, p = .001) and anxiety (r = .45, p < .001), and anxiety was in turn associated with EC (r = -.44, p < .001). To characterise the nature of this interrelationship, two mediation analyses were performed using the serial mediation model in PROCESS with 5000 resamples in bootstrapping. There was a significant indirect effect of EC on anxiety, through IS (b = -.06; BCa 95% CI [-.13, -.02]), and indirect effect on anxiety through EC (b = 1.62; BCa 95% CI [.59, 3.24]) with the mediators accounting for 29.07 and 26.04% of the total effect, respectively. CONCLUSIONS: Our study provides the first exploration of the IS-anxiety-self-regulation link in ASD. The finding that lower levels of self-regulation are related both to anxiety and IS behaviours points to self-regulation as a viable intervention target for both anxiety and IS behaviours. En ligne : http://dx.doi.org/10.1186/s13229-017-0158-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331 [article] Interrelationship between insistence on sameness, effortful control and anxiety in adolescents and young adults with autism spectrum disorder (ASD) [Texte imprimé et/ou numérique] / M. ULJAREVIC, Auteur ; A. L. RICHDALE, Auteur ; D. W. EVANS, Auteur ; Ru Ying CAI, Auteur ; S. R. LEEKAM, Auteur . - 36p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 36p. Mots-clés : Anxiety  Autism  Effortful control  Insistence on sameness  Self-regulation Index. décimale : PER Périodiques Résumé : BACKGROUND: Both self-regulation and insistence on sameness (IS) are related to anxiety, which is a common feature of individuals with autism spectrum disorder (ASD). Here, we aimed to characterise the IS-self-regulation-anxiety interrelationship by investigating the potential contribution made by self-regulation, assessed via effortful control (EC), to the IS-anxiety relationship in a sample of adolescents and young adults with ASD. METHOD: Seventy-one older adolescents and younger adults with ASD (49 males, 22 females; Mage = 18.71 years, SD = 2.51, range 14.42-24.81) completed the Adult Repetitive Behaviour Questionnaire-2, Effortful Control Scale of the Adult Temperament Questionnaire and the DSM-5 Dimensional Anxiety Scales. RESULTS: IS was associated with both EC (r = -.39, p = .001) and anxiety (r = .45, p < .001), and anxiety was in turn associated with EC (r = -.44, p < .001). To characterise the nature of this interrelationship, two mediation analyses were performed using the serial mediation model in PROCESS with 5000 resamples in bootstrapping. There was a significant indirect effect of EC on anxiety, through IS (b = -.06; BCa 95% CI [-.13, -.02]), and indirect effect on anxiety through EC (b = 1.62; BCa 95% CI [.59, 3.24]) with the mediators accounting for 29.07 and 26.04% of the total effect, respectively. CONCLUSIONS: Our study provides the first exploration of the IS-anxiety-self-regulation link in ASD. The finding that lower levels of self-regulation are related both to anxiety and IS behaviours points to self-regulation as a viable intervention target for both anxiety and IS behaviours. En ligne : http://dx.doi.org/10.1186/s13229-017-0158-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331

Balanced bifrontal transcranial direct current stimulation enhances working memory in adults with high-functioning autism: a sham-controlled crossover study / J. J. VAN STEENBURGH in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 40p. Titre : Balanced bifrontal transcranial direct current stimulation enhances working memory in adults with high-functioning autism: a sham-controlled crossover study Type de document : Texte imprimé et/ou numérique Auteurs : J. J. VAN STEENBURGH, Auteur ; M. VARVARIS, Auteur ; D. J. SCHRETLEN, Auteur ; T. D. VANNORSDALL, Auteur ; B. GORDON, Auteur Article en page(s) : 40p. Langues : Anglais (eng) Mots-clés : Autism  Dorsolateral prefrontal cortex  Transcranial direct current stimulation  Working memory Index. décimale : PER Périodiques Résumé : BACKGROUND: Working memory (WM) often is impaired in autism spectrum disorder (ASD). Such impairment may underlie core deficits in cognition and social functioning. Transcranial direct current stimulation (tDCS) has been shown to enhance WM in both healthy adults and clinical populations, but its efficacy in ASD is unknown. We predicted that bifrontal tDCS would improve WM performances of adults with high-functioning autism during active stimulation compared to sham stimulation and that such enhancement would generalize to an untrained task. METHODS: Twelve adults with high-functioning ASD engaged in a battery of WM tasks that included backward spatial span, backward digit span, spatial n-back and letter n-back. While engaged, 40 min of 1.5 mA bifrontal stimulation was applied over the left and the right dorsolateral prefrontal cortices (DLPFC). Using a single-blind crossover design, each participant received left anodal/right cathodal stimulation, right anodal/left cathodal stimulation, or sham stimulation, in randomized counterbalanced order on three separate days. Following tDCS, participants again engaged in letter and spatial n-back tasks before taking the Brief Test of Attention (BTA). We used repeated-measures ANOVA to compare overall performance on the WM battery as measured by a composite of z-scores for all five measures. Post hoc ANOVAs, t tests, Friedman's tests, and Wilcoxon signed-rank tests were used to measure the online and offline effects of tDCS and to assess performances on individual measures. RESULTS: Compared to sham stimulation, both left DLPFC anodal stimulation (t11 = 5.4, p = 0.0002) and right DLPFC anodal stimulation (t11 = 3.57, p = 0.004) improved overall WM performance. Left anodal stimulation (t11 = 3.9, p = 0.003) and right anodal stimulation (t11 = 2.7, p = 0.019) enhanced performances during stimulation. Enhancement transferred to an untrained task 50 min after right anodal stimulation (z11 = 2.263, p = 0.024). The tasks that showed the largest effects of active stimulation were spatial span backward (z11 = 2.39, p = 0.017) and BTA (z11 = 2.263, p = 0.024). CONCLUSIONS: In adults with high-functioning ASD, active bifrontal tDCS given during WM tasks appears to improve performance. TDCS benefits also transferred to an untrained task completed shortly after stimulation. These results suggest that tDCS can improve WM task performance and could reduce some core deficits of autism. TRIAL REGISTRATION: NCT01602263. En ligne : http://dx.doi.org/10.1186/s13229-017-0152-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331 [article] Balanced bifrontal transcranial direct current stimulation enhances working memory in adults with high-functioning autism: a sham-controlled crossover study [Texte imprimé et/ou numérique] / J. J. VAN STEENBURGH, Auteur ; M. VARVARIS, Auteur ; D. J. SCHRETLEN, Auteur ; T. D. VANNORSDALL, Auteur ; B. GORDON, Auteur . - 40p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 40p. Mots-clés : Autism  Dorsolateral prefrontal cortex  Transcranial direct current stimulation  Working memory Index. décimale : PER Périodiques Résumé : BACKGROUND: Working memory (WM) often is impaired in autism spectrum disorder (ASD). Such impairment may underlie core deficits in cognition and social functioning. Transcranial direct current stimulation (tDCS) has been shown to enhance WM in both healthy adults and clinical populations, but its efficacy in ASD is unknown. We predicted that bifrontal tDCS would improve WM performances of adults with high-functioning autism during active stimulation compared to sham stimulation and that such enhancement would generalize to an untrained task. METHODS: Twelve adults with high-functioning ASD engaged in a battery of WM tasks that included backward spatial span, backward digit span, spatial n-back and letter n-back. While engaged, 40 min of 1.5 mA bifrontal stimulation was applied over the left and the right dorsolateral prefrontal cortices (DLPFC). Using a single-blind crossover design, each participant received left anodal/right cathodal stimulation, right anodal/left cathodal stimulation, or sham stimulation, in randomized counterbalanced order on three separate days. Following tDCS, participants again engaged in letter and spatial n-back tasks before taking the Brief Test of Attention (BTA). We used repeated-measures ANOVA to compare overall performance on the WM battery as measured by a composite of z-scores for all five measures. Post hoc ANOVAs, t tests, Friedman's tests, and Wilcoxon signed-rank tests were used to measure the online and offline effects of tDCS and to assess performances on individual measures. RESULTS: Compared to sham stimulation, both left DLPFC anodal stimulation (t11 = 5.4, p = 0.0002) and right DLPFC anodal stimulation (t11 = 3.57, p = 0.004) improved overall WM performance. Left anodal stimulation (t11 = 3.9, p = 0.003) and right anodal stimulation (t11 = 2.7, p = 0.019) enhanced performances during stimulation. Enhancement transferred to an untrained task 50 min after right anodal stimulation (z11 = 2.263, p = 0.024). The tasks that showed the largest effects of active stimulation were spatial span backward (z11 = 2.39, p = 0.017) and BTA (z11 = 2.263, p = 0.024). CONCLUSIONS: In adults with high-functioning ASD, active bifrontal tDCS given during WM tasks appears to improve performance. TDCS benefits also transferred to an untrained task completed shortly after stimulation. These results suggest that tDCS can improve WM task performance and could reduce some core deficits of autism. TRIAL REGISTRATION: NCT01602263. En ligne : http://dx.doi.org/10.1186/s13229-017-0152-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331

Vitamin D treatment during pregnancy prevents autism-related phenotypes in a mouse model of maternal immune activation / S. VUILLERMOT in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 9p. Titre : Vitamin D treatment during pregnancy prevents autism-related phenotypes in a mouse model of maternal immune activation Type de document : Texte imprimé et/ou numérique Auteurs : S. VUILLERMOT, Auteur ; W. LUAN, Auteur ; U. MEYER, Auteur ; D. EYLES, Auteur Article en page(s) : 9p. Langues : Anglais (eng) Mots-clés : Animals  Behavior, Animal/*drug effects  Child Development Disorders, Pervasive/chemically induced/*prevention & control  Cytokines/*blood  Disease Models, Animal  Female  Humans  Mice  Phenotype  Poly I-C  Polynucleotides/*adverse effects  Pregnancy  Prenatal Exposure Delayed Effects/chemically induced/*prevention & control  Social Behavior  Stereotyped Behavior/*drug effects  Vitamin D/*administration & dosage  *Autism  *Cytokines  *Dopamine  *Maternal immune activation  *Neurodevelopmental disorders  *Schizophrenia  *Vitamin D Index. décimale : PER Périodiques Résumé : BACKGROUND: Prenatal exposure to infection is a recognized environmental risk factor for neuropsychiatric disorders of developmental origins such as autism or schizophrenia. Experimental work in animals indicates that this link is mediated by maternal immune activation (MIA) involving interactions between cytokine-associated inflammatory events, oxidative stress, and other pathophysiological processes such as hypoferremia and zinc deficiency. Maternal administration of the viral mimic polyriboinosinic-polyribocytidylic acid (poly(I:C)) in mice produces several behavioral phenotypes in adult offspring of relevance to autism spectrum disorder (ASD) and other neurodevelopmental disorders. METHODS: Here, we investigated whether some of these phenotypes might also present in juveniles. In addition, given the known immunomodulatory and neuroprotective effects of vitamin D, we also investigated whether the co-administration of vitamin D could block MIA-induced ASD-related behaviors. We co-administered the hormonally active form of vitamin D, 1alpha,25 dihydroxy vitamin D3 (1,25OHD), simultaneously with poly(I:C) and examined (i) social interaction, stereotyped behavior, emotional learning and memory, and innate anxiety-like behavior in juveniles and (ii) the levels of the pro-inflammatory cytokines IL-1beta, IL-6 and TNF-alpha in maternal plasma and fetal brains. RESULTS: We show that like adult offspring that were exposed to MIA, juveniles display similar deficits in social approach behavior. Juvenile MIA offspring also show abnormal stereotyped digging and impaired acquisition and expression of tone-cued fear conditioning. Importantly, our study reveals that prenatal administration of 1,25OHD abolishes all these behavioral deficits in poly(I:C)-treated juveniles. However, prenatal administration of vitamin D had no effect on pro-inflammatory cytokine levels in dams or in fetal brains suggesting the anti-inflammatory actions of vitamin D are not the critical mechanism for its preventive actions in this ASD animal model. CONCLUSIONS: This work raises the possibility that early dietary supplementation with vitamin D may open new avenues for a successful attenuation or even prevention of neurodevelopmental disorders following maternal inflammation during pregnancy. En ligne : http://dx.doi.org/10.1186/s13229-017-0125-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331 [article] Vitamin D treatment during pregnancy prevents autism-related phenotypes in a mouse model of maternal immune activation [Texte imprimé et/ou numérique] / S. VUILLERMOT, Auteur ; W. LUAN, Auteur ; U. MEYER, Auteur ; D. EYLES, Auteur . - 9p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 9p. Mots-clés : Animals  Behavior, Animal/*drug effects  Child Development Disorders, Pervasive/chemically induced/*prevention & control  Cytokines/*blood  Disease Models, Animal  Female  Humans  Mice  Phenotype  Poly I-C  Polynucleotides/*adverse effects  Pregnancy  Prenatal Exposure Delayed Effects/chemically induced/*prevention & control  Social Behavior  Stereotyped Behavior/*drug effects  Vitamin D/*administration & dosage  *Autism  *Cytokines  *Dopamine  *Maternal immune activation  *Neurodevelopmental disorders  *Schizophrenia  *Vitamin D Index. décimale : PER Périodiques Résumé : BACKGROUND: Prenatal exposure to infection is a recognized environmental risk factor for neuropsychiatric disorders of developmental origins such as autism or schizophrenia. Experimental work in animals indicates that this link is mediated by maternal immune activation (MIA) involving interactions between cytokine-associated inflammatory events, oxidative stress, and other pathophysiological processes such as hypoferremia and zinc deficiency. Maternal administration of the viral mimic polyriboinosinic-polyribocytidylic acid (poly(I:C)) in mice produces several behavioral phenotypes in adult offspring of relevance to autism spectrum disorder (ASD) and other neurodevelopmental disorders. METHODS: Here, we investigated whether some of these phenotypes might also present in juveniles. In addition, given the known immunomodulatory and neuroprotective effects of vitamin D, we also investigated whether the co-administration of vitamin D could block MIA-induced ASD-related behaviors. We co-administered the hormonally active form of vitamin D, 1alpha,25 dihydroxy vitamin D3 (1,25OHD), simultaneously with poly(I:C) and examined (i) social interaction, stereotyped behavior, emotional learning and memory, and innate anxiety-like behavior in juveniles and (ii) the levels of the pro-inflammatory cytokines IL-1beta, IL-6 and TNF-alpha in maternal plasma and fetal brains. RESULTS: We show that like adult offspring that were exposed to MIA, juveniles display similar deficits in social approach behavior. Juvenile MIA offspring also show abnormal stereotyped digging and impaired acquisition and expression of tone-cued fear conditioning. Importantly, our study reveals that prenatal administration of 1,25OHD abolishes all these behavioral deficits in poly(I:C)-treated juveniles. However, prenatal administration of vitamin D had no effect on pro-inflammatory cytokine levels in dams or in fetal brains suggesting the anti-inflammatory actions of vitamin D are not the critical mechanism for its preventive actions in this ASD animal model. CONCLUSIONS: This work raises the possibility that early dietary supplementation with vitamin D may open new avenues for a successful attenuation or even prevention of neurodevelopmental disorders following maternal inflammation during pregnancy. En ligne : http://dx.doi.org/10.1186/s13229-017-0125-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331

The association between maternal use of folic acid supplements during pregnancy and risk of autism spectrum disorders in children: a meta-analysis / M. WANG in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 51p. Titre : The association between maternal use of folic acid supplements during pregnancy and risk of autism spectrum disorders in children: a meta-analysis Type de document : Texte imprimé et/ou numérique Auteurs : M. WANG, Auteur ; K. LI, Auteur ; D. ZHAO, Auteur ; L. LI, Auteur Article en page(s) : 51p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorders  Children  Folic acid supplements  Maternal  Meta-analysis Index. décimale : PER Périodiques Résumé : Previous reviews have been conducted to evaluate the association between maternal use of folic acid supplements during pregnancy and risk of autism spectrum disorders (ASD) in children, with no definitive conclusion. We therefore conducted a more comprehensive meta-analysis to reassess the relationship between folic acid and the risk of ASD. The electronic databases PubMed, Web of Knowledge, and Wanfang Data were carefully searched to find eligible studies as recent as March 2017. A random effects model was used to combine the relative risk (RR) with 95% confidence intervals (CI). Sensitivity analysis and publication bias were conducted. A total of 12 articles with 16 studies comprising 4514 ASD cases were included in this report. It was found that supplementation with folic acid during pregnancy could reduce the risk of ASD [RR = 0.771, 95% CI = 0.641-0.928, I(2) = 59.7%, Pheterogeneity = 0.001] as compared to those women without folic acid supplementation. The associations were significant among Asian, European, and American populations. In summary, this comprehensive meta-analysis suggested that maternal use of folic acid supplements during pregnancy could significantly reduce the risk of ASD in children regardless of ethnicity, as compared to those women who did not supplement with folic acid. En ligne : http://dx.doi.org/10.1186/s13229-017-0170-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331 [article] The association between maternal use of folic acid supplements during pregnancy and risk of autism spectrum disorders in children: a meta-analysis [Texte imprimé et/ou numérique] / M. WANG, Auteur ; K. LI, Auteur ; D. ZHAO, Auteur ; L. LI, Auteur . - 51p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 51p. Mots-clés : Autism spectrum disorders  Children  Folic acid supplements  Maternal  Meta-analysis Index. décimale : PER Périodiques Résumé : Previous reviews have been conducted to evaluate the association between maternal use of folic acid supplements during pregnancy and risk of autism spectrum disorders (ASD) in children, with no definitive conclusion. We therefore conducted a more comprehensive meta-analysis to reassess the relationship between folic acid and the risk of ASD. The electronic databases PubMed, Web of Knowledge, and Wanfang Data were carefully searched to find eligible studies as recent as March 2017. A random effects model was used to combine the relative risk (RR) with 95% confidence intervals (CI). Sensitivity analysis and publication bias were conducted. A total of 12 articles with 16 studies comprising 4514 ASD cases were included in this report. It was found that supplementation with folic acid during pregnancy could reduce the risk of ASD [RR = 0.771, 95% CI = 0.641-0.928, I(2) = 59.7%, Pheterogeneity = 0.001] as compared to those women without folic acid supplementation. The associations were significant among Asian, European, and American populations. In summary, this comprehensive meta-analysis suggested that maternal use of folic acid supplements during pregnancy could significantly reduce the risk of ASD in children regardless of ethnicity, as compared to those women who did not supplement with folic acid. En ligne : http://dx.doi.org/10.1186/s13229-017-0170-8 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331

CRISPR/Cas9-mediated heterozygous knockout of the autism gene CHD8 and characterization of its transcriptional networks in cerebral organoids derived from iPS cells / P. WANG in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 11p. Titre : CRISPR/Cas9-mediated heterozygous knockout of the autism gene CHD8 and characterization of its transcriptional networks in cerebral organoids derived from iPS cells Type de document : Texte imprimé et/ou numérique Auteurs : P. WANG, Auteur ; R. MOKHTARI, Auteur ; E. PEDROSA, Auteur ; M. KIRSCHENBAUM, Auteur ; C. BAYRAK, Auteur ; D. ZHENG, Auteur ; H. M. LACHMAN, Auteur Article en page(s) : 11p. Langues : Anglais (eng) Mots-clés : Autism Spectrum Disorder/genetics  Bipolar Disorder/genetics  CRISPR-Cas Systems  Cell Differentiation  Cells, Cultured  DNA-Binding Proteins/*genetics  Gene Expression Profiling/*methods  Gene Expression Regulation  Gene Knockout Techniques  *Gene Regulatory Networks  Humans  Induced Pluripotent Stem Cells/*cytology  Mental Disorders/*genetics  Mutation  Organoids/*cytology  Schizophrenia/genetics  Sequence Analysis, RNA/*methods  Telencephalon/*cytology  Transcription Factors/*genetics  *Autism  *Beta-catenin  *Bipolar disorder  *Cancer  *Dlx6-as1  *Distal-less homeobox  *Gabaergic  *Hmga2  *Schizophrenia  *Tcf4  *Wnt  *Znf132 Index. décimale : PER Périodiques Résumé : BACKGROUND: CHD8 (chromodomain helicase DNA-binding protein 8), which codes for a member of the CHD family of ATP-dependent chromatin-remodeling factors, is one of the most commonly mutated genes in autism spectrum disorders (ASD) identified in exome-sequencing studies. Loss of function mutations in the gene have also been found in schizophrenia (SZ) and intellectual disabilities and influence cancer cell proliferation. We previously reported an RNA-seq analysis carried out on neural progenitor cells (NPCs) and monolayer neurons derived from induced pluripotent stem (iPS) cells that were heterozygous for CHD8 knockout (KO) alleles generated using CRISPR-Cas9 gene editing. A significant number of ASD and SZ candidate genes were among those that were differentially expressed in a comparison of heterozygous KO lines (CHD8(+/-)) vs isogenic controls (CHD8(+/-)), including the SZ and bipolar disorder (BD) candidate gene TCF4, which was markedly upregulated in CHD8(+/-) neuronal cells. METHODS: In the current study, RNA-seq was carried out on CHD8(+/-) and isogenic control (CHD8(+/+)) cerebral organoids, which are 3-dimensional structures derived from iPS cells that model the developing human telencephalon. RESULTS: TCF4 expression was, again, significantly upregulated. Pathway analysis carried out on differentially expressed genes (DEGs) revealed an enrichment of genes involved in neurogenesis, neuronal differentiation, forebrain development, Wnt/beta-catenin signaling, and axonal guidance, similar to our previous study on NPCs and monolayer neurons. There was also significant overlap in our CHD8(+/-) DEGs with those found in a transcriptome analysis carried out by another group using cerebral organoids derived from a family with idiopathic ASD. Remarkably, the top DEG in our respective studies was the non-coding RNA DLX6-AS1, which was markedly upregulated in both studies; DLX6-AS1 regulates the expression of members of the DLX (distal-less homeobox) gene family. DLX1 was also upregulated in both studies. DLX genes code for transcription factors that play a key role in GABAergic interneuron differentiation. Significant overlap was also found in a transcriptome study carried out by another group using iPS cell-derived neurons from patients with BD, a condition characterized by dysregulated WNT/beta-catenin signaling in a subgroup of affected individuals. CONCLUSIONS: Overall, the findings show that distinct ASD, SZ, and BD candidate genes converge on common molecular targets-an important consideration for developing novel therapeutics in genetically heterogeneous complex traits. En ligne : http://dx.doi.org/10.1186/s13229-017-0124-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331 [article] CRISPR/Cas9-mediated heterozygous knockout of the autism gene CHD8 and characterization of its transcriptional networks in cerebral organoids derived from iPS cells [Texte imprimé et/ou numérique] / P. WANG, Auteur ; R. MOKHTARI, Auteur ; E. PEDROSA, Auteur ; M. KIRSCHENBAUM, Auteur ; C. BAYRAK, Auteur ; D. ZHENG, Auteur ; H. M. LACHMAN, Auteur . - 11p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 11p. Mots-clés : Autism Spectrum Disorder/genetics  Bipolar Disorder/genetics  CRISPR-Cas Systems  Cell Differentiation  Cells, Cultured  DNA-Binding Proteins/*genetics  Gene Expression Profiling/*methods  Gene Expression Regulation  Gene Knockout Techniques  *Gene Regulatory Networks  Humans  Induced Pluripotent Stem Cells/*cytology  Mental Disorders/*genetics  Mutation  Organoids/*cytology  Schizophrenia/genetics  Sequence Analysis, RNA/*methods  Telencephalon/*cytology  Transcription Factors/*genetics  *Autism  *Beta-catenin  *Bipolar disorder  *Cancer  *Dlx6-as1  *Distal-less homeobox  *Gabaergic  *Hmga2  *Schizophrenia  *Tcf4  *Wnt  *Znf132 Index. décimale : PER Périodiques Résumé : BACKGROUND: CHD8 (chromodomain helicase DNA-binding protein 8), which codes for a member of the CHD family of ATP-dependent chromatin-remodeling factors, is one of the most commonly mutated genes in autism spectrum disorders (ASD) identified in exome-sequencing studies. Loss of function mutations in the gene have also been found in schizophrenia (SZ) and intellectual disabilities and influence cancer cell proliferation. We previously reported an RNA-seq analysis carried out on neural progenitor cells (NPCs) and monolayer neurons derived from induced pluripotent stem (iPS) cells that were heterozygous for CHD8 knockout (KO) alleles generated using CRISPR-Cas9 gene editing. A significant number of ASD and SZ candidate genes were among those that were differentially expressed in a comparison of heterozygous KO lines (CHD8(+/-)) vs isogenic controls (CHD8(+/-)), including the SZ and bipolar disorder (BD) candidate gene TCF4, which was markedly upregulated in CHD8(+/-) neuronal cells. METHODS: In the current study, RNA-seq was carried out on CHD8(+/-) and isogenic control (CHD8(+/+)) cerebral organoids, which are 3-dimensional structures derived from iPS cells that model the developing human telencephalon. RESULTS: TCF4 expression was, again, significantly upregulated. Pathway analysis carried out on differentially expressed genes (DEGs) revealed an enrichment of genes involved in neurogenesis, neuronal differentiation, forebrain development, Wnt/beta-catenin signaling, and axonal guidance, similar to our previous study on NPCs and monolayer neurons. There was also significant overlap in our CHD8(+/-) DEGs with those found in a transcriptome analysis carried out by another group using cerebral organoids derived from a family with idiopathic ASD. Remarkably, the top DEG in our respective studies was the non-coding RNA DLX6-AS1, which was markedly upregulated in both studies; DLX6-AS1 regulates the expression of members of the DLX (distal-less homeobox) gene family. DLX1 was also upregulated in both studies. DLX genes code for transcription factors that play a key role in GABAergic interneuron differentiation. Significant overlap was also found in a transcriptome study carried out by another group using iPS cell-derived neurons from patients with BD, a condition characterized by dysregulated WNT/beta-catenin signaling in a subgroup of affected individuals. CONCLUSIONS: Overall, the findings show that distinct ASD, SZ, and BD candidate genes converge on common molecular targets-an important consideration for developing novel therapeutics in genetically heterogeneous complex traits. En ligne : http://dx.doi.org/10.1186/s13229-017-0124-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331

Identification of autism-related MECP2 mutations by whole-exome sequencing and functional validation / Z. WEN in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 43p. Titre : Identification of autism-related MECP2 mutations by whole-exome sequencing and functional validation Type de document : Texte imprimé et/ou numérique Auteurs : Z. WEN, Auteur ; T. L. CHENG, Auteur ; G. Z. LI, Auteur ; S. B. SUN, Auteur ; S. Y. YU, Auteur ; Y. ZHANG, Auteur ; Y. S. DU, Auteur ; Z. QIU, Auteur Article en page(s) : 43p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  Methyl-CpG-binding protein-2 (MeCP2)  Neural development  Whole-exome sequencing Index. décimale : PER Périodiques Résumé : BACKGROUND: Methyl-CpG-binding protein-2 (MeCP2) is a critical regulator for neural development. Either loss- or gain-of-function leads to severe neurodevelopmental disorders, such as Rett syndrome (RTT) and autism spectrum disorder (ASD). We set out to screen for MECP2 mutations in patients of ASD and determine whether these autism-related mutations may compromise the proper function of MeCP2. METHODS: Whole-exome sequencing was performed to screen MECP2 and other ASD candidate genes for 120 patients diagnosed with ASD. The parents of patients who were identified with MECP2 mutation were selected for further Sanger sequencing. Each patient accomplished the case report form including general information and clinical scales applied to assess their clinical features. Mouse cortical neurons and HEK-293 cells were cultured and transfected with MeCP2 wild-type (WT) or mutant to examine the function of autism-associated MeCP2 mutants. HEK-293 cells were used to examine the expression of MeCP2 mutant constructs with Western blot. Mouse cortical neurons were used to analyze neurites and axon outgrowth by immunofluorescence experiments. RESULTS: We identified three missense mutations of MECP2 from three autism patients by whole-exome sequencing: p.P152L (c.455C>T), p.P376S (c.1162C>T), and p.R294X (c.880C>T). Among these mutations, p.P152L and p.R294X were de novo mutations, whereas p.P376S was inherited maternally. The diagnosis of RTT was excluded in all three autism patients. Abnormalities of dendritic and axonal growth were found after autism-related MeCP2 mutants were expressed in mouse cortical neurons; suggesting that autism-related MECP2 mutations impair the proper development of neurons. CONCLUSIONS: Our study identified genetic mutations of the MECP2 gene in autism patients, which were previously considered to be associated primarily with RTT. This finding suggests that loss-of-function mutations of MECP2 may also lead to autism spectrum disorders. En ligne : http://dx.doi.org/10.1186/s13229-017-0157-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331 [article] Identification of autism-related MECP2 mutations by whole-exome sequencing and functional validation [Texte imprimé et/ou numérique] / Z. WEN, Auteur ; T. L. CHENG, Auteur ; G. Z. LI, Auteur ; S. B. SUN, Auteur ; S. Y. YU, Auteur ; Y. ZHANG, Auteur ; Y. S. DU, Auteur ; Z. QIU, Auteur . - 43p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 43p. Mots-clés : Autism spectrum disorder  Methyl-CpG-binding protein-2 (MeCP2)  Neural development  Whole-exome sequencing Index. décimale : PER Périodiques Résumé : BACKGROUND: Methyl-CpG-binding protein-2 (MeCP2) is a critical regulator for neural development. Either loss- or gain-of-function leads to severe neurodevelopmental disorders, such as Rett syndrome (RTT) and autism spectrum disorder (ASD). We set out to screen for MECP2 mutations in patients of ASD and determine whether these autism-related mutations may compromise the proper function of MeCP2. METHODS: Whole-exome sequencing was performed to screen MECP2 and other ASD candidate genes for 120 patients diagnosed with ASD. The parents of patients who were identified with MECP2 mutation were selected for further Sanger sequencing. Each patient accomplished the case report form including general information and clinical scales applied to assess their clinical features. Mouse cortical neurons and HEK-293 cells were cultured and transfected with MeCP2 wild-type (WT) or mutant to examine the function of autism-associated MeCP2 mutants. HEK-293 cells were used to examine the expression of MeCP2 mutant constructs with Western blot. Mouse cortical neurons were used to analyze neurites and axon outgrowth by immunofluorescence experiments. RESULTS: We identified three missense mutations of MECP2 from three autism patients by whole-exome sequencing: p.P152L (c.455C>T), p.P376S (c.1162C>T), and p.R294X (c.880C>T). Among these mutations, p.P152L and p.R294X were de novo mutations, whereas p.P376S was inherited maternally. The diagnosis of RTT was excluded in all three autism patients. Abnormalities of dendritic and axonal growth were found after autism-related MeCP2 mutants were expressed in mouse cortical neurons; suggesting that autism-related MECP2 mutations impair the proper development of neurons. CONCLUSIONS: Our study identified genetic mutations of the MECP2 gene in autism patients, which were previously considered to be associated primarily with RTT. This finding suggests that loss-of-function mutations of MECP2 may also lead to autism spectrum disorders. En ligne : http://dx.doi.org/10.1186/s13229-017-0157-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331

A brain proteomic investigation of rapamycin effects in the Tsc1(+/-) mouse model / H. WESSELING in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 41p. Titre : A brain proteomic investigation of rapamycin effects in the Tsc1(+/-) mouse model Type de document : Texte imprimé et/ou numérique Auteurs : H. WESSELING, Auteur ; Y. ELGERSMA, Auteur ; S. BAHN, Auteur Article en page(s) : 41p. Langues : Anglais (eng) Mots-clés : Animal model  Proteomics  Rapamycin  Srm  Tuberous sclerosis Index. décimale : PER Périodiques Résumé : BACKGROUND: Tuberous sclerosis complex (TSC) is a rare monogenic disorder characterized by benign tumors in multiple organs as well as a high prevalence of epilepsy, intellectual disability and autism. TSC is caused by inactivating mutations in the TSC1 or TSC2 genes. Heterozygocity induces hyperactivation of mTOR which can be inhibited by mTOR inhibitors, such as rapamycin, which have proven efficacy in the treatment of TSC-associated symptoms. The aim of the present study was (1) to identify molecular changes associated with social and cognitive deficits in the brain tissue of Tsc1(+/-) mice and (2) to investigate the molecular effects of rapamycin treatment, which has been shown to ameliorate genotype-related behavioural deficits. METHODS: Molecular alterations in the frontal cortex and hippocampus of Tsc1(+/-) and control mice, with or without rapamycin treatment, were investigated. A quantitative mass spectrometry-based shotgun proteomic approach (LC-MS(E)) was employed as an unbiased method to detect changes in protein levels. Changes identified in the initial profiling stage were validated using selected reaction monitoring (SRM). Protein Set Enrichment Analysis was employed to identify dysregulated pathways. RESULTS: LC-MS(E) analysis of Tsc1(+/-) mice and controls (n = 30) identified 51 proteins changed in frontal cortex and 108 in the hippocampus. Bioinformatic analysis combined with targeted proteomic validation revealed several dysregulated molecular pathways. Using targeted assays, proteomic alterations in the hippocampus validated the pathways "myelination", "dendrite," and "oxidative stress", an upregulation of ribosomal proteins and the mTOR kinase. LC-MS(E) analysis was also employed on Tsc1(+/-) and wildtype mice (n = 34) treated with rapamycin or vehicle. Rapamycin treatment exerted a stronger proteomic effect in Tsc1(+/-) mice with significant changes (mainly decreased expression) in 231 and 106 proteins, respectively. The cellular pathways "oxidative stress" and "apoptosis" were found to be affected in Tsc1(+/-) mice and the cellular compartments "myelin sheet" and "neurofilaments" were affected by rapamycin treatment. Thirty-three proteins which were altered in Tsc1(+/-) mice were normalized following rapamycin treatment, amongst them oxidative stress related proteins, myelin-specific and ribosomal proteins. CONCLUSIONS: Molecular changes in the Tsc1(+/-) mouse brain were more prominent in the hippocampus compared to the frontal cortex. Pathways linked to myelination and oxidative stress response were prominently affected and, at least in part, normalized following rapamycin treatment. The results could aid in the identification of novel drug targets for the treatment of cognitive, social and psychiatric symptoms in autism spectrum disorders. Similar pathways have also been implicated in other psychiatric and neurodegenerative disorders and could imply similar disease processes. Thus, the potential efficacy of mTOR inhibitors warrants further investigation not only for autism spectrum disorders but also for other neuropsychiatric and neurodegenerative diseases. En ligne : http://dx.doi.org/10.1186/s13229-017-0151-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331 [article] A brain proteomic investigation of rapamycin effects in the Tsc1(+/-) mouse model [Texte imprimé et/ou numérique] / H. WESSELING, Auteur ; Y. ELGERSMA, Auteur ; S. BAHN, Auteur . - 41p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 41p. Mots-clés : Animal model  Proteomics  Rapamycin  Srm  Tuberous sclerosis Index. décimale : PER Périodiques Résumé : BACKGROUND: Tuberous sclerosis complex (TSC) is a rare monogenic disorder characterized by benign tumors in multiple organs as well as a high prevalence of epilepsy, intellectual disability and autism. TSC is caused by inactivating mutations in the TSC1 or TSC2 genes. Heterozygocity induces hyperactivation of mTOR which can be inhibited by mTOR inhibitors, such as rapamycin, which have proven efficacy in the treatment of TSC-associated symptoms. The aim of the present study was (1) to identify molecular changes associated with social and cognitive deficits in the brain tissue of Tsc1(+/-) mice and (2) to investigate the molecular effects of rapamycin treatment, which has been shown to ameliorate genotype-related behavioural deficits. METHODS: Molecular alterations in the frontal cortex and hippocampus of Tsc1(+/-) and control mice, with or without rapamycin treatment, were investigated. A quantitative mass spectrometry-based shotgun proteomic approach (LC-MS(E)) was employed as an unbiased method to detect changes in protein levels. Changes identified in the initial profiling stage were validated using selected reaction monitoring (SRM). Protein Set Enrichment Analysis was employed to identify dysregulated pathways. RESULTS: LC-MS(E) analysis of Tsc1(+/-) mice and controls (n = 30) identified 51 proteins changed in frontal cortex and 108 in the hippocampus. Bioinformatic analysis combined with targeted proteomic validation revealed several dysregulated molecular pathways. Using targeted assays, proteomic alterations in the hippocampus validated the pathways "myelination", "dendrite," and "oxidative stress", an upregulation of ribosomal proteins and the mTOR kinase. LC-MS(E) analysis was also employed on Tsc1(+/-) and wildtype mice (n = 34) treated with rapamycin or vehicle. Rapamycin treatment exerted a stronger proteomic effect in Tsc1(+/-) mice with significant changes (mainly decreased expression) in 231 and 106 proteins, respectively. The cellular pathways "oxidative stress" and "apoptosis" were found to be affected in Tsc1(+/-) mice and the cellular compartments "myelin sheet" and "neurofilaments" were affected by rapamycin treatment. Thirty-three proteins which were altered in Tsc1(+/-) mice were normalized following rapamycin treatment, amongst them oxidative stress related proteins, myelin-specific and ribosomal proteins. CONCLUSIONS: Molecular changes in the Tsc1(+/-) mouse brain were more prominent in the hippocampus compared to the frontal cortex. Pathways linked to myelination and oxidative stress response were prominently affected and, at least in part, normalized following rapamycin treatment. The results could aid in the identification of novel drug targets for the treatment of cognitive, social and psychiatric symptoms in autism spectrum disorders. Similar pathways have also been implicated in other psychiatric and neurodegenerative disorders and could imply similar disease processes. Thus, the potential efficacy of mTOR inhibitors warrants further investigation not only for autism spectrum disorders but also for other neuropsychiatric and neurodegenerative diseases. En ligne : http://dx.doi.org/10.1186/s13229-017-0151-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331

Clinical evaluation of autistic symptoms in women with anorexia nervosa / H. WESTWOOD in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 12p. Titre : Clinical evaluation of autistic symptoms in women with anorexia nervosa Type de document : Texte imprimé et/ou numérique Auteurs : H. WESTWOOD, Auteur ; W. MANDY, Auteur ; K. TCHANTURIA, Auteur Article en page(s) : 12p. Langues : Anglais (eng) Mots-clés : Adult  Affective Symptoms/epidemiology  Anorexia Nervosa/*complications/*psychology  Autism Spectrum Disorder/*diagnosis  Cross-Sectional Studies  Female  Humans  Middle Aged  Obsessive-Compulsive Disorder/epidemiology  Psychiatric Status Rating Scales  Self Report  Young Adult  *Ados-2  *Anorexia nervosa  *Autism spectrum disorder  *Eating disorder  *Female autism Index. décimale : PER Périodiques Résumé : BACKGROUND: Despite a suggested link between anorexia nervosa (AN) and autism spectrum disorder (ASD), previous studies have used self-report or diagnostic criteria to assess for ASD in AN populations, rather than direct observation of symptom characteristic of ASD. The aim of this study was to use a standardised, clinical assessment of ASD, the Autism Diagnostic Observation Schedule, 2nd Edition (ADOS-2), to investigate the presence of autistic symptoms in a cross-sectional sample of women with AN. METHODS: Sixty women were recruited from inpatient or day-patient specialist eating disorder services. Each participant underwent the ADOS-2 assessment and completed a set of self-report questionnaires assessing eating disorder pathology and other psychiatric symptoms. IQ was also assessed. RESULTS: Fourteen women (23.3%) scored above clinical cutoff for ASD on the ADOS-2. Only eight of these women displayed repetitive or restrictive behaviours, while all 14 had difficulties with social affect. Elevated ASD symptoms were associated with increased alexithymia and obsessive-compulsive symptoms, but not specific eating disorder pathology. CONCLUSIONS: ASD symptoms are over-represented in women with severe AN and appear to be associated with other psychiatric symptoms, which warrant further investigation and consideration in treatment. En ligne : http://dx.doi.org/10.1186/s13229-017-0128-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331 [article] Clinical evaluation of autistic symptoms in women with anorexia nervosa [Texte imprimé et/ou numérique] / H. WESTWOOD, Auteur ; W. MANDY, Auteur ; K. TCHANTURIA, Auteur . - 12p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 12p. Mots-clés : Adult  Affective Symptoms/epidemiology  Anorexia Nervosa/*complications/*psychology  Autism Spectrum Disorder/*diagnosis  Cross-Sectional Studies  Female  Humans  Middle Aged  Obsessive-Compulsive Disorder/epidemiology  Psychiatric Status Rating Scales  Self Report  Young Adult  *Ados-2  *Anorexia nervosa  *Autism spectrum disorder  *Eating disorder  *Female autism Index. décimale : PER Périodiques Résumé : BACKGROUND: Despite a suggested link between anorexia nervosa (AN) and autism spectrum disorder (ASD), previous studies have used self-report or diagnostic criteria to assess for ASD in AN populations, rather than direct observation of symptom characteristic of ASD. The aim of this study was to use a standardised, clinical assessment of ASD, the Autism Diagnostic Observation Schedule, 2nd Edition (ADOS-2), to investigate the presence of autistic symptoms in a cross-sectional sample of women with AN. METHODS: Sixty women were recruited from inpatient or day-patient specialist eating disorder services. Each participant underwent the ADOS-2 assessment and completed a set of self-report questionnaires assessing eating disorder pathology and other psychiatric symptoms. IQ was also assessed. RESULTS: Fourteen women (23.3%) scored above clinical cutoff for ASD on the ADOS-2. Only eight of these women displayed repetitive or restrictive behaviours, while all 14 had difficulties with social affect. Elevated ASD symptoms were associated with increased alexithymia and obsessive-compulsive symptoms, but not specific eating disorder pathology. CONCLUSIONS: ASD symptoms are over-represented in women with severe AN and appear to be associated with other psychiatric symptoms, which warrant further investigation and consideration in treatment. En ligne : http://dx.doi.org/10.1186/s13229-017-0128-x Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331

d-Cycloserine enhances durability of social skills training in autism spectrum disorder / L. K. WINK in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 2p. Titre : d-Cycloserine enhances durability of social skills training in autism spectrum disorder Type de document : Texte imprimé et/ou numérique Auteurs : L. K. WINK, Auteur ; N. F. MINSHAWI, Auteur ; R. C. SHAFFER, Auteur ; M. H. PLAWECKI, Auteur ; D. J. POSEY, Auteur ; P. S. HORN, Auteur ; R. ADAMS, Auteur ; Ernest V. PEDAPATI, Auteur ; T. L. SCHAEFER, Auteur ; C. J. MCDOUGLE, Auteur ; N. B. SWIEZY, Auteur ; C. A. ERICKSON, Auteur Article en page(s) : 2p. Langues : Anglais (eng) Mots-clés : Autism Spectrum Disorder/*drug therapy/psychology  Child  Child, Preschool  Cycloserine/*administration & dosage/pharmacology  Double-Blind Method  Drug Administration Schedule  Female  Humans  Learning/*drug effects  Male  Severity of Illness Index  Social Behavior  Treatment Outcome  *Autism  *Autism spectrum disorder  *Social skills training  *d-Cycloserine Index. décimale : PER Périodiques Résumé : BACKGROUND: d-Cycloserine (DCS) enhances extinction learning across species, but it has proven challenging to identify consistent benefit of DCS when added to therapeutic interventions. We conducted a placebo-controlled trial of DCS to potentiate social skills training in autism spectrum disorder (ASD) but found substantial improvement in both the DCS and placebo groups at the conclusion of active treatment. Here, we assess the impact of DCS 11 weeks following active treatment to evaluate the impact of DCS on treatment response durability. METHODS: Study participants included 60 outpatient youth with ASD, ages 5-11 years, all with IQ above 70, and significantly impaired social functioning who completed a 10-week active treatment phase during which they received weekly single doses of 50 mg of DCS or placebo administered 30 min prior to group social skills training. Following the 10-week active treatment phase, blinded follow-up assessments occurred at week 11 and week 22. The primary outcome measure for our durability of treatment evaluation was the parent-rated social responsiveness scale (SRS) total raw score at week 22. RESULTS: Analysis of the SRS total raw score demonstrated significant decrease for the DCS group compared to the placebo group (p = 0.042) indicating greater maintenance of treatment effect in the DCS group. DCS was well tolerated, with irritability being the most frequently reported adverse effect in both groups. CONCLUSIONS: The findings of this study suggest that DCS may help youth with ASD to maintain skills gained during sort-term social skills training. Larger-scale studies with longer follow-up will be necessary to further understand the long-term impact of DCS paired with structured social skills training. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01086475. En ligne : http://dx.doi.org/10.1186/s13229-017-0116-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331 [article] d-Cycloserine enhances durability of social skills training in autism spectrum disorder [Texte imprimé et/ou numérique] / L. K. WINK, Auteur ; N. F. MINSHAWI, Auteur ; R. C. SHAFFER, Auteur ; M. H. PLAWECKI, Auteur ; D. J. POSEY, Auteur ; P. S. HORN, Auteur ; R. ADAMS, Auteur ; Ernest V. PEDAPATI, Auteur ; T. L. SCHAEFER, Auteur ; C. J. MCDOUGLE, Auteur ; N. B. SWIEZY, Auteur ; C. A. ERICKSON, Auteur . - 2p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 2p. Mots-clés : Autism Spectrum Disorder/*drug therapy/psychology  Child  Child, Preschool  Cycloserine/*administration & dosage/pharmacology  Double-Blind Method  Drug Administration Schedule  Female  Humans  Learning/*drug effects  Male  Severity of Illness Index  Social Behavior  Treatment Outcome  *Autism  *Autism spectrum disorder  *Social skills training  *d-Cycloserine Index. décimale : PER Périodiques Résumé : BACKGROUND: d-Cycloserine (DCS) enhances extinction learning across species, but it has proven challenging to identify consistent benefit of DCS when added to therapeutic interventions. We conducted a placebo-controlled trial of DCS to potentiate social skills training in autism spectrum disorder (ASD) but found substantial improvement in both the DCS and placebo groups at the conclusion of active treatment. Here, we assess the impact of DCS 11 weeks following active treatment to evaluate the impact of DCS on treatment response durability. METHODS: Study participants included 60 outpatient youth with ASD, ages 5-11 years, all with IQ above 70, and significantly impaired social functioning who completed a 10-week active treatment phase during which they received weekly single doses of 50 mg of DCS or placebo administered 30 min prior to group social skills training. Following the 10-week active treatment phase, blinded follow-up assessments occurred at week 11 and week 22. The primary outcome measure for our durability of treatment evaluation was the parent-rated social responsiveness scale (SRS) total raw score at week 22. RESULTS: Analysis of the SRS total raw score demonstrated significant decrease for the DCS group compared to the placebo group (p = 0.042) indicating greater maintenance of treatment effect in the DCS group. DCS was well tolerated, with irritability being the most frequently reported adverse effect in both groups. CONCLUSIONS: The findings of this study suggest that DCS may help youth with ASD to maintain skills gained during sort-term social skills training. Larger-scale studies with longer follow-up will be necessary to further understand the long-term impact of DCS paired with structured social skills training. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01086475. En ligne : http://dx.doi.org/10.1186/s13229-017-0116-1 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331

Neural circuitry at age 6 months associated with later repetitive behavior and sensory responsiveness in autism / J. J. WOLFF in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 8p. Titre : Neural circuitry at age 6 months associated with later repetitive behavior and sensory responsiveness in autism Type de document : Texte imprimé et/ou numérique Auteurs : J. J. WOLFF, Auteur ; M. R. SWANSON, Auteur ; J. T. ELISON, Auteur ; G. GERIG, Auteur ; J. R. PRUETT, Auteur ; M. A. STYNER, Auteur ; C. VACHET, Auteur ; Kelly N. BOTTERON, Auteur ; Stephen R. DAGER, Auteur ; A. M. ESTES, Auteur ; Heather C. HAZLETT, Auteur ; Robert T. SCHULTZ, Auteur ; M. D. SHEN, Auteur ; Lonnie ZWAIGENBAUM, Auteur ; J. PIVEN, Auteur Article en page(s) : 8p. Langues : Anglais (eng) Mots-clés : Autism Spectrum Disorder/diagnostic imaging/*psychology  Brain/diagnostic imaging/*physiology  Brain Mapping/*methods  Child, Preschool  Diffusion Tensor Imaging/*methods  Female  Humans  Infant  Longitudinal Studies  Male  Stereotyped Behavior/*physiology  *Autism  *Diffusion tensor imaging  *Infant  *Longitudinal  *Repetitive behavior  *White matter Index. décimale : PER Périodiques Résumé : BACKGROUND: Restricted and repetitive behaviors are defining features of autism spectrum disorder (ASD). Under revised diagnostic criteria for ASD, this behavioral domain now includes atypical responses to sensory stimuli. To date, little is known about the neural circuitry underlying these features of ASD early in life. METHODS: Longitudinal diffusion tensor imaging data were collected from 217 infants at high familial risk for ASD. Forty-four of these infants were diagnosed with ASD at age 2. Targeted cortical, cerebellar, and striatal white matter pathways were defined and measured at ages 6, 12, and 24 months. Dependent variables included the Repetitive Behavior Scale-Revised and the Sensory Experiences Questionnaire. RESULTS: Among children diagnosed with ASD, repetitive behaviors and sensory response patterns were strongly correlated, even when accounting for developmental level or social impairment. Longitudinal analyses indicated that the genu and cerebellar pathways were significantly associated with both repetitive behaviors and sensory responsiveness but not social deficits. At age 6 months, fractional anisotropy in the genu significantly predicted repetitive behaviors and sensory responsiveness at age 2. Cerebellar pathways significantly predicted later sensory responsiveness. Exploratory analyses suggested a possible disordinal interaction based on diagnostic status for the association between fractional anisotropy and repetitive behavior. CONCLUSIONS: Our findings suggest that restricted and repetitive behaviors contributing to a diagnosis of ASD at age 2 years are associated with structural properties of callosal and cerebellar white matter pathways measured during infancy and toddlerhood. We further identified that repetitive behaviors and unusual sensory response patterns co-occur and share common brain-behavior relationships. These results were strikingly specific given the absence of association between targeted pathways and social deficits. En ligne : http://dx.doi.org/10.1186/s13229-017-0126-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331 [article] Neural circuitry at age 6 months associated with later repetitive behavior and sensory responsiveness in autism [Texte imprimé et/ou numérique] / J. J. WOLFF, Auteur ; M. R. SWANSON, Auteur ; J. T. ELISON, Auteur ; G. GERIG, Auteur ; J. R. PRUETT, Auteur ; M. A. STYNER, Auteur ; C. VACHET, Auteur ; Kelly N. BOTTERON, Auteur ; Stephen R. DAGER, Auteur ; A. M. ESTES, Auteur ; Heather C. HAZLETT, Auteur ; Robert T. SCHULTZ, Auteur ; M. D. SHEN, Auteur ; Lonnie ZWAIGENBAUM, Auteur ; J. PIVEN, Auteur . - 8p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 8p. Mots-clés : Autism Spectrum Disorder/diagnostic imaging/*psychology  Brain/diagnostic imaging/*physiology  Brain Mapping/*methods  Child, Preschool  Diffusion Tensor Imaging/*methods  Female  Humans  Infant  Longitudinal Studies  Male  Stereotyped Behavior/*physiology  *Autism  *Diffusion tensor imaging  *Infant  *Longitudinal  *Repetitive behavior  *White matter Index. décimale : PER Périodiques Résumé : BACKGROUND: Restricted and repetitive behaviors are defining features of autism spectrum disorder (ASD). Under revised diagnostic criteria for ASD, this behavioral domain now includes atypical responses to sensory stimuli. To date, little is known about the neural circuitry underlying these features of ASD early in life. METHODS: Longitudinal diffusion tensor imaging data were collected from 217 infants at high familial risk for ASD. Forty-four of these infants were diagnosed with ASD at age 2. Targeted cortical, cerebellar, and striatal white matter pathways were defined and measured at ages 6, 12, and 24 months. Dependent variables included the Repetitive Behavior Scale-Revised and the Sensory Experiences Questionnaire. RESULTS: Among children diagnosed with ASD, repetitive behaviors and sensory response patterns were strongly correlated, even when accounting for developmental level or social impairment. Longitudinal analyses indicated that the genu and cerebellar pathways were significantly associated with both repetitive behaviors and sensory responsiveness but not social deficits. At age 6 months, fractional anisotropy in the genu significantly predicted repetitive behaviors and sensory responsiveness at age 2. Cerebellar pathways significantly predicted later sensory responsiveness. Exploratory analyses suggested a possible disordinal interaction based on diagnostic status for the association between fractional anisotropy and repetitive behavior. CONCLUSIONS: Our findings suggest that restricted and repetitive behaviors contributing to a diagnosis of ASD at age 2 years are associated with structural properties of callosal and cerebellar white matter pathways measured during infancy and toddlerhood. We further identified that repetitive behaviors and unusual sensory response patterns co-occur and share common brain-behavior relationships. These results were strikingly specific given the absence of association between targeted pathways and social deficits. En ligne : http://dx.doi.org/10.1186/s13229-017-0126-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331

Mutations in RAB39B in individuals with intellectual disability, autism spectrum disorder, and macrocephaly / M. WOODBURY-SMITH in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 59p. Titre : Mutations in RAB39B in individuals with intellectual disability, autism spectrum disorder, and macrocephaly Type de document : Texte imprimé et/ou numérique Auteurs : M. WOODBURY-SMITH, Auteur ; E. DENEAULT, Auteur ; R. K. C. YUEN, Auteur ; S. WALKER, Auteur ; M. ZARREI, Auteur ; G. PELLECCHIA, Auteur ; J. L. HOWE, Auteur ; N. HOANG, Auteur ; M. UDDIN, Auteur ; C. R. MARSHALL, Auteur ; C. CHRYSLER, Auteur ; A. THOMPSON, Auteur ; P. SZATMARI, Auteur ; Stephen SCHERER, Auteur Article en page(s) : 59p. Langues : Anglais (eng) Mots-clés : Intellectual disability (ID)  Rab39b  RNAseq  Whole genome sequencing (WGS) Index. décimale : PER Périodiques Résumé : Background: Autism spectrum disorder (ASD), a developmental disorder of early childhood onset, affects males four times more frequently than females, suggesting a role for the sex chromosomes. In this study, we describe a family with ASD in which a predicted pathogenic nonsense mutation in the X-chromosome gene RAB39B segregates with ASD phenotype. Methods: Clinical phenotyping, microarray, and whole genome sequencing (WGS) were performed on the five members of this family. Maternal and female sibling X inactivation ratio was calculated, and phase was investigated. Mutant-induced pluripotent stem cells engineered for an exon 2 nonsense mutation were generated and differentiated into cortical neurons for expression and pathway analyses. Results: Two males with an inherited RAB39B mutation both presented with macrocephaly, intellectual disability (ID), and ASD. Their female sibling with the same mutation presented with ID and a broad autism phenotype. In contrast, their transmitting mother has no neurodevelopmental diagnosis. Our investigation of phase indicated maternal preferential inactivation of the mutated allele, with no such bias observed in the female sibling. We offer the explanation that this bias in X inactivation may explain the absence of a neurocognitive phenotype in the mother. Our cellular knockout model of RAB39B revealed an impact on expression in differentiated neurons for several genes implicated in brain development and function, supported by our pathway enrichment analysis. Conclusions: Penetrance for ASD is high among males but more variable among females with RAB39B mutations. A critical role for this gene in brain development and function is demonstrated. En ligne : http://dx.doi.org/10.1186/s13229-017-0175-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331 [article] Mutations in RAB39B in individuals with intellectual disability, autism spectrum disorder, and macrocephaly [Texte imprimé et/ou numérique] / M. WOODBURY-SMITH, Auteur ; E. DENEAULT, Auteur ; R. K. C. YUEN, Auteur ; S. WALKER, Auteur ; M. ZARREI, Auteur ; G. PELLECCHIA, Auteur ; J. L. HOWE, Auteur ; N. HOANG, Auteur ; M. UDDIN, Auteur ; C. R. MARSHALL, Auteur ; C. CHRYSLER, Auteur ; A. THOMPSON, Auteur ; P. SZATMARI, Auteur ; Stephen SCHERER, Auteur . - 59p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 59p. Mots-clés : Intellectual disability (ID)  Rab39b  RNAseq  Whole genome sequencing (WGS) Index. décimale : PER Périodiques Résumé : Background: Autism spectrum disorder (ASD), a developmental disorder of early childhood onset, affects males four times more frequently than females, suggesting a role for the sex chromosomes. In this study, we describe a family with ASD in which a predicted pathogenic nonsense mutation in the X-chromosome gene RAB39B segregates with ASD phenotype. Methods: Clinical phenotyping, microarray, and whole genome sequencing (WGS) were performed on the five members of this family. Maternal and female sibling X inactivation ratio was calculated, and phase was investigated. Mutant-induced pluripotent stem cells engineered for an exon 2 nonsense mutation were generated and differentiated into cortical neurons for expression and pathway analyses. Results: Two males with an inherited RAB39B mutation both presented with macrocephaly, intellectual disability (ID), and ASD. Their female sibling with the same mutation presented with ID and a broad autism phenotype. In contrast, their transmitting mother has no neurodevelopmental diagnosis. Our investigation of phase indicated maternal preferential inactivation of the mutated allele, with no such bias observed in the female sibling. We offer the explanation that this bias in X inactivation may explain the absence of a neurocognitive phenotype in the mother. Our cellular knockout model of RAB39B revealed an impact on expression in differentiated neurons for several genes implicated in brain development and function, supported by our pathway enrichment analysis. Conclusions: Penetrance for ASD is high among males but more variable among females with RAB39B mutations. A critical role for this gene in brain development and function is demonstrated. En ligne : http://dx.doi.org/10.1186/s13229-017-0175-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331

Replicative genetic association study between functional polymorphisms in AVPR1A and social behavior scales of autism spectrum disorder in the Korean population / S. Y. YANG in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 44p. Titre : Replicative genetic association study between functional polymorphisms in AVPR1A and social behavior scales of autism spectrum disorder in the Korean population Type de document : Texte imprimé et/ou numérique Auteurs : S. Y. YANG, Auteur ; S. A. KIM, Auteur ; G. M. HUR, Auteur ; M. PARK, Auteur ; J. E. PARK, Auteur ; H. J. YOO, Auteur Article en page(s) : 44p. Langues : Anglais (eng) Mots-clés : Arginine vasopressin receptor 1A (AVPR1A)  Association  Autism spectrum disorder  Microsatellite  Promoter  Single nucleotide polymorphism Index. décimale : PER Périodiques Résumé : BACKGROUND: Arginine vasopressin has been shown to affect social and emotional behaviors, which is mediated by the arginine vasopressin receptor (AVPR1A). Genetic polymorphisms in the AVPR1A promoter region have been identified to be associated with susceptibility to social deficits in autism spectrum disorder (ASD). We hypothesize that alleles of polymorphisms in the promoter region of AVPR1A may differentially interact with certain transcriptional factors, which in turn affect quantitative traits, such as sociality, in children with autism. METHODS: We performed an association study between ASD and polymorphisms in the AVPR1A promoter region in the Korean population using a family-based association test (FBAT). We evaluated the correlation between genotypes and the quantitative traits that are related to sociality in children with autism. We also performed a promoter assay in T98G cells and evaluated the binding affinities of transcription factors to alleles of rs7294536. RESULTS: The polymorphisms-RS1, RS3, rs7294536, and rs10877969-were analyzed. Under the dominant model, RS1-310, the shorter allele, was preferentially transmitted. The FBAT showed that the rs7294536 A allele was also preferentially transmitted in an additive and dominant model under the bi-allelic mode. When quantitative traits were used in the FBAT, rs7294536 and rs10877969 were statistically significant in all genotype models and modes. Luciferase and electrophoretic mobility-shift assays suggest that the rs7294536 A/G allele results in a Nf-kappaB binding site that exhibits differential binding affinities depending on the allele. CONCLUSION: These results demonstrate that polymorphisms in the AVPR1A promoter region might be involved in pathophysiology of ASD and in functional regulation of the expression of AVPR1A. En ligne : http://dx.doi.org/10.1186/s13229-017-0161-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331 [article] Replicative genetic association study between functional polymorphisms in AVPR1A and social behavior scales of autism spectrum disorder in the Korean population [Texte imprimé et/ou numérique] / S. Y. YANG, Auteur ; S. A. KIM, Auteur ; G. M. HUR, Auteur ; M. PARK, Auteur ; J. E. PARK, Auteur ; H. J. YOO, Auteur . - 44p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 44p. Mots-clés : Arginine vasopressin receptor 1A (AVPR1A)  Association  Autism spectrum disorder  Microsatellite  Promoter  Single nucleotide polymorphism Index. décimale : PER Périodiques Résumé : BACKGROUND: Arginine vasopressin has been shown to affect social and emotional behaviors, which is mediated by the arginine vasopressin receptor (AVPR1A). Genetic polymorphisms in the AVPR1A promoter region have been identified to be associated with susceptibility to social deficits in autism spectrum disorder (ASD). We hypothesize that alleles of polymorphisms in the promoter region of AVPR1A may differentially interact with certain transcriptional factors, which in turn affect quantitative traits, such as sociality, in children with autism. METHODS: We performed an association study between ASD and polymorphisms in the AVPR1A promoter region in the Korean population using a family-based association test (FBAT). We evaluated the correlation between genotypes and the quantitative traits that are related to sociality in children with autism. We also performed a promoter assay in T98G cells and evaluated the binding affinities of transcription factors to alleles of rs7294536. RESULTS: The polymorphisms-RS1, RS3, rs7294536, and rs10877969-were analyzed. Under the dominant model, RS1-310, the shorter allele, was preferentially transmitted. The FBAT showed that the rs7294536 A allele was also preferentially transmitted in an additive and dominant model under the bi-allelic mode. When quantitative traits were used in the FBAT, rs7294536 and rs10877969 were statistically significant in all genotype models and modes. Luciferase and electrophoretic mobility-shift assays suggest that the rs7294536 A/G allele results in a Nf-kappaB binding site that exhibits differential binding affinities depending on the allele. CONCLUSION: These results demonstrate that polymorphisms in the AVPR1A promoter region might be involved in pathophysiology of ASD and in functional regulation of the expression of AVPR1A. En ligne : http://dx.doi.org/10.1186/s13229-017-0161-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331

Globally weaker and topologically different: resting-state connectivity in youth with autism / B. E. YERYS in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 39p. Titre : Globally weaker and topologically different: resting-state connectivity in youth with autism Type de document : Texte imprimé et/ou numérique Auteurs : B. E. YERYS, Auteur ; J. D. HERRINGTON, Auteur ; Theodore D. SATTERTHWAITE, Auteur ; L. GUY, Auteur ; Robert T. SCHULTZ, Auteur ; D. S. BASSETT, Auteur Article en page(s) : 39p. Langues : Anglais (eng) Mots-clés : Attention  Autism spectrum disorder  Children  Intrinsic networks  Social cognition Index. décimale : PER Périodiques Résumé : BACKGROUND: There is a lack of agreement about functional connectivity differences in individuals with autism spectrum disorder (ASD). Studies using absolute strength have found reduced connectivity, while those using relative strength--a measure of system topology--reveal mostly enhanced connectivity. We hypothesized that mixed findings may be driven by the metric of functional connectivity. METHODS: Resting-state echo planar 3 T functional magnetic resonance imaging scans were acquired on a Siemens Verio Scanner from 6 to 17-year-old youth with ASD (n = 81) and a matched typically developing control group (n = 82). All functional time series data were preprocessed using a confound regression procedure that has been previously validated in large-scale developmental datasets. It has also been shown to be highly effective at reducing the influence of motion artifact on connectivity data. We extracted time series data from a 333-node parcellation scheme, which was previously mapped to 13 functional systems. A Pearson's correlation was calculated and transformed to Fisher's z between every pair of nodes to create a weighted 333 x 333 adjacency matrix. Mean absolute functional connectivity strength was the mean Fisher's z of the matrix. Relative functional connectivity was corrected for individual differences in mean absolute functional connectivity (i.e., each connection in the matrix was divided by their mean z), and functional connectivity was evaluated within and across each of the functional networks in the parcellation scheme. RESULTS: Absolute functional connectivity strength was lower in ASD, and lower functional connectivity was correlated with greater ASD symptom severity. Relative functional connectivity was higher for the ASD group in the ventral attention and retrosplenial-temporal systems, with lower cross-system functional connectivity between the ventral attention and somatomotor-mouth systems. Functional connectivity within the ventral attention and retro-splenial systems correlated significantly with ASD symptom severity. CONCLUSIONS: Within a context of globally weaker functional connectivity, youth with ASD have an atypical topology of brain systems that support social perception and communication. This study clarifies the mixed results reported previously and demonstrates that the functional connectivity metric influences the observed direction of functional connectivity differences for individuals with ASD. En ligne : http://dx.doi.org/10.1186/s13229-017-0156-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331 [article] Globally weaker and topologically different: resting-state connectivity in youth with autism [Texte imprimé et/ou numérique] / B. E. YERYS, Auteur ; J. D. HERRINGTON, Auteur ; Theodore D. SATTERTHWAITE, Auteur ; L. GUY, Auteur ; Robert T. SCHULTZ, Auteur ; D. S. BASSETT, Auteur . - 39p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 39p. Mots-clés : Attention  Autism spectrum disorder  Children  Intrinsic networks  Social cognition Index. décimale : PER Périodiques Résumé : BACKGROUND: There is a lack of agreement about functional connectivity differences in individuals with autism spectrum disorder (ASD). Studies using absolute strength have found reduced connectivity, while those using relative strength--a measure of system topology--reveal mostly enhanced connectivity. We hypothesized that mixed findings may be driven by the metric of functional connectivity. METHODS: Resting-state echo planar 3 T functional magnetic resonance imaging scans were acquired on a Siemens Verio Scanner from 6 to 17-year-old youth with ASD (n = 81) and a matched typically developing control group (n = 82). All functional time series data were preprocessed using a confound regression procedure that has been previously validated in large-scale developmental datasets. It has also been shown to be highly effective at reducing the influence of motion artifact on connectivity data. We extracted time series data from a 333-node parcellation scheme, which was previously mapped to 13 functional systems. A Pearson's correlation was calculated and transformed to Fisher's z between every pair of nodes to create a weighted 333 x 333 adjacency matrix. Mean absolute functional connectivity strength was the mean Fisher's z of the matrix. Relative functional connectivity was corrected for individual differences in mean absolute functional connectivity (i.e., each connection in the matrix was divided by their mean z), and functional connectivity was evaluated within and across each of the functional networks in the parcellation scheme. RESULTS: Absolute functional connectivity strength was lower in ASD, and lower functional connectivity was correlated with greater ASD symptom severity. Relative functional connectivity was higher for the ASD group in the ventral attention and retrosplenial-temporal systems, with lower cross-system functional connectivity between the ventral attention and somatomotor-mouth systems. Functional connectivity within the ventral attention and retro-splenial systems correlated significantly with ASD symptom severity. CONCLUSIONS: Within a context of globally weaker functional connectivity, youth with ASD have an atypical topology of brain systems that support social perception and communication. This study clarifies the mixed results reported previously and demonstrates that the functional connectivity metric influences the observed direction of functional connectivity differences for individuals with ASD. En ligne : http://dx.doi.org/10.1186/s13229-017-0156-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331

Identification of mutations in the PI3K-AKT-mTOR signalling pathway in patients with macrocephaly and developmental delay and/or autism / K. S. YEUNG in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 66p. Titre : Identification of mutations in the PI3K-AKT-mTOR signalling pathway in patients with macrocephaly and developmental delay and/or autism Type de document : Texte imprimé et/ou numérique Auteurs : K. S. YEUNG, Auteur ; W. W. Y. TSO, Auteur ; J. J. K. IP, Auteur ; C. C. Y. MAK, Auteur ; G. K. C. LEUNG, Auteur ; M. H. Y. TSANG, Auteur ; D. YING, Auteur ; S. L. C. PEI, Auteur ; S. L. LEE, Auteur ; W. YANG, Auteur ; B. H. CHUNG, Auteur Article en page(s) : 66p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  Developmental delay  Mtor  Macrocephaly  Megalencephaly  Pik3ca  Ppp2r5d  Pten  Somatic mosaicism  Hong Kong/Hospital Authority Hong Kong West Cluster (UW 12-211), and written  consent was obtained from the patients' parents.Written informed consent was  obtained from the patients' parents for publication of their children's details  and accompanying images in this manuscript. The consent form is held by the  authors and is available for review by the Editor-in-Chief.The authors declare  that they have no competing interests.Springer Nature remains neutral with regard  to jurisdictional claims in published maps and institutional affiliations. Index. décimale : PER Périodiques Résumé : Background: Macrocephaly, which is defined as a head circumference greater than or equal to + 2 standard deviations, is a feature commonly observed in children with developmental delay and/or autism spectrum disorder. Although PTEN is a well-known gene identified in patients with this syndromic presentation, other genes in the PI3K-AKT-mTOR signalling pathway have also recently been suggested to have important roles. The aim of this study is to characterise the mutation spectrum of this group of patients. Methods: We performed whole-exome sequencing of 21 patients with macrocephaly and developmental delay/autism spectrum disorder. Sources of genomic DNA included blood, buccal mucosa and saliva. Germline mutations were validated by Sanger sequencing, whereas somatic mutations were validated by droplet digital PCR. Results: We identified ten pathogenic/likely pathogenic mutations in PTEN (n = 4), PIK3CA (n = 3), MTOR (n = 1) and PPP2R5D (n = 2) in ten patients. An additional PTEN mutation, which was classified as variant of unknown significance, was identified in a patient with a pathogenic PTEN mutation, making him harbour bi-allelic germline PTEN mutations. Two patients harboured somatic PIK3CA mutations, and the level of somatic mosaicism in blood DNA was low. Patients who tested positive for mutations in the PI3K-AKT-mTOR pathway had a lower developmental quotient than the rest of the cohort (DQ = 62.8 vs. 76.1, p = 0.021). Their dysmorphic features were non-specific, except for macrocephaly. Among the ten patients with identified mutations, brain magnetic resonance imaging was performed in nine, all of whom showed megalencephaly. Conclusion: We identified mutations in the PI3K-AKT-mTOR signalling pathway in nearly half of our patients with macrocephaly and developmental delay/autism spectrum disorder. These patients have subtle dysmorphic features and mild developmental issues. Clinically, patients with germline mutations are difficult to distinguish from patients with somatic mutations, and therefore, sequencing of buccal or saliva DNA is important to identify somatic mosaicism. Given the high diagnostic yield and the management implications, we suggest implementing comprehensive genetic testing in the PI3K-AKT-mTOR pathway in the clinical evaluation of patients with macrocephaly and developmental delay and/or autism spectrum disorder. En ligne : http://dx.doi.org/10.1186/s13229-017-0182-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331 [article] Identification of mutations in the PI3K-AKT-mTOR signalling pathway in patients with macrocephaly and developmental delay and/or autism [Texte imprimé et/ou numérique] / K. S. YEUNG, Auteur ; W. W. Y. TSO, Auteur ; J. J. K. IP, Auteur ; C. C. Y. MAK, Auteur ; G. K. C. LEUNG, Auteur ; M. H. Y. TSANG, Auteur ; D. YING, Auteur ; S. L. C. PEI, Auteur ; S. L. LEE, Auteur ; W. YANG, Auteur ; B. H. CHUNG, Auteur . - 66p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 66p. Mots-clés : Autism spectrum disorder  Developmental delay  Mtor  Macrocephaly  Megalencephaly  Pik3ca  Ppp2r5d  Pten  Somatic mosaicism  Hong Kong/Hospital Authority Hong Kong West Cluster (UW 12-211), and written  consent was obtained from the patients' parents.Written informed consent was  obtained from the patients' parents for publication of their children's details  and accompanying images in this manuscript. The consent form is held by the  authors and is available for review by the Editor-in-Chief.The authors declare  that they have no competing interests.Springer Nature remains neutral with regard  to jurisdictional claims in published maps and institutional affiliations. Index. décimale : PER Périodiques Résumé : Background: Macrocephaly, which is defined as a head circumference greater than or equal to + 2 standard deviations, is a feature commonly observed in children with developmental delay and/or autism spectrum disorder. Although PTEN is a well-known gene identified in patients with this syndromic presentation, other genes in the PI3K-AKT-mTOR signalling pathway have also recently been suggested to have important roles. The aim of this study is to characterise the mutation spectrum of this group of patients. Methods: We performed whole-exome sequencing of 21 patients with macrocephaly and developmental delay/autism spectrum disorder. Sources of genomic DNA included blood, buccal mucosa and saliva. Germline mutations were validated by Sanger sequencing, whereas somatic mutations were validated by droplet digital PCR. Results: We identified ten pathogenic/likely pathogenic mutations in PTEN (n = 4), PIK3CA (n = 3), MTOR (n = 1) and PPP2R5D (n = 2) in ten patients. An additional PTEN mutation, which was classified as variant of unknown significance, was identified in a patient with a pathogenic PTEN mutation, making him harbour bi-allelic germline PTEN mutations. Two patients harboured somatic PIK3CA mutations, and the level of somatic mosaicism in blood DNA was low. Patients who tested positive for mutations in the PI3K-AKT-mTOR pathway had a lower developmental quotient than the rest of the cohort (DQ = 62.8 vs. 76.1, p = 0.021). Their dysmorphic features were non-specific, except for macrocephaly. Among the ten patients with identified mutations, brain magnetic resonance imaging was performed in nine, all of whom showed megalencephaly. Conclusion: We identified mutations in the PI3K-AKT-mTOR signalling pathway in nearly half of our patients with macrocephaly and developmental delay/autism spectrum disorder. These patients have subtle dysmorphic features and mild developmental issues. Clinically, patients with germline mutations are difficult to distinguish from patients with somatic mutations, and therefore, sequencing of buccal or saliva DNA is important to identify somatic mosaicism. Given the high diagnostic yield and the management implications, we suggest implementing comprehensive genetic testing in the PI3K-AKT-mTOR pathway in the clinical evaluation of patients with macrocephaly and developmental delay and/or autism spectrum disorder. En ligne : http://dx.doi.org/10.1186/s13229-017-0182-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331

Transcriptome analysis of microglia in a mouse model of Rett syndrome: differential expression of genes associated with microglia/macrophage activation and cellular stress / D. ZHAO in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 17p. Titre : Transcriptome analysis of microglia in a mouse model of Rett syndrome: differential expression of genes associated with microglia/macrophage activation and cellular stress Type de document : Texte imprimé et/ou numérique Auteurs : D. ZHAO, Auteur ; R. MOKHTARI, Auteur ; E. PEDROSA, Auteur ; R. BIRNBAUM, Auteur ; D. ZHENG, Auteur ; H. M. LACHMAN, Auteur Article en page(s) : 17p. Langues : Anglais (eng) Mots-clés : Animals  Disease Models, Animal  Female  Gene Expression Profiling/*methods  Gene Expression Regulation  Heat-Shock Proteins/genetics  Humans  Macrophage Activation  Macrophages/*cytology  Methyl-CpG-Binding Protein 2/*deficiency  Mice  Microglia/*metabolism  Mutation  Oxidative Stress  Rett Syndrome/*genetics  Sequence Analysis, RNA/*methods  *Autism  *Heat shock  *Innate immune system  *M1 activation  *M2 activation  *Microglia  *Rett syndrome  *Schizophrenia Index. décimale : PER Périodiques Résumé : BACKGROUND: Rett syndrome (RTT) is a severe, neurodevelopmental disorder primarily affecting girls, characterized by progressive loss of cognitive, social, and motor skills after a relatively brief period of typical development. It is usually due to de novo loss of function mutations in the X-linked gene, MeCP2, which codes for the gene expression and chromatin regulator, methyl-CpG binding protein 2. Although the behavioral phenotype appears to be primarily due to neuronal Mecp2 deficiency in mice, other cell types, including astrocytes and oligodendrocytes, also appear to contribute to some aspects of the RTT phenotype. In addition, microglia may also play a role. However, the effect of Mecp2 deficiency in microglia on RTT pathogenesis is controversial. METHODS: In the current study, we applied whole transcriptome analysis using RNA-seq to gain insight into molecular pathways in microglia that might be dysregulated during the transition, in female mice heterozygous for an Mecp2-null allele (Mecp2(+/-); Het), from the pre-phenotypic (5 weeks) to the phenotypic phases (24 weeks). RESULTS: We found a significant overlap in differentially expressed genes (DEGs) with genes involved in regulating the extracellular matrix, and those that are activated or inhibited when macrophages and microglia are stimulated towards the M1 and M2 activation states. However, the M1- and M2-associated genes were different in the 5- and 24-week samples. In addition, a substantial decrease in the expression of nine members of the heat shock protein (HSP) family was found in the 5-week samples, but not at 24 weeks. CONCLUSIONS: These findings suggest that microglia from pre-phenotypic and phenotypic female mice are activated in a manner different from controls and that pre-phenotypic female mice may have alterations in their capacity to response to heat stress and other stressors that function through the HSP pathway. En ligne : http://dx.doi.org/10.1186/s13229-017-0134-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331 [article] Transcriptome analysis of microglia in a mouse model of Rett syndrome: differential expression of genes associated with microglia/macrophage activation and cellular stress [Texte imprimé et/ou numérique] / D. ZHAO, Auteur ; R. MOKHTARI, Auteur ; E. PEDROSA, Auteur ; R. BIRNBAUM, Auteur ; D. ZHENG, Auteur ; H. M. LACHMAN, Auteur . - 17p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 17p. Mots-clés : Animals  Disease Models, Animal  Female  Gene Expression Profiling/*methods  Gene Expression Regulation  Heat-Shock Proteins/genetics  Humans  Macrophage Activation  Macrophages/*cytology  Methyl-CpG-Binding Protein 2/*deficiency  Mice  Microglia/*metabolism  Mutation  Oxidative Stress  Rett Syndrome/*genetics  Sequence Analysis, RNA/*methods  *Autism  *Heat shock  *Innate immune system  *M1 activation  *M2 activation  *Microglia  *Rett syndrome  *Schizophrenia Index. décimale : PER Périodiques Résumé : BACKGROUND: Rett syndrome (RTT) is a severe, neurodevelopmental disorder primarily affecting girls, characterized by progressive loss of cognitive, social, and motor skills after a relatively brief period of typical development. It is usually due to de novo loss of function mutations in the X-linked gene, MeCP2, which codes for the gene expression and chromatin regulator, methyl-CpG binding protein 2. Although the behavioral phenotype appears to be primarily due to neuronal Mecp2 deficiency in mice, other cell types, including astrocytes and oligodendrocytes, also appear to contribute to some aspects of the RTT phenotype. In addition, microglia may also play a role. However, the effect of Mecp2 deficiency in microglia on RTT pathogenesis is controversial. METHODS: In the current study, we applied whole transcriptome analysis using RNA-seq to gain insight into molecular pathways in microglia that might be dysregulated during the transition, in female mice heterozygous for an Mecp2-null allele (Mecp2(+/-); Het), from the pre-phenotypic (5 weeks) to the phenotypic phases (24 weeks). RESULTS: We found a significant overlap in differentially expressed genes (DEGs) with genes involved in regulating the extracellular matrix, and those that are activated or inhibited when macrophages and microglia are stimulated towards the M1 and M2 activation states. However, the M1- and M2-associated genes were different in the 5- and 24-week samples. In addition, a substantial decrease in the expression of nine members of the heat shock protein (HSP) family was found in the 5-week samples, but not at 24 weeks. CONCLUSIONS: These findings suggest that microglia from pre-phenotypic and phenotypic female mice are activated in a manner different from controls and that pre-phenotypic female mice may have alterations in their capacity to response to heat stress and other stressors that function through the HSP pathway. En ligne : http://dx.doi.org/10.1186/s13229-017-0134-z Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331

Prenatal levonorgestrel exposure induces autism-like behavior in offspring through ERbeta suppression in the amygdala in Molecular Autism, 8 (2017)  

Public ISBD [article]  inMolecular Autism > 8 (2017) . - 46p. Titre : Prenatal levonorgestrel exposure induces autism-like behavior in offspring through ERbeta suppression in the amygdala Type de document : Texte imprimé et/ou numérique Article en page(s) : 46p. Langues : Anglais (eng) Mots-clés : Amygdala  Autism-like behavior  Estrogen receptor beta  Oral contraceptives  Oxidative stress Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is characterized by impairments in social communication and restricted or repetitive behaviors or interests. ASD is now diagnosed in more than one out of 100 children and is biased towards males by a ratio of at least 4:1. Many possible explanations and potential causative factors have been reported, such as genetics, sex, and environmental factors, although the detailed mechanisms of ASD remain unclear. METHODS: The dams were exposed through oral contraceptives to either vehicle control (VEH) alone, levonorgestrel (LNG) alone, ethinyl estradiol (EE) alone, or a combination of LNG/EE for 21 days during their pregnancy. The subsequent 10-week-old offspring were used for autism-like behavior testing, and the limbic tissues were isolated for analysis. In another experimental group, 8-week-old male offspring were treated by infusion of ERbeta overexpression/knockdown lentivirus in the amygdala, and the offspring were analyzed after 2 weeks. RESULTS: We show that prenatal exposure of either LNG alone or a LNG/EE combination, but not EE alone, results in suppression of ERbeta (estrogen receptor beta) and its target genes in the amygdala with autism-like behavior in male offspring, while there is a much smaller effect on female offspring. However, we find that there is no effect on the hippocampus and hypothalamus. Further investigation shows that ERbeta suppression is due to LNG-mediated altered methylation on the ERbeta promoter and results in tissue damage with oxidative stress and the dysfunction of mitochondria and fatty acid metabolism, which subsequently triggers autism-like behavior. Overexpression of ERbeta in the amygdala completely restores LNG-induced ERbeta suppression and autism-like behaviors in offspring, while ERbeta knockdown mimics this effect, indicating that ERbeta expression in the amygdala plays an important role in autism-like behavior development. CONCLUSIONS: We conclude that prenatal levonorgestrel exposure induces autism-like behavior in offspring through ERbeta suppression in the amygdala. To our knowledge, this is the first time the potential effect of oral contraceptives on the contribution of autism-like behavior in offspring has been discovered. En ligne : http://dx.doi.org/10.1186/s13229-017-0159-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331 [article] Prenatal levonorgestrel exposure induces autism-like behavior in offspring through ERbeta suppression in the amygdala [Texte imprimé et/ou numérique] . - 46p. Langues : Anglais (eng) in Molecular Autism > 8 (2017) . - 46p. Mots-clés : Amygdala  Autism-like behavior  Estrogen receptor beta  Oral contraceptives  Oxidative stress Index. décimale : PER Périodiques Résumé : BACKGROUND: Autism spectrum disorder (ASD) is characterized by impairments in social communication and restricted or repetitive behaviors or interests. ASD is now diagnosed in more than one out of 100 children and is biased towards males by a ratio of at least 4:1. Many possible explanations and potential causative factors have been reported, such as genetics, sex, and environmental factors, although the detailed mechanisms of ASD remain unclear. METHODS: The dams were exposed through oral contraceptives to either vehicle control (VEH) alone, levonorgestrel (LNG) alone, ethinyl estradiol (EE) alone, or a combination of LNG/EE for 21 days during their pregnancy. The subsequent 10-week-old offspring were used for autism-like behavior testing, and the limbic tissues were isolated for analysis. In another experimental group, 8-week-old male offspring were treated by infusion of ERbeta overexpression/knockdown lentivirus in the amygdala, and the offspring were analyzed after 2 weeks. RESULTS: We show that prenatal exposure of either LNG alone or a LNG/EE combination, but not EE alone, results in suppression of ERbeta (estrogen receptor beta) and its target genes in the amygdala with autism-like behavior in male offspring, while there is a much smaller effect on female offspring. However, we find that there is no effect on the hippocampus and hypothalamus. Further investigation shows that ERbeta suppression is due to LNG-mediated altered methylation on the ERbeta promoter and results in tissue damage with oxidative stress and the dysfunction of mitochondria and fatty acid metabolism, which subsequently triggers autism-like behavior. Overexpression of ERbeta in the amygdala completely restores LNG-induced ERbeta suppression and autism-like behaviors in offspring, while ERbeta knockdown mimics this effect, indicating that ERbeta expression in the amygdala plays an important role in autism-like behavior development. CONCLUSIONS: We conclude that prenatal levonorgestrel exposure induces autism-like behavior in offspring through ERbeta suppression in the amygdala. To our knowledge, this is the first time the potential effect of oral contraceptives on the contribution of autism-like behavior in offspring has been discovered. En ligne : http://dx.doi.org/10.1186/s13229-017-0159-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=331