Correction to: Mechanisms underlying the EEG biomarker in Dup15q syndrome / J. FROHLICH in Molecular Autism, 10 (2019)  

Public ISBD [article]  inMolecular Autism > 10 (2019) . - 37 p. Titre : Correction to: Mechanisms underlying the EEG biomarker in Dup15q syndrome Type de document : Texte imprimé et/ou numérique Auteurs : J. FROHLICH, Auteur ; L. T. REITER, Auteur ; V. SARAVANAPANDIAN, Auteur ; C. DISTEFANO, Auteur ; S. HUBERTY, Auteur ; C. HYDE, Auteur ; S. CHAMBERLAIN, Auteur ; Carrie E. BEARDEN, Auteur ; P. GOLSHANI, Auteur ; A. IRIMIA, Auteur ; R. W. OLSEN, Auteur ; J. F. HIPP, Auteur ; S. S. JESTE, Auteur Article en page(s) : 37 p. Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : [This corrects the article DOI: 10.1186/s13229-019-0280-6.]. En ligne : http://dx.doi.org/10.1186/s13229-019-0288-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=414 [article] Correction to: Mechanisms underlying the EEG biomarker in Dup15q syndrome [Texte imprimé et/ou numérique] / J. FROHLICH, Auteur ; L. T. REITER, Auteur ; V. SARAVANAPANDIAN, Auteur ; C. DISTEFANO, Auteur ; S. HUBERTY, Auteur ; C. HYDE, Auteur ; S. CHAMBERLAIN, Auteur ; Carrie E. BEARDEN, Auteur ; P. GOLSHANI, Auteur ; A. IRIMIA, Auteur ; R. W. OLSEN, Auteur ; J. F. HIPP, Auteur ; S. S. JESTE, Auteur . - 37 p. Langues : Anglais (eng) in Molecular Autism > 10 (2019) . - 37 p. Index. décimale : PER Périodiques Résumé : [This corrects the article DOI: 10.1186/s13229-019-0280-6.]. En ligne : http://dx.doi.org/10.1186/s13229-019-0288-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=414

Identification of a distinct developmental and behavioral profile in children with Dup15q syndrome / C. DISTEFANO in Journal of Neurodevelopmental Disorders, 8-1 (December 2016)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 8-1 (December 2016) . - p.19 Titre : Identification of a distinct developmental and behavioral profile in children with Dup15q syndrome Type de document : Texte imprimé et/ou numérique Auteurs : C. DISTEFANO, Auteur ; A. GULSRUD, Auteur ; S. HUBERTY, Auteur ; Connie KASARI, Auteur ; E. COOK, Auteur ; L. T. REITER, Auteur ; R. THIBERT, Auteur ; S. S. JESTE, Auteur Article en page(s) : p.19 Langues : Anglais (eng) Mots-clés : Adaptive functioning  Autism spectrum disorder  Duplication 15q syndrome  Intellectual disability  Social communication Index. décimale : PER Périodiques Résumé : BACKGROUND: One of the most common genetic variants associated with autism spectrum disorder (ASD) are duplications of chromosome 15q11.2-q13.1 (Dup15q syndrome). To identify distinctive developmental and behavioral features in Dup15q syndrome, we examined the social communication, adaptive, and cognitive skills in clinic-referred subjects and compared the characteristics of children with Dup15q syndrome to age/IQ-matched children with non-syndromic ASD. Behavior and development were also analyzed within the Dup15q group for differences related to copy number or epilepsy. METHODS: Participants included 13 children with Dup15q syndrome and 13 children with non-syndromic ASD, matched on chronological and mental age, ages 22 months-12 years. In the Dup15q group, ten participants had isodicentric and three had interstitial duplications. Four children had active epilepsy (all isodicentric). Participants were assessed for verbal and non-verbal cognition, ASD characteristics based on the Autism Diagnostic Observation Schedule (ADOS), and adaptive function based on the Vineland Adaptive Behavior Scales (VABS). Group comparisons were performed between Dup15q and ASD participants, as well as within the Dup15q group based on duplication type and epilepsy status. RESULTS: All children with Dup15q syndrome met the criteria for ASD; ASD severity scores were significantly lower than children in the non-syndromic ASD group. ADOS profiles demonstrated a relative strength in items related to social interest. Children with Dup15q syndrome also demonstrated significantly more impairment in motor and daily living skills. Within the Dup15q group, children with epilepsy demonstrated significantly lower cognitive and adaptive function than those without epilepsy. CONCLUSIONS: The relative strength observed in social interest and responsiveness in the context of impaired motor skills represents an important avenue for intervention, including aggressive treatment of epilepsy, early and consistent focus on motor skills, and intervention targeting joint attention and language within a play context, in order to build on social interest to further develop social communication abilities. Longitudinal research beginning in early development will elucidate the temporal relationships between developmental domains and neurological comorbidities in these children at high risk for neurodevelopmental disorders. En ligne : http://dx.doi.org/10.1186/s11689-016-9152-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=348 [article] Identification of a distinct developmental and behavioral profile in children with Dup15q syndrome [Texte imprimé et/ou numérique] / C. DISTEFANO, Auteur ; A. GULSRUD, Auteur ; S. HUBERTY, Auteur ; Connie KASARI, Auteur ; E. COOK, Auteur ; L. T. REITER, Auteur ; R. THIBERT, Auteur ; S. S. JESTE, Auteur . - p.19. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 8-1 (December 2016) . - p.19 Mots-clés : Adaptive functioning  Autism spectrum disorder  Duplication 15q syndrome  Intellectual disability  Social communication Index. décimale : PER Périodiques Résumé : BACKGROUND: One of the most common genetic variants associated with autism spectrum disorder (ASD) are duplications of chromosome 15q11.2-q13.1 (Dup15q syndrome). To identify distinctive developmental and behavioral features in Dup15q syndrome, we examined the social communication, adaptive, and cognitive skills in clinic-referred subjects and compared the characteristics of children with Dup15q syndrome to age/IQ-matched children with non-syndromic ASD. Behavior and development were also analyzed within the Dup15q group for differences related to copy number or epilepsy. METHODS: Participants included 13 children with Dup15q syndrome and 13 children with non-syndromic ASD, matched on chronological and mental age, ages 22 months-12 years. In the Dup15q group, ten participants had isodicentric and three had interstitial duplications. Four children had active epilepsy (all isodicentric). Participants were assessed for verbal and non-verbal cognition, ASD characteristics based on the Autism Diagnostic Observation Schedule (ADOS), and adaptive function based on the Vineland Adaptive Behavior Scales (VABS). Group comparisons were performed between Dup15q and ASD participants, as well as within the Dup15q group based on duplication type and epilepsy status. RESULTS: All children with Dup15q syndrome met the criteria for ASD; ASD severity scores were significantly lower than children in the non-syndromic ASD group. ADOS profiles demonstrated a relative strength in items related to social interest. Children with Dup15q syndrome also demonstrated significantly more impairment in motor and daily living skills. Within the Dup15q group, children with epilepsy demonstrated significantly lower cognitive and adaptive function than those without epilepsy. CONCLUSIONS: The relative strength observed in social interest and responsiveness in the context of impaired motor skills represents an important avenue for intervention, including aggressive treatment of epilepsy, early and consistent focus on motor skills, and intervention targeting joint attention and language within a play context, in order to build on social interest to further develop social communication abilities. Longitudinal research beginning in early development will elucidate the temporal relationships between developmental domains and neurological comorbidities in these children at high risk for neurodevelopmental disorders. En ligne : http://dx.doi.org/10.1186/s11689-016-9152-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=348

Mechanisms underlying the EEG biomarker in Dup15q syndrome / J. FROHLICH in Molecular Autism, 10 (2019)  

Public ISBD [article]  inMolecular Autism > 10 (2019) . - 29 p. Titre : Mechanisms underlying the EEG biomarker in Dup15q syndrome Type de document : Texte imprimé et/ou numérique Auteurs : J. FROHLICH, Auteur ; L. T. REITER, Auteur ; V. SARAVANAPANDIAN, Auteur ; C. DISTEFANO, Auteur ; S. HUBERTY, Auteur ; C. HYDE, Auteur ; S. CHAMBERLAIN, Auteur ; Carrie E. BEARDEN, Auteur ; P. GOLSHANI, Auteur ; A. IRIMIA, Auteur ; R. W. OLSEN, Auteur ; J. F. HIPP, Auteur ; S. S. JESTE, Auteur Article en page(s) : 29 p. Langues : Anglais (eng) Mots-clés : Autism  Biomarkers  Dup15q syndrome  Eeg  Gaba  Gabra5  Gabrb3  Gabrg3  Neurodevelopmental disorders  UBE3A Index. décimale : PER Périodiques Résumé : Background: Duplications of 15q11.2-q13.1 (Dup15q syndrome), including the paternally imprinted gene UBE3A and three nonimprinted gamma-aminobutyric acid type-A (GABAA) receptor genes, are highly penetrant for neurodevelopmental disorders such as autism spectrum disorder (ASD). To guide targeted treatments of Dup15q syndrome and other forms of ASD, biomarkers are needed that reflect molecular mechanisms of pathology. We recently described a beta EEG phenotype of Dup15q syndrome, but it remains unknown which specific genes drive this phenotype. Methods: To test the hypothesis that UBE3A overexpression is not necessary for the beta EEG phenotype, we compared EEG from a reference cohort of children with Dup15q syndrome (n = 27) to (1) the pharmacological effects of the GABAA modulator midazolam (n = 12) on EEG from healthy adults, (2) EEG from typically developing (TD) children (n = 14), and (3) EEG from two children with duplications of paternal 15q (i.e., the UBE3A-silenced allele). Results: Peak beta power was significantly increased in the reference cohort relative to TD controls. Midazolam administration recapitulated the beta EEG phenotype in healthy adults with a similar peak frequency in central channels (f = 23.0 Hz) as Dup15q syndrome (f = 23.1 Hz). Both paternal Dup15q syndrome cases displayed beta power comparable to the reference cohort. Conclusions: Our results suggest a critical role for GABAergic transmission in the Dup15q syndrome beta EEG phenotype, which cannot be explained by UBE3A dysfunction alone. If this mechanism is confirmed, the phenotype may be used as a marker of GABAergic pathology in clinical trials for Dup15q syndrome. En ligne : https://dx.doi.org/10.1186/s13229-019-0280-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=408 [article] Mechanisms underlying the EEG biomarker in Dup15q syndrome [Texte imprimé et/ou numérique] / J. FROHLICH, Auteur ; L. T. REITER, Auteur ; V. SARAVANAPANDIAN, Auteur ; C. DISTEFANO, Auteur ; S. HUBERTY, Auteur ; C. HYDE, Auteur ; S. CHAMBERLAIN, Auteur ; Carrie E. BEARDEN, Auteur ; P. GOLSHANI, Auteur ; A. IRIMIA, Auteur ; R. W. OLSEN, Auteur ; J. F. HIPP, Auteur ; S. S. JESTE, Auteur . - 29 p. Langues : Anglais (eng) in Molecular Autism > 10 (2019) . - 29 p. Mots-clés : Autism  Biomarkers  Dup15q syndrome  Eeg  Gaba  Gabra5  Gabrb3  Gabrg3  Neurodevelopmental disorders  UBE3A Index. décimale : PER Périodiques Résumé : Background: Duplications of 15q11.2-q13.1 (Dup15q syndrome), including the paternally imprinted gene UBE3A and three nonimprinted gamma-aminobutyric acid type-A (GABAA) receptor genes, are highly penetrant for neurodevelopmental disorders such as autism spectrum disorder (ASD). To guide targeted treatments of Dup15q syndrome and other forms of ASD, biomarkers are needed that reflect molecular mechanisms of pathology. We recently described a beta EEG phenotype of Dup15q syndrome, but it remains unknown which specific genes drive this phenotype. Methods: To test the hypothesis that UBE3A overexpression is not necessary for the beta EEG phenotype, we compared EEG from a reference cohort of children with Dup15q syndrome (n = 27) to (1) the pharmacological effects of the GABAA modulator midazolam (n = 12) on EEG from healthy adults, (2) EEG from typically developing (TD) children (n = 14), and (3) EEG from two children with duplications of paternal 15q (i.e., the UBE3A-silenced allele). Results: Peak beta power was significantly increased in the reference cohort relative to TD controls. Midazolam administration recapitulated the beta EEG phenotype in healthy adults with a similar peak frequency in central channels (f = 23.0 Hz) as Dup15q syndrome (f = 23.1 Hz). Both paternal Dup15q syndrome cases displayed beta power comparable to the reference cohort. Conclusions: Our results suggest a critical role for GABAergic transmission in the Dup15q syndrome beta EEG phenotype, which cannot be explained by UBE3A dysfunction alone. If this mechanism is confirmed, the phenotype may be used as a marker of GABAergic pathology in clinical trials for Dup15q syndrome. En ligne : https://dx.doi.org/10.1186/s13229-019-0280-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=408

Significant transcriptional changes in 15q duplication but not Angelman syndrome deletion stem cell-derived neurons / N. URRACA in Molecular Autism, 9 (2018)  

Public ISBD [article]  inMolecular Autism > 9 (2018) . - 6p. Titre : Significant transcriptional changes in 15q duplication but not Angelman syndrome deletion stem cell-derived neurons Type de document : Texte imprimé et/ou numérique Auteurs : N. URRACA, Auteur ; K. HOPE, Auteur ; A. K. VICTOR, Auteur ; T. G. BELGARD, Auteur ; R. MEMON, Auteur ; S. GOORHA, Auteur ; C. VALDEZ, Auteur ; Q. T. TRAN, Auteur ; S. SANCHEZ, Auteur ; J. RAMIREZ, Auteur ; M. DONALDSON, Auteur ; D. BRIDGES, Auteur ; L. T. REITER, Auteur Article en page(s) : 6p. Langues : Anglais (eng) Mots-clés : Autism  Genomic disorders  Neurogenetic syndrome  Stem cells  mRNAseq Index. décimale : PER Périodiques Résumé : Background: The inability to analyze gene expression in living neurons from Angelman (AS) and Duplication 15q (Dup15q) syndrome subjects has limited our understanding of these disorders at the molecular level. Method: Here, we use dental pulp stem cells (DPSC) from AS deletion, 15q Duplication, and neurotypical control subjects for whole transcriptome analysis. We identified 20 genes unique to AS neurons, 120 genes unique to 15q duplication, and 3 shared transcripts that were differentially expressed in DPSC neurons vs controls. Results: Copy number correlated with gene expression for most genes across the 15q11.2-q13.1 critical region. Two thirds of the genes differentially expressed in 15q duplication neurons were downregulated compared to controls including several transcription factors, while in AS differential expression was restricted primarily to the 15q region. Here, we show significant downregulation of the transcription factors FOXO1 and HAND2 in neurons from 15q duplication, but not AS deletion subjects suggesting that disruptions in transcriptional regulation may be a driving factor in the autism phenotype in Dup15q syndrome. Downstream analysis revealed downregulation of the ASD associated genes EHPB2 and RORA, both genes with FOXO1 binding sites. Genes upregulated in either Dup15q cortex or idiopathic ASD cortex both overlapped significantly with the most upregulated genes in Dup15q DPSC-derived neurons. Conclusions: Finding a significant increase in both HERC2 and UBE3A in Dup15q neurons and significant decrease in these two genes in AS deletion neurons may explain differences between AS deletion class and UBE3A specific classes of AS mutation where HERC2 is expressed at normal levels. Also, we identified an enrichment for FOXO1-regulated transcripts in Dup15q neurons including ASD-associated genes EHPB2 and RORA indicating a possible connection between this syndromic form of ASD and idiopathic cases. En ligne : http://dx.doi.org/10.1186/s13229-018-0191-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354 [article] Significant transcriptional changes in 15q duplication but not Angelman syndrome deletion stem cell-derived neurons [Texte imprimé et/ou numérique] / N. URRACA, Auteur ; K. HOPE, Auteur ; A. K. VICTOR, Auteur ; T. G. BELGARD, Auteur ; R. MEMON, Auteur ; S. GOORHA, Auteur ; C. VALDEZ, Auteur ; Q. T. TRAN, Auteur ; S. SANCHEZ, Auteur ; J. RAMIREZ, Auteur ; M. DONALDSON, Auteur ; D. BRIDGES, Auteur ; L. T. REITER, Auteur . - 6p. Langues : Anglais (eng) in Molecular Autism > 9 (2018) . - 6p. Mots-clés : Autism  Genomic disorders  Neurogenetic syndrome  Stem cells  mRNAseq Index. décimale : PER Périodiques Résumé : Background: The inability to analyze gene expression in living neurons from Angelman (AS) and Duplication 15q (Dup15q) syndrome subjects has limited our understanding of these disorders at the molecular level. Method: Here, we use dental pulp stem cells (DPSC) from AS deletion, 15q Duplication, and neurotypical control subjects for whole transcriptome analysis. We identified 20 genes unique to AS neurons, 120 genes unique to 15q duplication, and 3 shared transcripts that were differentially expressed in DPSC neurons vs controls. Results: Copy number correlated with gene expression for most genes across the 15q11.2-q13.1 critical region. Two thirds of the genes differentially expressed in 15q duplication neurons were downregulated compared to controls including several transcription factors, while in AS differential expression was restricted primarily to the 15q region. Here, we show significant downregulation of the transcription factors FOXO1 and HAND2 in neurons from 15q duplication, but not AS deletion subjects suggesting that disruptions in transcriptional regulation may be a driving factor in the autism phenotype in Dup15q syndrome. Downstream analysis revealed downregulation of the ASD associated genes EHPB2 and RORA, both genes with FOXO1 binding sites. Genes upregulated in either Dup15q cortex or idiopathic ASD cortex both overlapped significantly with the most upregulated genes in Dup15q DPSC-derived neurons. Conclusions: Finding a significant increase in both HERC2 and UBE3A in Dup15q neurons and significant decrease in these two genes in AS deletion neurons may explain differences between AS deletion class and UBE3A specific classes of AS mutation where HERC2 is expressed at normal levels. Also, we identified an enrichment for FOXO1-regulated transcripts in Dup15q neurons including ASD-associated genes EHPB2 and RORA indicating a possible connection between this syndromic form of ASD and idiopathic cases. En ligne : http://dx.doi.org/10.1186/s13229-018-0191-y Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=354

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