Autism spectrum disorder and epileptic encephalopathy: common causes, many questions / Siddharth SRIVASTAVA in Journal of Neurodevelopmental Disorders, 9-1 (December 2017)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 9-1 (December 2017) . - p.23 Titre : Autism spectrum disorder and epileptic encephalopathy: common causes, many questions Type de document : texte imprimé Auteurs : Siddharth SRIVASTAVA, Auteur ; Mustafa SAHIN, Auteur Article en page(s) : p.23 Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  Epileptic encephalopathy  Mendelian disorders Index. décimale : PER Périodiques Résumé : Epileptic encephalopathies represent a particularly severe form of epilepsy, associated with cognitive and behavioral deficits, including impaired social-communication and restricted, repetitive behaviors that are the hallmarks of autism spectrum disorder (ASD). With the advent of next-generation sequencing, the genetic landscape of epileptic encephalopathies is growing and demonstrates overlap with genes separately implicated in ASD. However, many questions remain about this connection, including whether epileptiform activity itself contributes to the development of ASD symptomatology. In this review, we compiled a database of genes associated with both epileptic encephalopathy and ASD, limiting our purview to Mendelian disorders not including inborn errors of metabolism, and we focused on the connection between ASD and epileptic encephalopathy rather than epilepsy broadly. Our review has four goals: to (1) discuss the overlapping presentations of ASD and monogenic epileptic encephalopathies; (2) examine the impact of the epilepsy itself on neurocognitive features, including ASD, in monogenic epileptic encephalopathies; (3) outline many of the genetic causes responsible for both ASD and epileptic encephalopathy; (4) provide an illustrative example of a final common pathway that may be implicated in both ASD and epileptic encephalopathy. We demonstrate that autistic features are a common association with monogenic epileptic encephalopathies. Certain epileptic encephalopathy syndromes, like infantile spasms, are especially linked to the development of ASD. The connection between seizures themselves and neurobehavioral deficits in these monogenic encephalopathies remains open to debate. Finally, advances in genetics have revealed many genes that overlap in ties to both ASD and epileptic encephalopathy and that play a role in diverse central nervous system processes. Increased attention to the autistic features of monogenic epileptic encephalopathies is warranted for both researchers and clinicians alike. En ligne : http://dx.doi.org/10.1186/s11689-017-9202-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=350 [article] Autism spectrum disorder and epileptic encephalopathy: common causes, many questions [texte imprimé] / Siddharth SRIVASTAVA, Auteur ; Mustafa SAHIN, Auteur . - p.23. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 9-1 (December 2017) . - p.23 Mots-clés : Autism spectrum disorder  Epileptic encephalopathy  Mendelian disorders Index. décimale : PER Périodiques Résumé : Epileptic encephalopathies represent a particularly severe form of epilepsy, associated with cognitive and behavioral deficits, including impaired social-communication and restricted, repetitive behaviors that are the hallmarks of autism spectrum disorder (ASD). With the advent of next-generation sequencing, the genetic landscape of epileptic encephalopathies is growing and demonstrates overlap with genes separately implicated in ASD. However, many questions remain about this connection, including whether epileptiform activity itself contributes to the development of ASD symptomatology. In this review, we compiled a database of genes associated with both epileptic encephalopathy and ASD, limiting our purview to Mendelian disorders not including inborn errors of metabolism, and we focused on the connection between ASD and epileptic encephalopathy rather than epilepsy broadly. Our review has four goals: to (1) discuss the overlapping presentations of ASD and monogenic epileptic encephalopathies; (2) examine the impact of the epilepsy itself on neurocognitive features, including ASD, in monogenic epileptic encephalopathies; (3) outline many of the genetic causes responsible for both ASD and epileptic encephalopathy; (4) provide an illustrative example of a final common pathway that may be implicated in both ASD and epileptic encephalopathy. We demonstrate that autistic features are a common association with monogenic epileptic encephalopathies. Certain epileptic encephalopathy syndromes, like infantile spasms, are especially linked to the development of ASD. The connection between seizures themselves and neurobehavioral deficits in these monogenic encephalopathies remains open to debate. Finally, advances in genetics have revealed many genes that overlap in ties to both ASD and epileptic encephalopathy and that play a role in diverse central nervous system processes. Increased attention to the autistic features of monogenic epileptic encephalopathies is warranted for both researchers and clinicians alike. En ligne : http://dx.doi.org/10.1186/s11689-017-9202-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=350

Brief Report: Role of Parent-Reported Executive Functioning and Anxiety in Insistence on Sameness in Individuals with Germline PTEN Mutations / Mirko ULJAREVIĆ in Journal of Autism and Developmental Disorders, 52-1 (January 2022)  

Public ISBD [article]  inJournal of Autism and Developmental Disorders > 52-1 (January 2022) . - p.414-422 Titre : Brief Report: Role of Parent-Reported Executive Functioning and Anxiety in Insistence on Sameness in Individuals with Germline PTEN Mutations Type de document : texte imprimé Auteurs : Mirko ULJAREVIĆ, Auteur ; Thomas W. FRAZIER, Auteur ; Gaëlle RACHED, Auteur ; Robyn M. BUSCH, Auteur ; Patricia KLAAS, Auteur ; Siddharth SRIVASTAVA, Auteur ; Julian A. MARTINEZ-AGOSTO, Auteur ; Mustafa SAHIN, Auteur ; Charis ENG, Auteur ; Antonio Y. HARDAN, Auteur Article en page(s) : p.414-422 Langues : Anglais (eng) Mots-clés : Anxiety/genetics  Autism Spectrum Disorder/genetics  Child  Child, Preschool  Germ Cells  Germ-Line Mutation  Humans  PTEN Phosphohydrolase/genetics  Parents  Anxiety  Executive functioning  Insistence on sameness  Macrocephaly  Pten Index. décimale : PER Périodiques Résumé : This study aimed to characterize the relationship between insistence on sameness (IS), executive functioning (EF) and anxiety among individuals with PTEN mutations and individuals with macrocephalic ASD. The sample included 38 individuals with PTEN mutation and ASD diagnosis (PTEN-ASD; M(age) = 8.93 years, SD(age) = 4.75), 23 with PTEN mutation without ASD (PTEN-no ASD; M(age) = 8.94 years; SD(age) = 4.85) and 25 with ASD and macrocephaly but with no PTEN mutation (Macro-ASD; M(age) = 11.99 years; SD(age) = 5.15). The final model accounted for 45.7% of variance in IS, with Set-Shifting EF subdomain as a unique independent predictor (t = 4.12, p < 0.001). This investigation provides the first preliminary evidence for the EF-anxiety-IS interrelationship in individuals with PTEN mutations and with macrocephalic ASD. En ligne : http://dx.doi.org/10.1007/s10803-021-04881-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=455 [article] Brief Report: Role of Parent-Reported Executive Functioning and Anxiety in Insistence on Sameness in Individuals with Germline PTEN Mutations [texte imprimé] / Mirko ULJAREVIĆ, Auteur ; Thomas W. FRAZIER, Auteur ; Gaëlle RACHED, Auteur ; Robyn M. BUSCH, Auteur ; Patricia KLAAS, Auteur ; Siddharth SRIVASTAVA, Auteur ; Julian A. MARTINEZ-AGOSTO, Auteur ; Mustafa SAHIN, Auteur ; Charis ENG, Auteur ; Antonio Y. HARDAN, Auteur . - p.414-422. Langues : Anglais (eng) in Journal of Autism and Developmental Disorders > 52-1 (January 2022) . - p.414-422 Mots-clés : Anxiety/genetics  Autism Spectrum Disorder/genetics  Child  Child, Preschool  Germ Cells  Germ-Line Mutation  Humans  PTEN Phosphohydrolase/genetics  Parents  Anxiety  Executive functioning  Insistence on sameness  Macrocephaly  Pten Index. décimale : PER Périodiques Résumé : This study aimed to characterize the relationship between insistence on sameness (IS), executive functioning (EF) and anxiety among individuals with PTEN mutations and individuals with macrocephalic ASD. The sample included 38 individuals with PTEN mutation and ASD diagnosis (PTEN-ASD; M(age) = 8.93 years, SD(age) = 4.75), 23 with PTEN mutation without ASD (PTEN-no ASD; M(age) = 8.94 years; SD(age) = 4.85) and 25 with ASD and macrocephaly but with no PTEN mutation (Macro-ASD; M(age) = 11.99 years; SD(age) = 5.15). The final model accounted for 45.7% of variance in IS, with Set-Shifting EF subdomain as a unique independent predictor (t = 4.12, p < 0.001). This investigation provides the first preliminary evidence for the EF-anxiety-IS interrelationship in individuals with PTEN mutations and with macrocephalic ASD. En ligne : http://dx.doi.org/10.1007/s10803-021-04881-5 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=455

Clinical and molecular outcomes from the 5-Year natural history study of SSADH Deficiency, a model metabolic neurodevelopmental disorder / Itay TOKATLY LATZER in Journal of Neurodevelopmental Disorders, 16 (2024)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 16 (2024) Titre : Clinical and molecular outcomes from the 5-Year natural history study of SSADH Deficiency, a model metabolic neurodevelopmental disorder Type de document : texte imprimé Auteurs : Itay TOKATLY LATZER, Auteur ; Jean-Baptiste ROULLET, Auteur ; Wardiya AFSHAR-SABER, Auteur ; Henry H.C. LEE, Auteur ; Mariarita BERTOLDI, Auteur ; Gabrielle E. MCGINTY, Auteur ; Melissa L. DIBACCO, Auteur ; Erland ARNING, Auteur ; Melissa TSUBOYAMA, Auteur ; Alexander ROTENBERG, Auteur ; Thomas OPLADEN, Auteur ; Kathrin JELTSCH, Auteur ; Àngels GARCÍA-CAZORLA, Auteur ; Natalia JULIÁ-PALACIOS, Auteur ; K Michael GIBSON, Auteur ; Mustafa SAHIN, Auteur ; Phillip L.. PEARL, Auteur Langues : Anglais (eng) Mots-clés : Adolescent  Animals  Child  Child, Preschool  Female  Humans  Male  Mice  Amino Acid Metabolism, Inborn  Errors/therapy/physiopathology/genetics/complications/metabolism  Brain/metabolism/physiopathology  Developmental Disabilities  Disease Models, Animal  GABAergic Neurons/metabolism  gamma-Aminobutyric Acid/metabolism  Induced Pluripotent Stem Cells/metabolism  Neurodevelopmental Disorders/metabolism/etiology/genetics  Succinate-Semialdehyde Dehydrogenase/deficiency/metabolism/genetics  Development  Gaba  Neurotransmitters  Succinic semialdehyde dehydrogenase  Inc., which develops treatments for SSADHD including gene replacement therapy  discussed in this study. Index. décimale : PER Périodiques Résumé : BACKGROUND: Succinic semialdehyde dehydrogenase deficiency (SSADHD) represents a model neurometabolic disease at the fulcrum of translational research within the Boston Children's Hospital Intellectual and Developmental Disabilities Research Centers (IDDRC), including the NIH-sponsored natural history study of clinical, neurophysiological, neuroimaging, and molecular markers, patient-derived induced pluripotent stem cells (iPSC) characterization, and development of a murine model for tightly regulated, cell-specific gene therapy. METHODS: SSADHD subjects underwent clinical evaluations, neuropsychological assessments, biochemical quantification of γ-aminobutyrate (GABA) and related metabolites, electroencephalography (standard and high density), magnetoencephalography, transcranial magnetic stimulation, magnetic resonance imaging and spectroscopy, and genetic tests. This was parallel to laboratory molecular investigations of in vitro GABAergic neurons derived from induced human pluripotent stem cells (hiPSCs) of SSADHD subjects and biochemical analyses performed on a versatile murine model that uses an inducible and reversible rescue strategy allowing on-demand and cell-specific gene therapy. RESULTS: The 62 SSADHD subjects [53% females, median (IQR) age of 9.6 (5.4-14.5) years] included in the study had a reported symptom onset at ∼ 6 months and were diagnosed at a median age of 4 years. Language developmental delays were more prominent than motor. Autism, epilepsy, movement disorders, sleep disturbances, and various psychiatric behaviors constituted the core of the disorder's clinical phenotype. Lower clinical severity scores, indicating worst severity, coincided with older age (R= -0.302, p = 0.03), as well as age-adjusted lower values of plasma γ-aminobutyrate (GABA) (R = 0.337, p = 0.02) and γ-hydroxybutyrate (GHB) (R = 0.360, p = 0.05). While epilepsy and psychiatric behaviors increase in severity with age, communication abilities and motor function tend to improve. iPSCs, which were differentiated into GABAergic neurons, represent the first in vitro neuronal model of SSADHD and express the neuronal marker microtubule-associated protein 2 (MAP2), as well as GABA. GABA-metabolism in induced GABAergic neurons could be reversed using CRISPR correction of the pathogenic variants or mRNA transfection and SSADHD iPSCs were associated with excessive glutamatergic activity and related synaptic excitation. CONCLUSIONS: Findings from the SSADHD Natural History Study converge with iPSC and animal model work focused on a common disorder within our IDDRC, deepening our knowledge of the pathophysiology and longitudinal clinical course of a complex neurodevelopmental disorder. This further enables the identification of biomarkers and changes throughout development that will be essential for upcoming targeted trials of enzyme replacement and gene therapy. En ligne : https://dx.doi.org/10.1186/s11689-024-09538-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=575 [article] Clinical and molecular outcomes from the 5-Year natural history study of SSADH Deficiency, a model metabolic neurodevelopmental disorder [texte imprimé] / Itay TOKATLY LATZER, Auteur ; Jean-Baptiste ROULLET, Auteur ; Wardiya AFSHAR-SABER, Auteur ; Henry H.C. LEE, Auteur ; Mariarita BERTOLDI, Auteur ; Gabrielle E. MCGINTY, Auteur ; Melissa L. DIBACCO, Auteur ; Erland ARNING, Auteur ; Melissa TSUBOYAMA, Auteur ; Alexander ROTENBERG, Auteur ; Thomas OPLADEN, Auteur ; Kathrin JELTSCH, Auteur ; Àngels GARCÍA-CAZORLA, Auteur ; Natalia JULIÁ-PALACIOS, Auteur ; K Michael GIBSON, Auteur ; Mustafa SAHIN, Auteur ; Phillip L.. PEARL, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 16 (2024) Mots-clés : Adolescent  Animals  Child  Child, Preschool  Female  Humans  Male  Mice  Amino Acid Metabolism, Inborn  Errors/therapy/physiopathology/genetics/complications/metabolism  Brain/metabolism/physiopathology  Developmental Disabilities  Disease Models, Animal  GABAergic Neurons/metabolism  gamma-Aminobutyric Acid/metabolism  Induced Pluripotent Stem Cells/metabolism  Neurodevelopmental Disorders/metabolism/etiology/genetics  Succinate-Semialdehyde Dehydrogenase/deficiency/metabolism/genetics  Development  Gaba  Neurotransmitters  Succinic semialdehyde dehydrogenase  Inc., which develops treatments for SSADHD including gene replacement therapy  discussed in this study. Index. décimale : PER Périodiques Résumé : BACKGROUND: Succinic semialdehyde dehydrogenase deficiency (SSADHD) represents a model neurometabolic disease at the fulcrum of translational research within the Boston Children's Hospital Intellectual and Developmental Disabilities Research Centers (IDDRC), including the NIH-sponsored natural history study of clinical, neurophysiological, neuroimaging, and molecular markers, patient-derived induced pluripotent stem cells (iPSC) characterization, and development of a murine model for tightly regulated, cell-specific gene therapy. METHODS: SSADHD subjects underwent clinical evaluations, neuropsychological assessments, biochemical quantification of γ-aminobutyrate (GABA) and related metabolites, electroencephalography (standard and high density), magnetoencephalography, transcranial magnetic stimulation, magnetic resonance imaging and spectroscopy, and genetic tests. This was parallel to laboratory molecular investigations of in vitro GABAergic neurons derived from induced human pluripotent stem cells (hiPSCs) of SSADHD subjects and biochemical analyses performed on a versatile murine model that uses an inducible and reversible rescue strategy allowing on-demand and cell-specific gene therapy. RESULTS: The 62 SSADHD subjects [53% females, median (IQR) age of 9.6 (5.4-14.5) years] included in the study had a reported symptom onset at ∼ 6 months and were diagnosed at a median age of 4 years. Language developmental delays were more prominent than motor. Autism, epilepsy, movement disorders, sleep disturbances, and various psychiatric behaviors constituted the core of the disorder's clinical phenotype. Lower clinical severity scores, indicating worst severity, coincided with older age (R= -0.302, p = 0.03), as well as age-adjusted lower values of plasma γ-aminobutyrate (GABA) (R = 0.337, p = 0.02) and γ-hydroxybutyrate (GHB) (R = 0.360, p = 0.05). While epilepsy and psychiatric behaviors increase in severity with age, communication abilities and motor function tend to improve. iPSCs, which were differentiated into GABAergic neurons, represent the first in vitro neuronal model of SSADHD and express the neuronal marker microtubule-associated protein 2 (MAP2), as well as GABA. GABA-metabolism in induced GABAergic neurons could be reversed using CRISPR correction of the pathogenic variants or mRNA transfection and SSADHD iPSCs were associated with excessive glutamatergic activity and related synaptic excitation. CONCLUSIONS: Findings from the SSADHD Natural History Study converge with iPSC and animal model work focused on a common disorder within our IDDRC, deepening our knowledge of the pathophysiology and longitudinal clinical course of a complex neurodevelopmental disorder. This further enables the identification of biomarkers and changes throughout development that will be essential for upcoming targeted trials of enzyme replacement and gene therapy. En ligne : https://dx.doi.org/10.1186/s11689-024-09538-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=575

Clinical, genetic, and cognitive correlates of seizure occurrences in Phelan-McDermid syndrome / Tess LEVY in Journal of Neurodevelopmental Disorders, 16 (2024)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 16 (2024) Titre : Clinical, genetic, and cognitive correlates of seizure occurrences in Phelan-McDermid syndrome Type de document : texte imprimé Auteurs : Tess LEVY, Auteur ; Jacob GLUCKMAN, Auteur ; Paige M. SIPER, Auteur ; Danielle HALPERN, Auteur ; Jessica ZWEIFACH, Auteur ; Rajna FILIP-DHIMA, Auteur ; J. Lloyd Jr HOLDER, Auteur ; M. Pilar TRELLES, Auteur ; Kristina JOHNSON, Auteur ; Jonathan A. BERNSTEIN, Auteur ; Elizabeth BERRY-KRAVIS, Auteur ; Craig M. POWELL, Auteur ; Latha Valluripalli SOORYA, Auteur ; Audrey THURM, Auteur ; Joseph D. BUXBAUM, Auteur ; Mustafa SAHIN, Auteur ; Alexander KOLEVZON, Auteur ; Siddharth SRIVASTAVA, Auteur ; DEVELOPMENTAL SYNAPTOPATHIES CONSORTIUM, Auteur Langues : Anglais (eng) Mots-clés : Humans  Male  Female  Seizures/genetics  Chromosome Deletion  Chromosome Disorders/complications/genetics/physiopathology  Chromosomes, Human, Pair 22/genetics  Child  Child, Preschool  Adolescent  Longitudinal Studies  Young Adult  Adult  Prospective Studies  Infant  Nerve Tissue Proteins/genetics  22q13  Epilepsy  Phelan-McDermid syndrome  Shank3  Seizures Index. décimale : PER Périodiques Résumé : BACKGROUND: Phelan-McDermid syndrome (PMS) is a genetic neurodevelopmental disorder caused by SHANK3 haploinsufficiency and is associated with an increased risk for seizures. Previous literature indicates that around one third of individuals with PMS also have epilepsy or seizures, with a wide range of types and ages of onset. Investigating the impact of seizures on intellectual and adaptive functioning for PMS is a primary concern for caregivers and is important to understanding the natural history of this syndrome. METHODS: We report on results from 98 individuals enrolled in a prospective, longitudinal study. We detailed seizure frequency, type, and age of onset, and we analyzed seizure occurrence with best estimate IQ, adaptive functioning, clinical features, and genotype. We conducted multiple linear regression analyses to assess the relationship between the presence of seizures and the Vineland Adaptive Behavior Scale, Second Edition (VABS-II) Adaptive Behavior Composite score and the best estimate full-scale IQ. We also performed Chi-square tests to explore associations between seizure prevalence and genetic groupings. Finally, we performed Chi-square tests and t-tests to explore the relationship between seizures and demographic features, features that manifest in infancy, and medical features. RESULTS: Seizures were present in 41% of the cohort, and age of onset was widely variable. The presence of seizures was associated with significantly lower adaptive and intellectual functioning. Genotype-phenotype analyses were discrepant, with no differences in seizure prevalence across genetic classes, but with more genes included in deletions of participants with 22q13 deletions and seizures compared to those with 22q13 deletions and no seizures. No clinical associations were found between the presence of seizures and sex, history of pre- or neonatal complications, early infancy, or medical features. In this cohort, generalized seizures were associated with developmental regression, which is a top concern for PMS caregivers. CONCLUSIONS: These results begin to eludicate correlates of seizures in individuals with PMS and highlight the importance of early seizure management. Importantly, presence of seizures was associated with adaptive and cognitive functioning. A larger cohort might be able to identify additional associations with medical features. Genetic findings suggest an increased capability to realize genotype-phenotype relationships when deletion size is taken into account. En ligne : https://dx.doi.org/10.1186/s11689-024-09541-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=575 [article] Clinical, genetic, and cognitive correlates of seizure occurrences in Phelan-McDermid syndrome [texte imprimé] / Tess LEVY, Auteur ; Jacob GLUCKMAN, Auteur ; Paige M. SIPER, Auteur ; Danielle HALPERN, Auteur ; Jessica ZWEIFACH, Auteur ; Rajna FILIP-DHIMA, Auteur ; J. Lloyd Jr HOLDER, Auteur ; M. Pilar TRELLES, Auteur ; Kristina JOHNSON, Auteur ; Jonathan A. BERNSTEIN, Auteur ; Elizabeth BERRY-KRAVIS, Auteur ; Craig M. POWELL, Auteur ; Latha Valluripalli SOORYA, Auteur ; Audrey THURM, Auteur ; Joseph D. BUXBAUM, Auteur ; Mustafa SAHIN, Auteur ; Alexander KOLEVZON, Auteur ; Siddharth SRIVASTAVA, Auteur ; DEVELOPMENTAL SYNAPTOPATHIES CONSORTIUM, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 16 (2024) Mots-clés : Humans  Male  Female  Seizures/genetics  Chromosome Deletion  Chromosome Disorders/complications/genetics/physiopathology  Chromosomes, Human, Pair 22/genetics  Child  Child, Preschool  Adolescent  Longitudinal Studies  Young Adult  Adult  Prospective Studies  Infant  Nerve Tissue Proteins/genetics  22q13  Epilepsy  Phelan-McDermid syndrome  Shank3  Seizures Index. décimale : PER Périodiques Résumé : BACKGROUND: Phelan-McDermid syndrome (PMS) is a genetic neurodevelopmental disorder caused by SHANK3 haploinsufficiency and is associated with an increased risk for seizures. Previous literature indicates that around one third of individuals with PMS also have epilepsy or seizures, with a wide range of types and ages of onset. Investigating the impact of seizures on intellectual and adaptive functioning for PMS is a primary concern for caregivers and is important to understanding the natural history of this syndrome. METHODS: We report on results from 98 individuals enrolled in a prospective, longitudinal study. We detailed seizure frequency, type, and age of onset, and we analyzed seizure occurrence with best estimate IQ, adaptive functioning, clinical features, and genotype. We conducted multiple linear regression analyses to assess the relationship between the presence of seizures and the Vineland Adaptive Behavior Scale, Second Edition (VABS-II) Adaptive Behavior Composite score and the best estimate full-scale IQ. We also performed Chi-square tests to explore associations between seizure prevalence and genetic groupings. Finally, we performed Chi-square tests and t-tests to explore the relationship between seizures and demographic features, features that manifest in infancy, and medical features. RESULTS: Seizures were present in 41% of the cohort, and age of onset was widely variable. The presence of seizures was associated with significantly lower adaptive and intellectual functioning. Genotype-phenotype analyses were discrepant, with no differences in seizure prevalence across genetic classes, but with more genes included in deletions of participants with 22q13 deletions and seizures compared to those with 22q13 deletions and no seizures. No clinical associations were found between the presence of seizures and sex, history of pre- or neonatal complications, early infancy, or medical features. In this cohort, generalized seizures were associated with developmental regression, which is a top concern for PMS caregivers. CONCLUSIONS: These results begin to eludicate correlates of seizures in individuals with PMS and highlight the importance of early seizure management. Importantly, presence of seizures was associated with adaptive and cognitive functioning. A larger cohort might be able to identify additional associations with medical features. Genetic findings suggest an increased capability to realize genotype-phenotype relationships when deletion size is taken into account. En ligne : https://dx.doi.org/10.1186/s11689-024-09541-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=575

Cross-level analysis of molecular and neurobehavioral function in a prospective series of patients with germline heterozygous PTEN mutations with and without autism / Thomas W. FRAZIER in Molecular Autism, 12 (2021)  

Public ISBD [article]  inMolecular Autism > 12 (2021) . - 5p. Titre : Cross-level analysis of molecular and neurobehavioral function in a prospective series of patients with germline heterozygous PTEN mutations with and without autism Type de document : texte imprimé Auteurs : Thomas W. FRAZIER, Auteur ; Ritika JAINI, Auteur ; Robyn M. BUSCH, Auteur ; Matthew WOLF, Auteur ; Tammy SADLER, Auteur ; Patricia KLAAS, Auteur ; Antonio Y. HARDAN, Auteur ; Julian A. MARTINEZ-AGOSTO, Auteur ; Mustafa SAHIN, Auteur ; Charis ENG, Auteur Article en page(s) : 5p. Langues : Anglais (eng) Mots-clés : Autism spectrum disorder  Behavior  Cognition  Molecular  Pten  Protein Index. décimale : PER Périodiques Résumé : BACKGROUND: PTEN is a well-established risk gene for autism spectrum disorder (ASD). Yet, little is known about how PTEN mutations and associated molecular processes influence neurobehavioral function in mutation carriers with (PTEN-ASD) and without ASD (PTEN no-ASD). The primary aim of the present study was to examine group differences in peripheral blood-derived PTEN pathway protein levels between PTEN-ASD, PTEN no-ASD, and idiopathic macrocephalic ASD patients (macro-ASD). Secondarily, associations between protein levels and neurobehavioral functions were examined in the full cohort. METHODS: Patients were recruited at four tertiary medical centers. Peripheral blood-derived protein levels from canonical PTEN pathways (PI3K/AKT and MAPK/ERK) were analyzed using Western blot analyses blinded to genotype and ASD status. Neurobehavioral measures included standardized assessments of global cognitive ability and multiple neurobehavioral domains. Analysis of variance models examined group differences in demographic, neurobehavioral, and protein measures. Bivariate correlations, structural models, and statistical learning procedures estimated associations between molecular and neurobehavioral variables. To complement patient data, Western blots for downstream proteins were generated to evaluate canonical PTEN pathways in the PTEN-m3m4 mouse model. RESULTS: Participants included 61 patients (25 PTEN-ASD, 16 PTEN no-ASD, and 20 macro-ASD). Decreased PTEN and S6 were observed in both PTEN mutation groups. Reductions in MnSOD and increases in P-S6 were observed in ASD groups. Elevated neural P-AKT/AKT and P-S6/S6 from PTEN murine models parallel our patient observations. Patient PTEN and AKT levels were independently associated with global cognitive ability, and p27 expression was associated with frontal sub-cortical functions. As a group, molecular measures added significant predictive value to several neurobehavioral domains over and above PTEN mutation status. LIMITATIONS: Sample sizes were small, precluding within-group analyses. Protein and neurobehavioral data were limited to a single evaluation. A small number of patients were excluded with invalid protein data, and cognitively impaired patients had missing data on some assessments. CONCLUSIONS: Several canonical PTEN pathway molecules appear to influence the presence of ASD and modify neurobehavioral function in PTEN mutation patients. Protein assays of the PTEN pathway may be useful for predicting neurobehavioral outcomes in PTEN patients. Future longitudinal analyses are needed to replicate these findings and evaluate within-group relationships between protein and neurobehavioral measures. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02461446. En ligne : http://dx.doi.org/10.1186/s13229-020-00406-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=442 [article] Cross-level analysis of molecular and neurobehavioral function in a prospective series of patients with germline heterozygous PTEN mutations with and without autism [texte imprimé] / Thomas W. FRAZIER, Auteur ; Ritika JAINI, Auteur ; Robyn M. BUSCH, Auteur ; Matthew WOLF, Auteur ; Tammy SADLER, Auteur ; Patricia KLAAS, Auteur ; Antonio Y. HARDAN, Auteur ; Julian A. MARTINEZ-AGOSTO, Auteur ; Mustafa SAHIN, Auteur ; Charis ENG, Auteur . - 5p. Langues : Anglais (eng) in Molecular Autism > 12 (2021) . - 5p. Mots-clés : Autism spectrum disorder  Behavior  Cognition  Molecular  Pten  Protein Index. décimale : PER Périodiques Résumé : BACKGROUND: PTEN is a well-established risk gene for autism spectrum disorder (ASD). Yet, little is known about how PTEN mutations and associated molecular processes influence neurobehavioral function in mutation carriers with (PTEN-ASD) and without ASD (PTEN no-ASD). The primary aim of the present study was to examine group differences in peripheral blood-derived PTEN pathway protein levels between PTEN-ASD, PTEN no-ASD, and idiopathic macrocephalic ASD patients (macro-ASD). Secondarily, associations between protein levels and neurobehavioral functions were examined in the full cohort. METHODS: Patients were recruited at four tertiary medical centers. Peripheral blood-derived protein levels from canonical PTEN pathways (PI3K/AKT and MAPK/ERK) were analyzed using Western blot analyses blinded to genotype and ASD status. Neurobehavioral measures included standardized assessments of global cognitive ability and multiple neurobehavioral domains. Analysis of variance models examined group differences in demographic, neurobehavioral, and protein measures. Bivariate correlations, structural models, and statistical learning procedures estimated associations between molecular and neurobehavioral variables. To complement patient data, Western blots for downstream proteins were generated to evaluate canonical PTEN pathways in the PTEN-m3m4 mouse model. RESULTS: Participants included 61 patients (25 PTEN-ASD, 16 PTEN no-ASD, and 20 macro-ASD). Decreased PTEN and S6 were observed in both PTEN mutation groups. Reductions in MnSOD and increases in P-S6 were observed in ASD groups. Elevated neural P-AKT/AKT and P-S6/S6 from PTEN murine models parallel our patient observations. Patient PTEN and AKT levels were independently associated with global cognitive ability, and p27 expression was associated with frontal sub-cortical functions. As a group, molecular measures added significant predictive value to several neurobehavioral domains over and above PTEN mutation status. LIMITATIONS: Sample sizes were small, precluding within-group analyses. Protein and neurobehavioral data were limited to a single evaluation. A small number of patients were excluded with invalid protein data, and cognitively impaired patients had missing data on some assessments. CONCLUSIONS: Several canonical PTEN pathway molecules appear to influence the presence of ASD and modify neurobehavioral function in PTEN mutation patients. Protein assays of the PTEN pathway may be useful for predicting neurobehavioral outcomes in PTEN patients. Future longitudinal analyses are needed to replicate these findings and evaluate within-group relationships between protein and neurobehavioral measures. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02461446. En ligne : http://dx.doi.org/10.1186/s13229-020-00406-6 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=442

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