Behavioral signatures related to genetic disorders in autism / Hilgo BRUINING in Molecular Autism, (February 2014)  

Public ISBD [article]  inMolecular Autism > (February 2014) Titre : Behavioral signatures related to genetic disorders in autism Type de document : Texte imprimé et/ou numérique Auteurs : Hilgo BRUINING, Auteur ; Marinus EIJKEMANS, Auteur ; Martien KAS, Auteur ; Sarah CURRAN, Auteur ; Jacob VORSTMAN, Auteur ; Patrick BOLTON, Auteur Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) is well recognized to be genetically heterogeneous. It is assumed that the genetic risk factors give rise to a broad spectrum of indistinguishable behavioral presentations. We tested this assumption by analyzing the Autism Diagnostic Interview-Revised (ADI-R) symptom profiles in samples comprising six genetic disorders that carry an increased risk for ASD (22q11.2 deletion, Down's syndrome, Prader-Willi, supernumerary marker chromosome 15, tuberous sclerosis complex and Klinefelter syndrome; total n=322 cases, groups ranging in sample sizes from 21 to 90 cases). We mined the data to test the existence and specificity of ADI-R profiles using a multiclass extension of support vector machine (SVM) learning. We subsequently applied the SVM genetic disorder algorithm on idiopathic ASD profiles from the Autism Genetics Resource Exchange (AGRE). Genetic disorders were associated with behavioral specificity, indicated by the accuracy and certainty of SVM predictions; one-by-one genetic disorder stratifications were highly accurate leading to 63% accuracy of correct genotype prediction when all six genetic disorder groups were analyzed simultaneously. Application of the SVM algorithm to AGRE cases indicated that the algorithm could detect similarity of genetic behavioral signatures in idiopathic ASD subjects. Also, affected sib pairs in the AGRE were behaviorally more similar when they had been allocated to the same genetic disorder group. Our findings provide evidence for genotype-phenotype correlations in relation to autistic symptomatology. SVM algorithms may be used to stratify idiopathic cases of ASD according to behavioral signature patterns associated with genetic disorders. Together, the results suggest a new approach for disentangling the heterogeneity of ASD. En ligne : http://dx.doi.org/10.1186/2040-2392-5-11 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227 [article] Behavioral signatures related to genetic disorders in autism [Texte imprimé et/ou numérique] / Hilgo BRUINING, Auteur ; Marinus EIJKEMANS, Auteur ; Martien KAS, Auteur ; Sarah CURRAN, Auteur ; Jacob VORSTMAN, Auteur ; Patrick BOLTON, Auteur. Langues : Anglais (eng) in Molecular Autism > (February 2014) Index. décimale : PER Périodiques Résumé : Autism spectrum disorder (ASD) is well recognized to be genetically heterogeneous. It is assumed that the genetic risk factors give rise to a broad spectrum of indistinguishable behavioral presentations. We tested this assumption by analyzing the Autism Diagnostic Interview-Revised (ADI-R) symptom profiles in samples comprising six genetic disorders that carry an increased risk for ASD (22q11.2 deletion, Down's syndrome, Prader-Willi, supernumerary marker chromosome 15, tuberous sclerosis complex and Klinefelter syndrome; total n=322 cases, groups ranging in sample sizes from 21 to 90 cases). We mined the data to test the existence and specificity of ADI-R profiles using a multiclass extension of support vector machine (SVM) learning. We subsequently applied the SVM genetic disorder algorithm on idiopathic ASD profiles from the Autism Genetics Resource Exchange (AGRE). Genetic disorders were associated with behavioral specificity, indicated by the accuracy and certainty of SVM predictions; one-by-one genetic disorder stratifications were highly accurate leading to 63% accuracy of correct genotype prediction when all six genetic disorder groups were analyzed simultaneously. Application of the SVM algorithm to AGRE cases indicated that the algorithm could detect similarity of genetic behavioral signatures in idiopathic ASD subjects. Also, affected sib pairs in the AGRE were behaviorally more similar when they had been allocated to the same genetic disorder group. Our findings provide evidence for genotype-phenotype correlations in relation to autistic symptomatology. SVM algorithms may be used to stratify idiopathic cases of ASD according to behavioral signature patterns associated with genetic disorders. Together, the results suggest a new approach for disentangling the heterogeneity of ASD. En ligne : http://dx.doi.org/10.1186/2040-2392-5-11 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=227

Effects of Bumetanide on Neurocognitive Functioning in Children with Autism Spectrum Disorder: Secondary Analysis of a Randomized Placebo-Controlled Trial / Dorinde M. VAN ANDEL in Journal of Autism and Developmental Disorders, 54-3 (March 2024)  

Public ISBD [article]  inJournal of Autism and Developmental Disorders > 54-3 (March 2024) . - p.894-904 Titre : Effects of Bumetanide on Neurocognitive Functioning in Children with Autism Spectrum Disorder: Secondary Analysis of a Randomized Placebo-Controlled Trial Type de document : Texte imprimé et/ou numérique Auteurs : Dorinde M. VAN ANDEL, Auteur ; Jan J. SPRENGERS, Auteur ; Marsh KÖNIGS, Auteur ; Maretha V. DE JONGE, Auteur ; Hilgo BRUINING, Auteur Article en page(s) : p.894-904 Langues : Anglais (eng) Index. décimale : PER Périodiques Résumé : We present the secondary-analysis of neurocognitive tests in the 'Bumetanide in Autism Medication and Biomarker' (BAMBI;EUDRA-CT-2014-001560-35) study, a randomized double-blind placebo-controlled (1:1) trial testing 3-months bumetanide treatment (??1 mg twice-daily) in unmedicated children 7-15 years with ASD. Children with IQ???70 were analyzed for baseline deficits and treatment-effects on the intention-to-treat-population with generalized-linear-models, principal component analysis and network analysis. Ninety-two children were allocated to treatment and 83 eligible for analyses. Heterogeneous neurocognitive impairments were found that were unaffected by bumetanide treatment. Network analysis showed higher modularity after treatment (mean difference:-0.165, 95%CI:-0.317 to ??0.013,p = .034) and changes in the relative importance of response inhibition in the neurocognitive network (mean difference:-0.037, 95%CI:-0.073 to ??0.001,p = .042). This study offers perspectives to include neurocognitive tests in ASD trials. En ligne : https://doi.org/10.1007/s10803-022-05841-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=524 [article] Effects of Bumetanide on Neurocognitive Functioning in Children with Autism Spectrum Disorder: Secondary Analysis of a Randomized Placebo-Controlled Trial [Texte imprimé et/ou numérique] / Dorinde M. VAN ANDEL, Auteur ; Jan J. SPRENGERS, Auteur ; Marsh KÖNIGS, Auteur ; Maretha V. DE JONGE, Auteur ; Hilgo BRUINING, Auteur . - p.894-904. Langues : Anglais (eng) in Journal of Autism and Developmental Disorders > 54-3 (March 2024) . - p.894-904 Index. décimale : PER Périodiques Résumé : We present the secondary-analysis of neurocognitive tests in the 'Bumetanide in Autism Medication and Biomarker' (BAMBI;EUDRA-CT-2014-001560-35) study, a randomized double-blind placebo-controlled (1:1) trial testing 3-months bumetanide treatment (??1 mg twice-daily) in unmedicated children 7-15 years with ASD. Children with IQ???70 were analyzed for baseline deficits and treatment-effects on the intention-to-treat-population with generalized-linear-models, principal component analysis and network analysis. Ninety-two children were allocated to treatment and 83 eligible for analyses. Heterogeneous neurocognitive impairments were found that were unaffected by bumetanide treatment. Network analysis showed higher modularity after treatment (mean difference:-0.165, 95%CI:-0.317 to ??0.013,p = .034) and changes in the relative importance of response inhibition in the neurocognitive network (mean difference:-0.037, 95%CI:-0.073 to ??0.001,p = .042). This study offers perspectives to include neurocognitive tests in ASD trials. En ligne : https://doi.org/10.1007/s10803-022-05841-3 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=524

Effects of bumetanide on neurodevelopmental impairments in patients with tuberous sclerosis complex: an open-label pilot study / Dorinde M. VAN ANDEL in Molecular Autism, 11 (2020)  

Public ISBD [article]  inMolecular Autism > 11 (2020) . - 30 p. Titre : Effects of bumetanide on neurodevelopmental impairments in patients with tuberous sclerosis complex: an open-label pilot study Type de document : Texte imprimé et/ou numérique Auteurs : Dorinde M. VAN ANDEL, Auteur ; Jan J. SPRENGERS, Auteur ; Bob ORANJE, Auteur ; Floor E. SCHEEPERS, Auteur ; Floor E. JANSEN, Auteur ; Hilgo BRUINING, Auteur Article en page(s) : 30 p. Langues : Anglais (eng) Mots-clés : Bumetanide  Erp  Irritability  NKCC1 antagonist  Neurocognitive task  Open-label  Tand  Tuberous sclerosis complex Index. décimale : PER Périodiques Résumé : BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal dominant disease that affects multiple organs including the brain. TSC is strongly associated with broad neurodevelopmental disorders, including autism spectrum disorder symptomatology. Preclinical TSC studies have indicated altered neuronal chloride homeostasis affecting the polarity of ?-aminobutyric acid (GABA) ergic transmission as a potential treatment target. Bumetanide, a selective NKCC1 chloride importer antagonist, may attenuate depolarizing GABA action, and in that way reduce disease burden. In this open-label pilot study, we tested the effect of bumetanide on a variety of neurophysiological, cognitive, and behavioral measures in children with TSC. METHODS: Participants were treated with bumetanide (2dd 0.5-1.0?mg) for 13?weeks in an open-label trial. The Aberrant Behavior Checklist-Irritability (ABC-I) subscale was chosen as the primary endpoint. Secondary endpoints included other behavioral questionnaires in addition to event-related potentials (ERP) and neuropsychological tests if tolerated. Additionally, the treatment effect on seizure frequency and quality of life was assessed. Endpoint data were collected at baseline, after 91?days of treatment and after a 28-day wash-out period. RESULTS: Fifteen patients (8-21-years old) with TSC were included of which 13 patients completed the study. Treatment was well-tolerated with only expected adverse events due to the diuretic effects of bumetanide. Irritable behavior (ABC-I) showed significant improvement after treatment in 11 out of 13 patients (t(12) = 4.41, p = .001, d = .773). A favorable effect was also found for social behavior (Social Responsiveness Scale) (t(11) = 4.01, p = .002, d = .549) and hyperactive behavior (ABC-hyperactivity subscale) (t(12) = 3.65, p = .003, d = .686). Moreover, patients rated their own health-related quality of life higher after treatment. At baseline, TSC patients showed several atypical ERPs versus typically developing peers of which prepulse inhibition was significantly decreased in the TSC group. Neuropsychological measurements showed no change and bumetanide had no effect on seizure frequency. LIMITATIONS: The sample size and open-label design of this pilot study warrant caution when interpreting outcome measures. CONCLUSIONS: Bumetanide treatment is a potential treatment to alleviate the behavioral burden and quality of life associated with TSC. More elaborate trials are needed to determine the application and effect size of bumetanide for the TSC population. Trial registration EU Clinical Trial Register, EudraCT 2016-002408-13 (www.clinicaltrialsregister.eu/ctr-search/trial/2016-002408-13/NL). Registered 25 July 2016. En ligne : http://dx.doi.org/10.1186/s13229-020-00335-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427 [article] Effects of bumetanide on neurodevelopmental impairments in patients with tuberous sclerosis complex: an open-label pilot study [Texte imprimé et/ou numérique] / Dorinde M. VAN ANDEL, Auteur ; Jan J. SPRENGERS, Auteur ; Bob ORANJE, Auteur ; Floor E. SCHEEPERS, Auteur ; Floor E. JANSEN, Auteur ; Hilgo BRUINING, Auteur . - 30 p. Langues : Anglais (eng) in Molecular Autism > 11 (2020) . - 30 p. Mots-clés : Bumetanide  Erp  Irritability  NKCC1 antagonist  Neurocognitive task  Open-label  Tand  Tuberous sclerosis complex Index. décimale : PER Périodiques Résumé : BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal dominant disease that affects multiple organs including the brain. TSC is strongly associated with broad neurodevelopmental disorders, including autism spectrum disorder symptomatology. Preclinical TSC studies have indicated altered neuronal chloride homeostasis affecting the polarity of ?-aminobutyric acid (GABA) ergic transmission as a potential treatment target. Bumetanide, a selective NKCC1 chloride importer antagonist, may attenuate depolarizing GABA action, and in that way reduce disease burden. In this open-label pilot study, we tested the effect of bumetanide on a variety of neurophysiological, cognitive, and behavioral measures in children with TSC. METHODS: Participants were treated with bumetanide (2dd 0.5-1.0?mg) for 13?weeks in an open-label trial. The Aberrant Behavior Checklist-Irritability (ABC-I) subscale was chosen as the primary endpoint. Secondary endpoints included other behavioral questionnaires in addition to event-related potentials (ERP) and neuropsychological tests if tolerated. Additionally, the treatment effect on seizure frequency and quality of life was assessed. Endpoint data were collected at baseline, after 91?days of treatment and after a 28-day wash-out period. RESULTS: Fifteen patients (8-21-years old) with TSC were included of which 13 patients completed the study. Treatment was well-tolerated with only expected adverse events due to the diuretic effects of bumetanide. Irritable behavior (ABC-I) showed significant improvement after treatment in 11 out of 13 patients (t(12) = 4.41, p = .001, d = .773). A favorable effect was also found for social behavior (Social Responsiveness Scale) (t(11) = 4.01, p = .002, d = .549) and hyperactive behavior (ABC-hyperactivity subscale) (t(12) = 3.65, p = .003, d = .686). Moreover, patients rated their own health-related quality of life higher after treatment. At baseline, TSC patients showed several atypical ERPs versus typically developing peers of which prepulse inhibition was significantly decreased in the TSC group. Neuropsychological measurements showed no change and bumetanide had no effect on seizure frequency. LIMITATIONS: The sample size and open-label design of this pilot study warrant caution when interpreting outcome measures. CONCLUSIONS: Bumetanide treatment is a potential treatment to alleviate the behavioral burden and quality of life associated with TSC. More elaborate trials are needed to determine the application and effect size of bumetanide for the TSC population. Trial registration EU Clinical Trial Register, EudraCT 2016-002408-13 (www.clinicaltrialsregister.eu/ctr-search/trial/2016-002408-13/NL). Registered 25 July 2016. En ligne : http://dx.doi.org/10.1186/s13229-020-00335-4 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=427

Limited impact of Cntn4 mutation on autism-related traits in developing and adult C57BL/6J mice / R. T. MOLENHUIS in Journal of Neurodevelopmental Disorders, 8-1 (December 2016)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 8-1 (December 2016) . - p.6 Titre : Limited impact of Cntn4 mutation on autism-related traits in developing and adult C57BL/6J mice Type de document : Texte imprimé et/ou numérique Auteurs : R. T. MOLENHUIS, Auteur ; Hilgo BRUINING, Auteur ; E. REMMELINK, Auteur ; L. DE VISSER, Auteur ; M. LOOS, Auteur ; J. P. H. BURBACH, Auteur ; M. J. KAS, Auteur Article en page(s) : p.6 Langues : Anglais (eng) Mots-clés : 3p deletion syndrome  Autism spectrum disorder  Behavior  Cntn4  Developmental trajectories  Hyperreactivity  Mouse model  Negative findings  Reversal learning  Schizophrenia Index. décimale : PER Périodiques Résumé : BACKGROUND: Mouse models offer an essential tool to unravel the impact of genetic mutations on autism-related phenotypes. The behavioral impact of some important candidate gene models for autism spectrum disorder (ASD) has not yet been studied, and existing characterizations mostly describe behavioral phenotypes at adult ages, disregarding the developmental nature of the disorder. In this context, the behavioral influence of CNTN4, one of the strongest suggested ASD candidate genes, is unknown. Here, we used our recently established developmental test battery to characterize the consequences of disruption of contactin 4 (Cntn4) on neurological, sensory, cognitive, and behavioral phenotypes across different developmental stages. METHODS: C57BL/6J mice with heterozygous and homozygous disruption of Cntn4 were studied through an extensive, partially longitudinal, test battery at various developmental stages, including various paradigms testing social and restricted repetitive behaviors. RESULTS: Developmental neurological and cognitive screenings revealed no significant differences between genotypes, and ASD-related behavioral domains were also unchanged in Cntn4-deficient versus wild-type mice. The impact of Cntn4-deficiency was found to be limited to increased startle responsiveness following auditory stimuli of different high amplitudes in heterozygous and homozygous Cntn4-deficient mice and enhanced acquisition in a spatial learning task in homozygous mice. CONCLUSIONS: Disruption of Cntn4 in the C57BL/6J background does not affect specific autism-related phenotypes in developing or adult mice but causes subtle non-disorder specific changes in sensory behavioral responses and cognitive performance. En ligne : http://dx.doi.org/10.1186/s11689-016-9140-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=348 [article] Limited impact of Cntn4 mutation on autism-related traits in developing and adult C57BL/6J mice [Texte imprimé et/ou numérique] / R. T. MOLENHUIS, Auteur ; Hilgo BRUINING, Auteur ; E. REMMELINK, Auteur ; L. DE VISSER, Auteur ; M. LOOS, Auteur ; J. P. H. BURBACH, Auteur ; M. J. KAS, Auteur . - p.6. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 8-1 (December 2016) . - p.6 Mots-clés : 3p deletion syndrome  Autism spectrum disorder  Behavior  Cntn4  Developmental trajectories  Hyperreactivity  Mouse model  Negative findings  Reversal learning  Schizophrenia Index. décimale : PER Périodiques Résumé : BACKGROUND: Mouse models offer an essential tool to unravel the impact of genetic mutations on autism-related phenotypes. The behavioral impact of some important candidate gene models for autism spectrum disorder (ASD) has not yet been studied, and existing characterizations mostly describe behavioral phenotypes at adult ages, disregarding the developmental nature of the disorder. In this context, the behavioral influence of CNTN4, one of the strongest suggested ASD candidate genes, is unknown. Here, we used our recently established developmental test battery to characterize the consequences of disruption of contactin 4 (Cntn4) on neurological, sensory, cognitive, and behavioral phenotypes across different developmental stages. METHODS: C57BL/6J mice with heterozygous and homozygous disruption of Cntn4 were studied through an extensive, partially longitudinal, test battery at various developmental stages, including various paradigms testing social and restricted repetitive behaviors. RESULTS: Developmental neurological and cognitive screenings revealed no significant differences between genotypes, and ASD-related behavioral domains were also unchanged in Cntn4-deficient versus wild-type mice. The impact of Cntn4-deficiency was found to be limited to increased startle responsiveness following auditory stimuli of different high amplitudes in heterozygous and homozygous Cntn4-deficient mice and enhanced acquisition in a spatial learning task in homozygous mice. CONCLUSIONS: Disruption of Cntn4 in the C57BL/6J background does not affect specific autism-related phenotypes in developing or adult mice but causes subtle non-disorder specific changes in sensory behavioral responses and cognitive performance. En ligne : http://dx.doi.org/10.1186/s11689-016-9140-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=348

Mechanism-based interventions for ASD cannot be implemented using conventional trial designs / Jan J. SPRENGERS in Autism Research, 17-2 (February 2024)  

Public ISBD [article]  inAutism Research > 17-2 (February 2024) . - p.202-203 Titre : Mechanism-based interventions for ASD cannot be implemented using conventional trial designs Type de document : Texte imprimé et/ou numérique Auteurs : Jan J. SPRENGERS, Auteur ; Lisa GEERTJENS, Auteur ; Hilgo BRUINING, Auteur Article en page(s) : p.202-203 Langues : Anglais (eng) Index. décimale : PER Périodiques En ligne : https://doi.org/10.1002/aur.3086 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=522 [article] Mechanism-based interventions for ASD cannot be implemented using conventional trial designs [Texte imprimé et/ou numérique] / Jan J. SPRENGERS, Auteur ; Lisa GEERTJENS, Auteur ; Hilgo BRUINING, Auteur . - p.202-203. Langues : Anglais (eng) in Autism Research > 17-2 (February 2024) . - p.202-203 Index. décimale : PER Périodiques En ligne : https://doi.org/10.1002/aur.3086 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=522

Modeling the quantitative nature of neurodevelopmental disorders using Collaborative Cross mice / R. T. MOLENHUIS in Molecular Autism, 9 (2018)  

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Profiles of autism characteristics in thirteen genetic syndromes: a machine learning approach / Alice WELHAM ; Dawn ADAMS ; Stacey BISSELL ; Hilgo BRUINING ; Hayley CRAWFORD ; Kate EDEN ; Lisa NELSON ; Christopher OLIVER ; Laurie POWIS ; Caroline RICHARDS ; Jane WAITE ; Peter WATSON ; Hefin RHYS ; Lucy WILDE ; Kate WOODCOCK ; Joanna MOSS in Molecular Autism, 14 (2023)  

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Sensory modulation disorders in childhood epilepsy / J. S. VAN CAMPEN in Journal of Neurodevelopmental Disorders, 7-1 (December 2015)  

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The Social Behavioral Phenotype in Boys and Girls with an Extra X Chromosome (Klinefelter Syndrome and Trisomy X): A Comparison with Autism Spectrum Disorder / Sophie RIJN in Journal of Autism and Developmental Disorders, 44-2 (February 2014)  

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