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Joseph D. Buxbaum - One of the best experts on this subject based on the ideXlab platform.
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Intestinal dysmotility in a zebrafish ( Danio rerio ) shank3a;shank3b mutant model of autism
Molecular Autism, 2019Co-Authors: David M. James, Joseph D. Buxbaum, Yuji Kajiwara, Robert A. Kozol, Adam L. Wahl, Emily C. Storrs, Mason Klein, Baharak Moshiree, Julia E. DallmanAbstract:Background and aims Autism spectrum disorder (ASD) is currently estimated to affect more than 1% of the world population. For people with ASD, gastrointestinal (GI) distress is a commonly reported but a poorly understood co-occurring symptom. Here, we investigate the physiological basis for GI distress in ASD by studying gut function in a zebrafish model of Phelan-McDermid Syndrome (PMS), a condition caused by mutations in the SHANK3 gene.
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behavior phenotyping of a mouse model of phelan mcdermid Syndrome with a full deletion of shank3 gene
European Neuropsychopharmacology, 2019Co-Authors: Elodie Drapeau, Mohammed Riad, Yuji Kajiwara, Joseph D. BuxbaumAbstract:Background Phelan-McDermid Syndrome (PMS) is a rare genetic Syndrome in which one copy of the q13 portion of chromosome 22 is missing or mutated leading to a global developmental delay, hypotonia, delayed or absent speech, intellectual disability, and autistic behaviors. SHANK3, a gene coding for a key structural part of the post-synaptic density, is the critical gene for the core neurological and behavioral symptoms in this Syndrome, and the loss of one copy of SHANK3, occurring through intragenic deletion or point mutation, is sufficient to cause Phelan-McDermid Syndrome. However, the size of the region affected can be highly variable, from point mutation to up to 8 Mb deletions and the deletion size seems to be correlated with the Syndrome severity. Due to multiple intragenic promoters and alternatively spliced coding exons within the gene, several Shank3 isoforms have been identified in human and mouse brains. Methods Numerous mouse models have been generated but most target only some of those isoforms while the vast majority of SHANK3 mutations found in PMS patients are deletions of the entire gene. Our aim is based on a novel mouse model, in which all Shank3 isoforms are disrupted and which more closely mirrors the most common genetic mutations found in PMS and our goal was to investigate the behavioral consequences of a disruption of all isoforms of Shank3. Results Our laboratory had previously created a mouse model with a deletion of exons 4 to 9 leading to the disruption of the full length Shank3 protein. We used a Cre-LoxP strategy to add an additional LoxP site flanking exon 22 and disrupt all isoforms. We carried an extensive behavioral phenotyping of neonate, young and adult wild-type, heterozygote and homozygote mice with a battery of test designed to assess the main feature of PMS including neurodevelopmental milestones, sensory and motor functions, sociability, stereotypies and cognitive functioning. Discussion Mice with a full deletion of Shank3 are more severely affected than previously published mouse model with a partial deletion. Abnormal Mendelian ratios at the time of weaning were observed showing a significant deficit for homozygote mice that can be partially explained by an increase of early postnatal lethality. Both sensory and motor disabilities were detected in neonate and adult mice. While social performances and interest for social stimuli were not impaired, the homozygote mice displayed a strong object avoidance and escape behavior. Additionally, we observed a deficit in both initial training and reversal of Barnes maze, a spatial memory task involving hippocampal-prefrontal circuits. Electrophysiological recording showed that both long-term potentiation and long-term depression are impaired in Shank3 deficient mice. Our new mouse model of PMS recapitulates the core symptoms of PMS providing an improvement of both construction and face validity compared to previous model. Ongoing experiments will identify neural mechanisms and brain circuitry involved in PMS and will use this model to screen potential treatments for Shank3-haploinsufficiency.
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Intestinal dysmotility in a zebrafish (Danio rerio) shank3a;shank3b mutant model of autism
BMC, 2019Co-Authors: David M. James, Joseph D. Buxbaum, Yuji Kajiwara, Robert A. Kozol, Adam L. Wahl, Emily C. Storrs, Mason Klein, Baharak Moshiree, Julia E. DallmanAbstract:Abstract Background and aims Autism spectrum disorder (ASD) is currently estimated to affect more than 1% of the world population. For people with ASD, gastrointestinal (GI) distress is a commonly reported but a poorly understood co-occurring symptom. Here, we investigate the physiological basis for GI distress in ASD by studying gut function in a zebrafish model of Phelan-McDermid Syndrome (PMS), a condition caused by mutations in the SHANK3 gene. Methods To generate a zebrafish model of PMS, we used CRISPR/Cas9 to introduce clinically related C-terminal frameshift mutations in shank3a and shank3b zebrafish paralogues (shank3abΔC). Because PMS is caused by SHANK3 haploinsufficiency, we assessed the digestive tract (DT) structure and function in zebrafish shank3abΔC +/− heterozygotes. Human SHANK3 mRNA was then used to rescue DT phenotypes in larval zebrafish. Results Significantly slower rates of DT peristaltic contractions (p
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Behavioral Phenotyping of an Improved Mouse Model of Phelan-McDermid Syndrome with a Complete Deletion of the Shank3 Gene.
eneuro, 2018Co-Authors: Elodie Drapeau, Mohammed Riad, Yuji Kajiwara, Joseph D. BuxbaumAbstract:Phelan-McDermid Syndrome (PMS) is a rare genetic disorder in which one copy of the SHANK3 gene is missing or mutated, leading to a global developmental delay, intellectual disability (ID), and autism. Multiple intragenic promoters and alternatively spliced exons are responsible for the formation of numerous isoforms. Many genetically-modified mouse models of PMS have been generated but most disrupt only some of the isoforms. In contrast, the vast majority of known SHANK3 mutations found in patients involve deletions that disrupt all isoforms. Here, we report the production and thorough behavioral characterization of a new mouse model in which all Shank3 isoforms are disrupted. Domains and tasks examined in adults included measures of general health, neurological reflexes, motor abilities, sensory reactivity, social behavior, repetitive behaviors, cognition and behavioral inflexibility, and anxiety. Our mice are more severely affected than previously published models. While the deficits were typically more pronounced in homozygotes, an intermediate phenotype was observed for heterozygotes in many paradigms. As in other Shank3 mouse models, stereotypies, including increased grooming, were observed. Additionally, sensory alterations were detected in both neonatal and adult mice, and motor behavior was strongly altered, especially in the open field and rotarod locomotor tests. While social behaviors measured with the three-chambered social approach and male-female interaction tests were not strongly impacted, Shank3-deficient mice displayed a strong escape behavior and avoidance of inanimate objects in novel object recognition, repetitive novel object contact, marble burying, and nest building tasks, indicating increased novelty-induced anxiety. Similarly, increased freezing was observed during fear conditioning training and amygdala-dependent cued retrieval. Finally, deficits were observed in both initial training and reversal in the Barnes maze and in contextual fear testing, which are memory tasks involving hippocampal-prefrontal circuits. In contrast, working memory in the Y-maze spontaneous alternation test was not altered. This new mouse model of PMS, engineered to most closely represent human mutations, recapitulates core symptoms of PMS providing improvements for both construct and face validity, compared to previous models.
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behavioral phenotyping of an improved mouse model of phelan mcdermid Syndrome with a complete deletion of the shank3 gene
eNeuro, 2018Co-Authors: Elodie Drapeau, Mohammed Riad, Yuji Kajiwara, Joseph D. BuxbaumAbstract:Abstract Phelan-McDermid Syndrome (PMS) is a rare genetic disorder in which one copy of the SHANK3 gene is missing or mutated, leading to a global developmental delay, intellectual disability, and autism. Multiple intragenic promoters and alternatively spliced exons are responsible for the formation of numerous isoforms. Many genetically-modified mouse models of PMS have been generated but most disrupt only some of the isoforms. In contrast, the vast majority of known SHANK3 mutations found in patients involve deletions that disrupt all isoforms. Here, we report the production and thorough behavioral characterization of a new mouse model in which all Shank3 isoforms are disrupted. Domains and tasks examined in adults included measures of general health, neurological reflexes, motor abilities, sensory reactivity, social behavior, repetitive behaviors, cognition and behavioral inflexibility and anxiety. Our mice are more severely affected than previously published models. While the deficits were typically more pronounced in homozygotes, an intermediate phenotype was observed for heterozygotes in many paradigms. As in other Shank3 mouse models, stereotypies, including increased grooming, were observed. Additionally, sensory alterations were detected in both neonatal and adult mice and motor behavior was strongly altered, especially in the open field and rotarod locomotor tests. While social behaviors measured with the 3-chambered social approach and male-female interaction tests were not strongly impacted, Shank3-deficient mice displayed a strong escape behavior and avoidance of inanimate objects in novel object recognition, repetitive novel object contact, marble burying and nest building tasks, indicating increased novelty-induced anxiety. Similarly, increased freezing was observed during fear conditioning training and amygdala-dependent cued retrieval. Finally, deficits were observed in both initial training and reversal in the Barnes maze and in contextual fear memory that are memory tasks involving hippocampal-prefrontal circuits. In contrast, working memory in the Y-maze spontaneous alternation test was not altered. This new mouse model of PMS, engineered to most closely represent human mutations, recapitulates core symptoms of PMS providing improvements for both construct and face validity, compared to previous models. Significant Statement Phelan-McDermid Syndrome, caused by happloinsufficiency of Shank3 , is a severe and complex neurodevelopmental disorder. This study investigates the behavioral consequences of a disruption of all Shank3 isoforms in neonatal and adult mice using a detailed battery o f tests tailored to investigate core symptoms and usual comorbidities of PMS. We found that our new model is more severely affected than previously published mouse models with only partial deletions of Shank3 and more closely recapitulates symptoms of PMS thus providing improvements for both construct and face validity. Our results highlight the significance of using a mouse model with a complete deletion of Shank3 for studying mechanisms underlying autism spectrum disorder and PMS, carrying preclinical studies and testing test novel therapeutic approaches.
C.m.a. Van Ravenswaaij-arts - One of the best experts on this subject based on the ideXlab platform.
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Is there an effect of intranasal insulin on development and behaviour in Phelan-McDermid Syndrome? A randomized, double-blind, placebo-controlled trial.
European Journal of Human Genetics, 2016Co-Authors: Renée J. Zwanenburg, Edwin R. Van Den Heuvel, Gianni Bocca, Selma A.j. Ruiter, Jh Dillingh, Boudien C.t. Flapper, C.m.a. Van Ravenswaaij-artsAbstract:Phelan-McDermid Syndrome (PMS) or 22q13.3 deletion Syndrome is a rare neurodevelopmental disorder with at least 60 children and 35 adults diagnosed in the Netherlands. Clinical features are moderate to severe intellectual disability and behavioural problems in the autism spectrum. Other researchers had observed a beneficial effect of intranasal insulin on development and behaviour in a pilot study in six children with PMS. To validate this effect, we conducted a randomized, double-blind, placebo-controlled clinical trial using a stepped-wedge design. From March 2013 to June 2015, 25 children aged 1-16 years with a molecularly confirmed 22q13.3 deletion including the SHANK3 gene participated in the clinical trial for a period of 18 months. Starting 6 months before the trial, children were systematically assessed for cognitive, language and motor development and for adaptive, social and emotional behaviour every 6 months. The second, third and fourth assessments were followed by daily nose sprays containing either intranasal insulin or intranasal placebo for a 6-month period. A fifth assessment was done directly after the end of the trial. Intranasal insulin did not cause serious adverse events. It increased the level of developmental functioning by 0.4-1.4 months per 6-month period, but the effect was not statistically significant in this small group. We found a stronger effect of intranasal insulin, being significant for cognition and social skills, for children older than 3 years, who usually show a decrease of developmental growth. However, clinical trials in larger study populations are required to prove the therapeutic effect of intranasal insulin in PMS.
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Developmental phenotype in Phelan-McDermid (22q13.3 deletion) Syndrome: a systematic and prospective study in 34 children
Journal of Neurodevelopmental Disorders, 2016Co-Authors: Renée J. Zwanenburg, Edwin R. Van Den Heuvel, Selma A.j. Ruiter, Boudien C.t. Flapper, C.m.a. Van Ravenswaaij-artsAbstract:Background Phelan-McDermid Syndrome (PMS) or 22q13.3 deletion Syndrome is characterized by global developmental delay, cognitive deficits, and behaviour in the autism spectrum. Knowledge about developmental and behavioural characteristics of this rare chromosomal disorder is still limited despite a rapid growing number of diagnoses. Our aim was to study a new and relatively large cohort to further characterize the developmental phenotype of children with PMS.
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Phelan-McDermid Syndrome: Neuropsychological phenotype, cerebellar functioning and treatment selection
Journal of The International Neuropsychological Society, 2016Co-Authors: Jos I.m. Egger, Willem M.a. Verhoeven, C.m.a. Van Ravenswaaij-arts, Renée J. Zwanenburg, C. Bonaglia, Tjitske KleefstraAbstract:Objective: The 22q13.3 deletion Syndrome or Phelan-McDermid Syndrome is characterized by a variable degree of intellectual disability, impaired speech and language as well as social communicative skills, and mild dysmorphic features. The SHANK3 gene is thought to be a major contributor to the phenotype. Apart from the Syndrome associated autistic features, symptoms from the bipolar spectrum can be discerned, in particular behaviour instability and fluctuating mood culminating in a (hypo)manic state. In case of coincident major somatic events, a deteriorating course may occur. Participants and Methods: The present study comprises seven adult patients (four females, three males; aged 21-44 years) with genetically proven Phelan-McDermid Syndrome. Data from medical records were collected and extensive assessment of neuropsychological variables was performed to identify cognitive characteristics and their relation with psychopathology and treatment. Results: All patients showed profound communication deficits and their developmental functioning ranged from 1;0 to 6;3 years. In addition, they had slow speed of information processing, impairment of attentional and executive functions, and cognitive alexithymia. As to psychopathology, features from the affective and anxiety domains were prominent findings in these seven patients suggesting the presence of a bipolar spectrum disorder,that could be effectively moderated with mood stabilizing agents. Conclusions: Results are discussed in terms of the putative involvement of structural brain abnormalities, in particular cerebellar vermis hypoplasia and corpus callosum thinning and their cognitive and emotional sequellae. It is concluded that treatment of 22q13.3 associated psychopathology should include prescription of mood stabilizing agents in combination with individually tailored contextual neuropsychological measures.
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A stepped wedge design for testing an effect of intranasal insulin on cognitive development of children with Phelan-McDermid Syndrome: A comparison of different designs
Statistical Methods in Medical Research, 2014Co-Authors: Edwin R. Van Den Heuvel, Renée J. Zwanenburg, C.m.a. Van Ravenswaaij-artsAbstract:This paper compares the power of the parallel group design, the matched-pairs design, and several options for the stepped wedge and delayed start designs for testing a possible effect of intranasal insulin with respect to placebo on developmental growth of children with a rare disorder like Phelan-McDermid Syndrome. A subject-specific linear mixed effects model for the primary outcome developmental age in a longitudinal setting with five time points was assumed. Monte Carlo simulation studies with small sample sizes were applied since the rare disorder prohibits large trials. The stepped wedge designs, which were initially preferred for ethical reasons, appear to be competitive in power to other designs and were in some settings even the best. The assumed statistical model also demonstrates that all of the designs can be viewed as a stepped wedge or delayed treatment design. Our results show that the stepped wedge design is an appropriate alternative for randomized controlled trials on developmental growth with small numbers of participants under the formulated statistical conditions.
Yuji Kajiwara - One of the best experts on this subject based on the ideXlab platform.
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Intestinal dysmotility in a zebrafish ( Danio rerio ) shank3a;shank3b mutant model of autism
Molecular Autism, 2019Co-Authors: David M. James, Joseph D. Buxbaum, Yuji Kajiwara, Robert A. Kozol, Adam L. Wahl, Emily C. Storrs, Mason Klein, Baharak Moshiree, Julia E. DallmanAbstract:Background and aims Autism spectrum disorder (ASD) is currently estimated to affect more than 1% of the world population. For people with ASD, gastrointestinal (GI) distress is a commonly reported but a poorly understood co-occurring symptom. Here, we investigate the physiological basis for GI distress in ASD by studying gut function in a zebrafish model of Phelan-McDermid Syndrome (PMS), a condition caused by mutations in the SHANK3 gene.
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behavior phenotyping of a mouse model of phelan mcdermid Syndrome with a full deletion of shank3 gene
European Neuropsychopharmacology, 2019Co-Authors: Elodie Drapeau, Mohammed Riad, Yuji Kajiwara, Joseph D. BuxbaumAbstract:Background Phelan-McDermid Syndrome (PMS) is a rare genetic Syndrome in which one copy of the q13 portion of chromosome 22 is missing or mutated leading to a global developmental delay, hypotonia, delayed or absent speech, intellectual disability, and autistic behaviors. SHANK3, a gene coding for a key structural part of the post-synaptic density, is the critical gene for the core neurological and behavioral symptoms in this Syndrome, and the loss of one copy of SHANK3, occurring through intragenic deletion or point mutation, is sufficient to cause Phelan-McDermid Syndrome. However, the size of the region affected can be highly variable, from point mutation to up to 8 Mb deletions and the deletion size seems to be correlated with the Syndrome severity. Due to multiple intragenic promoters and alternatively spliced coding exons within the gene, several Shank3 isoforms have been identified in human and mouse brains. Methods Numerous mouse models have been generated but most target only some of those isoforms while the vast majority of SHANK3 mutations found in PMS patients are deletions of the entire gene. Our aim is based on a novel mouse model, in which all Shank3 isoforms are disrupted and which more closely mirrors the most common genetic mutations found in PMS and our goal was to investigate the behavioral consequences of a disruption of all isoforms of Shank3. Results Our laboratory had previously created a mouse model with a deletion of exons 4 to 9 leading to the disruption of the full length Shank3 protein. We used a Cre-LoxP strategy to add an additional LoxP site flanking exon 22 and disrupt all isoforms. We carried an extensive behavioral phenotyping of neonate, young and adult wild-type, heterozygote and homozygote mice with a battery of test designed to assess the main feature of PMS including neurodevelopmental milestones, sensory and motor functions, sociability, stereotypies and cognitive functioning. Discussion Mice with a full deletion of Shank3 are more severely affected than previously published mouse model with a partial deletion. Abnormal Mendelian ratios at the time of weaning were observed showing a significant deficit for homozygote mice that can be partially explained by an increase of early postnatal lethality. Both sensory and motor disabilities were detected in neonate and adult mice. While social performances and interest for social stimuli were not impaired, the homozygote mice displayed a strong object avoidance and escape behavior. Additionally, we observed a deficit in both initial training and reversal of Barnes maze, a spatial memory task involving hippocampal-prefrontal circuits. Electrophysiological recording showed that both long-term potentiation and long-term depression are impaired in Shank3 deficient mice. Our new mouse model of PMS recapitulates the core symptoms of PMS providing an improvement of both construction and face validity compared to previous model. Ongoing experiments will identify neural mechanisms and brain circuitry involved in PMS and will use this model to screen potential treatments for Shank3-haploinsufficiency.
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Intestinal dysmotility in a zebrafish (Danio rerio) shank3a;shank3b mutant model of autism
BMC, 2019Co-Authors: David M. James, Joseph D. Buxbaum, Yuji Kajiwara, Robert A. Kozol, Adam L. Wahl, Emily C. Storrs, Mason Klein, Baharak Moshiree, Julia E. DallmanAbstract:Abstract Background and aims Autism spectrum disorder (ASD) is currently estimated to affect more than 1% of the world population. For people with ASD, gastrointestinal (GI) distress is a commonly reported but a poorly understood co-occurring symptom. Here, we investigate the physiological basis for GI distress in ASD by studying gut function in a zebrafish model of Phelan-McDermid Syndrome (PMS), a condition caused by mutations in the SHANK3 gene. Methods To generate a zebrafish model of PMS, we used CRISPR/Cas9 to introduce clinically related C-terminal frameshift mutations in shank3a and shank3b zebrafish paralogues (shank3abΔC). Because PMS is caused by SHANK3 haploinsufficiency, we assessed the digestive tract (DT) structure and function in zebrafish shank3abΔC +/− heterozygotes. Human SHANK3 mRNA was then used to rescue DT phenotypes in larval zebrafish. Results Significantly slower rates of DT peristaltic contractions (p
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Behavioral Phenotyping of an Improved Mouse Model of Phelan-McDermid Syndrome with a Complete Deletion of the Shank3 Gene.
eneuro, 2018Co-Authors: Elodie Drapeau, Mohammed Riad, Yuji Kajiwara, Joseph D. BuxbaumAbstract:Phelan-McDermid Syndrome (PMS) is a rare genetic disorder in which one copy of the SHANK3 gene is missing or mutated, leading to a global developmental delay, intellectual disability (ID), and autism. Multiple intragenic promoters and alternatively spliced exons are responsible for the formation of numerous isoforms. Many genetically-modified mouse models of PMS have been generated but most disrupt only some of the isoforms. In contrast, the vast majority of known SHANK3 mutations found in patients involve deletions that disrupt all isoforms. Here, we report the production and thorough behavioral characterization of a new mouse model in which all Shank3 isoforms are disrupted. Domains and tasks examined in adults included measures of general health, neurological reflexes, motor abilities, sensory reactivity, social behavior, repetitive behaviors, cognition and behavioral inflexibility, and anxiety. Our mice are more severely affected than previously published models. While the deficits were typically more pronounced in homozygotes, an intermediate phenotype was observed for heterozygotes in many paradigms. As in other Shank3 mouse models, stereotypies, including increased grooming, were observed. Additionally, sensory alterations were detected in both neonatal and adult mice, and motor behavior was strongly altered, especially in the open field and rotarod locomotor tests. While social behaviors measured with the three-chambered social approach and male-female interaction tests were not strongly impacted, Shank3-deficient mice displayed a strong escape behavior and avoidance of inanimate objects in novel object recognition, repetitive novel object contact, marble burying, and nest building tasks, indicating increased novelty-induced anxiety. Similarly, increased freezing was observed during fear conditioning training and amygdala-dependent cued retrieval. Finally, deficits were observed in both initial training and reversal in the Barnes maze and in contextual fear testing, which are memory tasks involving hippocampal-prefrontal circuits. In contrast, working memory in the Y-maze spontaneous alternation test was not altered. This new mouse model of PMS, engineered to most closely represent human mutations, recapitulates core symptoms of PMS providing improvements for both construct and face validity, compared to previous models.
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behavioral phenotyping of an improved mouse model of phelan mcdermid Syndrome with a complete deletion of the shank3 gene
eNeuro, 2018Co-Authors: Elodie Drapeau, Mohammed Riad, Yuji Kajiwara, Joseph D. BuxbaumAbstract:Abstract Phelan-McDermid Syndrome (PMS) is a rare genetic disorder in which one copy of the SHANK3 gene is missing or mutated, leading to a global developmental delay, intellectual disability, and autism. Multiple intragenic promoters and alternatively spliced exons are responsible for the formation of numerous isoforms. Many genetically-modified mouse models of PMS have been generated but most disrupt only some of the isoforms. In contrast, the vast majority of known SHANK3 mutations found in patients involve deletions that disrupt all isoforms. Here, we report the production and thorough behavioral characterization of a new mouse model in which all Shank3 isoforms are disrupted. Domains and tasks examined in adults included measures of general health, neurological reflexes, motor abilities, sensory reactivity, social behavior, repetitive behaviors, cognition and behavioral inflexibility and anxiety. Our mice are more severely affected than previously published models. While the deficits were typically more pronounced in homozygotes, an intermediate phenotype was observed for heterozygotes in many paradigms. As in other Shank3 mouse models, stereotypies, including increased grooming, were observed. Additionally, sensory alterations were detected in both neonatal and adult mice and motor behavior was strongly altered, especially in the open field and rotarod locomotor tests. While social behaviors measured with the 3-chambered social approach and male-female interaction tests were not strongly impacted, Shank3-deficient mice displayed a strong escape behavior and avoidance of inanimate objects in novel object recognition, repetitive novel object contact, marble burying and nest building tasks, indicating increased novelty-induced anxiety. Similarly, increased freezing was observed during fear conditioning training and amygdala-dependent cued retrieval. Finally, deficits were observed in both initial training and reversal in the Barnes maze and in contextual fear memory that are memory tasks involving hippocampal-prefrontal circuits. In contrast, working memory in the Y-maze spontaneous alternation test was not altered. This new mouse model of PMS, engineered to most closely represent human mutations, recapitulates core symptoms of PMS providing improvements for both construct and face validity, compared to previous models. Significant Statement Phelan-McDermid Syndrome, caused by happloinsufficiency of Shank3 , is a severe and complex neurodevelopmental disorder. This study investigates the behavioral consequences of a disruption of all Shank3 isoforms in neonatal and adult mice using a detailed battery o f tests tailored to investigate core symptoms and usual comorbidities of PMS. We found that our new model is more severely affected than previously published mouse models with only partial deletions of Shank3 and more closely recapitulates symptoms of PMS thus providing improvements for both construct and face validity. Our results highlight the significance of using a mouse model with a complete deletion of Shank3 for studying mechanisms underlying autism spectrum disorder and PMS, carrying preclinical studies and testing test novel therapeutic approaches.
Renée J. Zwanenburg - One of the best experts on this subject based on the ideXlab platform.
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Is there an effect of intranasal insulin on development and behaviour in Phelan-McDermid Syndrome? A randomized, double-blind, placebo-controlled trial.
European Journal of Human Genetics, 2016Co-Authors: Renée J. Zwanenburg, Edwin R. Van Den Heuvel, Gianni Bocca, Selma A.j. Ruiter, Jh Dillingh, Boudien C.t. Flapper, C.m.a. Van Ravenswaaij-artsAbstract:Phelan-McDermid Syndrome (PMS) or 22q13.3 deletion Syndrome is a rare neurodevelopmental disorder with at least 60 children and 35 adults diagnosed in the Netherlands. Clinical features are moderate to severe intellectual disability and behavioural problems in the autism spectrum. Other researchers had observed a beneficial effect of intranasal insulin on development and behaviour in a pilot study in six children with PMS. To validate this effect, we conducted a randomized, double-blind, placebo-controlled clinical trial using a stepped-wedge design. From March 2013 to June 2015, 25 children aged 1-16 years with a molecularly confirmed 22q13.3 deletion including the SHANK3 gene participated in the clinical trial for a period of 18 months. Starting 6 months before the trial, children were systematically assessed for cognitive, language and motor development and for adaptive, social and emotional behaviour every 6 months. The second, third and fourth assessments were followed by daily nose sprays containing either intranasal insulin or intranasal placebo for a 6-month period. A fifth assessment was done directly after the end of the trial. Intranasal insulin did not cause serious adverse events. It increased the level of developmental functioning by 0.4-1.4 months per 6-month period, but the effect was not statistically significant in this small group. We found a stronger effect of intranasal insulin, being significant for cognition and social skills, for children older than 3 years, who usually show a decrease of developmental growth. However, clinical trials in larger study populations are required to prove the therapeutic effect of intranasal insulin in PMS.
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Developmental phenotype in Phelan-McDermid (22q13.3 deletion) Syndrome: a systematic and prospective study in 34 children
Journal of Neurodevelopmental Disorders, 2016Co-Authors: Renée J. Zwanenburg, Edwin R. Van Den Heuvel, Selma A.j. Ruiter, Boudien C.t. Flapper, C.m.a. Van Ravenswaaij-artsAbstract:Background Phelan-McDermid Syndrome (PMS) or 22q13.3 deletion Syndrome is characterized by global developmental delay, cognitive deficits, and behaviour in the autism spectrum. Knowledge about developmental and behavioural characteristics of this rare chromosomal disorder is still limited despite a rapid growing number of diagnoses. Our aim was to study a new and relatively large cohort to further characterize the developmental phenotype of children with PMS.
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Phelan-McDermid Syndrome: Neuropsychological phenotype, cerebellar functioning and treatment selection
Journal of The International Neuropsychological Society, 2016Co-Authors: Jos I.m. Egger, Willem M.a. Verhoeven, C.m.a. Van Ravenswaaij-arts, Renée J. Zwanenburg, C. Bonaglia, Tjitske KleefstraAbstract:Objective: The 22q13.3 deletion Syndrome or Phelan-McDermid Syndrome is characterized by a variable degree of intellectual disability, impaired speech and language as well as social communicative skills, and mild dysmorphic features. The SHANK3 gene is thought to be a major contributor to the phenotype. Apart from the Syndrome associated autistic features, symptoms from the bipolar spectrum can be discerned, in particular behaviour instability and fluctuating mood culminating in a (hypo)manic state. In case of coincident major somatic events, a deteriorating course may occur. Participants and Methods: The present study comprises seven adult patients (four females, three males; aged 21-44 years) with genetically proven Phelan-McDermid Syndrome. Data from medical records were collected and extensive assessment of neuropsychological variables was performed to identify cognitive characteristics and their relation with psychopathology and treatment. Results: All patients showed profound communication deficits and their developmental functioning ranged from 1;0 to 6;3 years. In addition, they had slow speed of information processing, impairment of attentional and executive functions, and cognitive alexithymia. As to psychopathology, features from the affective and anxiety domains were prominent findings in these seven patients suggesting the presence of a bipolar spectrum disorder,that could be effectively moderated with mood stabilizing agents. Conclusions: Results are discussed in terms of the putative involvement of structural brain abnormalities, in particular cerebellar vermis hypoplasia and corpus callosum thinning and their cognitive and emotional sequellae. It is concluded that treatment of 22q13.3 associated psychopathology should include prescription of mood stabilizing agents in combination with individually tailored contextual neuropsychological measures.
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A stepped wedge design for testing an effect of intranasal insulin on cognitive development of children with Phelan-McDermid Syndrome: A comparison of different designs
Statistical Methods in Medical Research, 2014Co-Authors: Edwin R. Van Den Heuvel, Renée J. Zwanenburg, C.m.a. Van Ravenswaaij-artsAbstract:This paper compares the power of the parallel group design, the matched-pairs design, and several options for the stepped wedge and delayed start designs for testing a possible effect of intranasal insulin with respect to placebo on developmental growth of children with a rare disorder like Phelan-McDermid Syndrome. A subject-specific linear mixed effects model for the primary outcome developmental age in a longitudinal setting with five time points was assumed. Monte Carlo simulation studies with small sample sizes were applied since the rare disorder prohibits large trials. The stepped wedge designs, which were initially preferred for ethical reasons, appear to be competitive in power to other designs and were in some settings even the best. The assumed statistical model also demonstrates that all of the designs can be viewed as a stepped wedge or delayed treatment design. Our results show that the stepped wedge design is an appropriate alternative for randomized controlled trials on developmental growth with small numbers of participants under the formulated statistical conditions.
Sara M. Sarasua - One of the best experts on this subject based on the ideXlab platform.
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functional genomics analysis of phelan mcdermid Syndrome 22q13 region during human neurodevelopment
PLOS ONE, 2019Co-Authors: Catherine A. Ziats, Sara M. Sarasua, Audrey Thurm, Luke P Grosvenor, Susan E Swedo, Ahmed Mahfouz, Owen M Rennert, Mark N ZiatsAbstract:Phelan-McDermid Syndrome (PMS) is a neurodevelopmental disorder characterized by varying degrees of intellectual disability, severely delayed language development and specific facial features, and is caused by a deletion within chromosome 22q13.3. SHANK3, which is located at the terminal end of this region, has been repeatedly implicated in other neurodevelopmental disorders and deletion of this gene specifically is thought to cause much of the neurologic symptoms characteristic of PMS. However, it is still unclear to what extent SHANK3 deletions contribute to the PMS phenotype, and what other genes nearby are causal to the neurologic disease. In an effort to better understand the functional landscape of the PMS region during normal neurodevelopment, we assessed RNA-sequencing (RNA-seq) expression data collected from post-mortem brain tissue from developmentally normal subjects over the course of prenatal to adolescent age and analyzed expression changes of 65 genes on 22q13. We found that the majority of genes within this region were expressed in the brain, with ATNX10, MLC1, MAPK8IP2, and SULT4A1 having the highest overall expression. Analysis of the temporal profiles of the highest expressed genes revealed a trend towards peak expression during the early post-natal period, followed by a drop in expression later in development. Spatial analysis revealed significant region specific differences in the expression of SHANK3, MAPK8IP2, and SULT4A1. Region specific expression over time revealed a consistently unique gene expression profile within the cerebellum, providing evidence for a distinct developmental program within this region. Exon-specific expression of SHANK3 showed higher expression within exons contributing to known brain specific functional isoforms. Overall, we provide an updated roadmap of the PMS region, implicating several genes and time periods as important during neurodevelopment, with the hope that this information can help us better understand the phenotypic heterogeneity of PMS.
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22q13 2q13 32 genomic regions associated with severity of speech delay developmental delay and physical features in phelan mcdermid Syndrome
Genetics in Medicine, 2014Co-Authors: Sara M. Sarasua, Katy Phelan, Luigi Boccuto, Jonathan D. Rollins, Julianne S. Collins, Alka Dwivedi, Chin-fu Chen, Curtis R Rogers, Julia L Sharp, Barbara R. DupontAbstract:Phelan–McDermid Syndrome is a developmental disability Syndrome with varying deletions of 22q13 and varying clinical severity. We tested the hypothesis that, in addition to loss of the telomeric gene SHANK3, specific genomic regions within 22q13 are associated with important clinical features. We used a customized oligo array comparative genomic hybridization of 22q12.3-terminus to obtain deletion breakpoints in a cohort of 70 patients with terminal 22q13 deletions. We used association and receiver operating characteristic statistical methods in a novel manner and also incorporated protein interaction networks to identify 22q13 genomic locations and genes associated with clinical features. Specific genomic regions and candidate genes within 22q13.2q13.32 were associated with severity of speech/language delay, neonatal hypotonia, delayed age at walking, hair-pulling behaviors, male genital anomalies, dysplastic toenails, large/fleshy hands, macrocephaly, short and tall stature, facial asymmetry, and atypical reflexes. We also found regions suggestive of a negative association with autism spectrum disorders. This work advances the field of research beyond the observation of a correlation between deletion size and phenotype and identifies candidate 22q13 loci, and in some cases specific genes, associated with singular clinical features observed in Phelan–McDermid Syndrome. Our statistical approach may be useful in genotype–phenotype analyses for other microdeletion or microduplication Syndromes. Genet Med 2014:16(4):318–328.
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association between deletion size and important phenotypes expands the genomic region of interest in phelan mcdermid Syndrome 22q13 deletion Syndrome
Journal of Medical Genetics, 2011Co-Authors: Sara M. Sarasua, Katy Phelan, Luigi Boccuto, Jonathan D. Rollins, Barbara R. Dupont, Alka Dwivedi, Chin-fu Chen, Curtis R Rogers, Julianne S. CollinsAbstract:Background The clinical features of Phelan–McDermid Syndrome (also known as 22q13 deletion Syndrome) are highly variable and include hypotonia, speech and other developmental delays, autistic traits and mildly dysmorphic features. Patient deletion sizes are also highly variable, prompting this genotype–phenotype association study. Methods Terminal deletion breakpoints were identified for 71 individuals in a patient cohort using a custom-designed high-resolution oligonucleotide array comparative genomic hybridisation platform with a resolution of 100 bp. Results Patient deletion sizes were highly variable, ranging from 0.22 to 9.22 Mb, and no common breakpoint was observed. SHANK3 , the major candidate gene for the neurologic features of the Syndrome, was deleted in all cases. Sixteen features (neonatal hypotonia, neonatal hyporeflexia, neonatal feeding problems, speech/language delay, delayed age at crawling, delayed age at walking, severity of developmental delay, male genital anomalies, dysplastic toenails, large or fleshy hands, macrocephaly, tall stature, facial asymmetry, full brow, atypical reflexes and dolichocephaly) were found to be significantly associated with larger deletion sizes, suggesting the role of additional genes or regulatory regions proximal to SHANK3 . Individuals with autism spectrum disorders (ASDs) were found to have smaller deletion sizes (median deletion size of 3.39 Mb) than those without ASDs (median deletion size 6.03 Mb, p=0.0144). This may reflect the difficulty in diagnosing ASDs in individuals with severe developmental delay. Conclusions This genotype–phenotype analysis explains some of the phenotypic variability in the Syndrome and identifies new genomic regions with a high likelihood for causing important developmental phenotypes such as speech delay.