Down-regulation of the brain-specific cell-adhesion molecule contactin-3 in tuberous sclerosis complex during the early postnatal period / Anatoly KOROTKOV in Journal of Neurodevelopmental Disorders, 14 (2022)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 14 (2022) Titre : Down-regulation of the brain-specific cell-adhesion molecule contactin-3 in tuberous sclerosis complex during the early postnatal period Type de document : texte imprimé Auteurs : Anatoly KOROTKOV, Auteur ; Mark J. LUINENBURG, Auteur ; Alessia ROMAGNOLO, Auteur ; Till S. ZIMMER, Auteur ; Jackelien VAN SCHEPPINGEN, Auteur ; Anika BONGAARTS, Auteur ; Diede W.M. BROEKAART, Auteur ; Jasper J. ANINK, Auteur ; Caroline MIJNSBERGEN, Auteur ; Floor E. JANSEN, Auteur ; Wim VAN HECKE, Auteur ; Wim G. SPLIET, Auteur ; Peter C. VAN RIJEN, Auteur ; Martha FEUCHT, Auteur ; Johannes A. HAINFELLNER, Auteur ; Pavel KRSEK, Auteur ; Josef ZAMECNIK, Auteur ; Peter B. CRINO, Auteur ; Katarzyna KOTULSKA, Auteur ; Lieven LAGAE, Auteur ; Anna C. JANSEN, Auteur ; David J.. KWIATKOWSKI, Auteur ; Sergiusz JOZWIAK, Auteur ; Paolo CURATOLO, Auteur ; Angelika MÃœHLEBNER, Auteur ; Erwin A. VAN VLIET, Auteur ; James D. MILLS, Auteur ; Eleonora ARONICA, Auteur Langues : Anglais (eng) Mots-clés : Adolescent  Adult  Autism Spectrum Disorder/complications/metabolism  Brain/metabolism  Child  Child, Preschool  Contactins/genetics/metabolism  Down-Regulation  Humans  Infant  Infant, Newborn  Middle Aged  Tuberous Sclerosis/complications/metabolism  Young Adult  Cell adhesion  Cerebral cortex development  Epilepsy  Neurodevelopmental disorders  mTORopathies Index. décimale : PER Périodiques Résumé : BACKGROUND: The genetic disorder tuberous sclerosis complex (TSC) is frequently accompanied by the development of neuropsychiatric disorders, including autism spectrum disorder and intellectual disability, with varying degrees of impairment. These co-morbidities in TSC have been linked to the structural brain abnormalities, such as cortical tubers, and recurrent epileptic seizures (in 70-80% cases). Previous transcriptomic analysis of cortical tubers revealed dysregulation of genes involved in cell adhesion in the brain, which may be associated with the neurodevelopmental deficits in TSC. In this study we aimed to investigate the expression of one of these genes - cell-adhesion molecule contactin-3. METHODS: Reverse transcription quantitative polymerase chain reaction for the contactin-3 gene (CNTN3) was performed in resected cortical tubers from TSC patients with drug-resistant epilepsy (n = 35, age range: 1-48 years) and compared to autopsy-derived cortical control tissue (n = 27, age range: 0-44 years), as well as by western blot analysis of contactin-3 (n = 7 vs n = 7, age range: 0-3 years for both TSC and controls) and immunohistochemistry (n = 5 TSC vs n = 4 controls). The expression of contactin-3 was further analyzed in fetal and postnatal control tissue by western blotting and in-situ hybridization, as well as in the SH-SY5Y neuroblastoma cell line differentiation model in vitro. RESULTS: CNTN3 gene expression was lower in cortical tubers from patients across a wide range of ages (fold change = - 0.5, p < 0.001) as compared to controls. Contactin-3 protein expression was lower in the age range of 0-3 years old (fold change = - 3.8, p < 0.001) as compared to the age-matched controls. In control brain tissue, contactin-3 gene and protein expression could be detected during fetal development, peaked around birth and during infancy and declined in the adult brain. CNTN3 expression was induced in the differentiated SH-SY5Y neuroblastoma cells in vitro (fold change = 6.2, p < 0.01). CONCLUSIONS: Our data show a lower expression of contactin-3 in cortical tubers of TSC patients during early postnatal period as compared to controls, which may affect normal brain development and might contribute to neuropsychiatric co-morbidities observed in patients with TSC. En ligne : https://dx.doi.org/10.1186/s11689-022-09416-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=574 [article] Down-regulation of the brain-specific cell-adhesion molecule contactin-3 in tuberous sclerosis complex during the early postnatal period [texte imprimé] / Anatoly KOROTKOV, Auteur ; Mark J. LUINENBURG, Auteur ; Alessia ROMAGNOLO, Auteur ; Till S. ZIMMER, Auteur ; Jackelien VAN SCHEPPINGEN, Auteur ; Anika BONGAARTS, Auteur ; Diede W.M. BROEKAART, Auteur ; Jasper J. ANINK, Auteur ; Caroline MIJNSBERGEN, Auteur ; Floor E. JANSEN, Auteur ; Wim VAN HECKE, Auteur ; Wim G. SPLIET, Auteur ; Peter C. VAN RIJEN, Auteur ; Martha FEUCHT, Auteur ; Johannes A. HAINFELLNER, Auteur ; Pavel KRSEK, Auteur ; Josef ZAMECNIK, Auteur ; Peter B. CRINO, Auteur ; Katarzyna KOTULSKA, Auteur ; Lieven LAGAE, Auteur ; Anna C. JANSEN, Auteur ; David J.. KWIATKOWSKI, Auteur ; Sergiusz JOZWIAK, Auteur ; Paolo CURATOLO, Auteur ; Angelika MÃœHLEBNER, Auteur ; Erwin A. VAN VLIET, Auteur ; James D. MILLS, Auteur ; Eleonora ARONICA, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 14 (2022) Mots-clés : Adolescent  Adult  Autism Spectrum Disorder/complications/metabolism  Brain/metabolism  Child  Child, Preschool  Contactins/genetics/metabolism  Down-Regulation  Humans  Infant  Infant, Newborn  Middle Aged  Tuberous Sclerosis/complications/metabolism  Young Adult  Cell adhesion  Cerebral cortex development  Epilepsy  Neurodevelopmental disorders  mTORopathies Index. décimale : PER Périodiques Résumé : BACKGROUND: The genetic disorder tuberous sclerosis complex (TSC) is frequently accompanied by the development of neuropsychiatric disorders, including autism spectrum disorder and intellectual disability, with varying degrees of impairment. These co-morbidities in TSC have been linked to the structural brain abnormalities, such as cortical tubers, and recurrent epileptic seizures (in 70-80% cases). Previous transcriptomic analysis of cortical tubers revealed dysregulation of genes involved in cell adhesion in the brain, which may be associated with the neurodevelopmental deficits in TSC. In this study we aimed to investigate the expression of one of these genes - cell-adhesion molecule contactin-3. METHODS: Reverse transcription quantitative polymerase chain reaction for the contactin-3 gene (CNTN3) was performed in resected cortical tubers from TSC patients with drug-resistant epilepsy (n = 35, age range: 1-48 years) and compared to autopsy-derived cortical control tissue (n = 27, age range: 0-44 years), as well as by western blot analysis of contactin-3 (n = 7 vs n = 7, age range: 0-3 years for both TSC and controls) and immunohistochemistry (n = 5 TSC vs n = 4 controls). The expression of contactin-3 was further analyzed in fetal and postnatal control tissue by western blotting and in-situ hybridization, as well as in the SH-SY5Y neuroblastoma cell line differentiation model in vitro. RESULTS: CNTN3 gene expression was lower in cortical tubers from patients across a wide range of ages (fold change = - 0.5, p < 0.001) as compared to controls. Contactin-3 protein expression was lower in the age range of 0-3 years old (fold change = - 3.8, p < 0.001) as compared to the age-matched controls. In control brain tissue, contactin-3 gene and protein expression could be detected during fetal development, peaked around birth and during infancy and declined in the adult brain. CNTN3 expression was induced in the differentiated SH-SY5Y neuroblastoma cells in vitro (fold change = 6.2, p < 0.01). CONCLUSIONS: Our data show a lower expression of contactin-3 in cortical tubers of TSC patients during early postnatal period as compared to controls, which may affect normal brain development and might contribute to neuropsychiatric co-morbidities observed in patients with TSC. En ligne : https://dx.doi.org/10.1186/s11689-022-09416-2 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=574

Natural clusters of tuberous sclerosis complex (TSC)-associated neuropsychiatric disorders (TAND): new findings from the TOSCA TAND research project / Petrus J. DE VRIES in Journal of Neurodevelopmental Disorders, 12 (2020)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 12 (2020) Titre : Natural clusters of tuberous sclerosis complex (TSC)-associated neuropsychiatric disorders (TAND): new findings from the TOSCA TAND research project Type de document : texte imprimé Auteurs : Petrus J. DE VRIES, Auteur ; Elena BELOUSOVA, Auteur ; Mirjana P. BENEDIK, Auteur ; Tom CARTER, Auteur ; Vincent COTTIN, Auteur ; Paolo CURATOLO, Auteur ; Lisa D'AMATO, Auteur ; Guillaume BEURE D'AUGÈRES, Auteur ; José C. FERREIRA, Auteur ; Martha FEUCHT, Auteur ; Carla FLADROWSKI, Auteur ; Christoph HERTZBERG, Auteur ; Sergiusz JOZWIAK, Auteur ; John A. LAWSON, Auteur ; Alfons MACAYA, Auteur ; Ruben MARQUES, Auteur ; Rima NABBOUT, Auteur ; Finbar O'CALLAGHAN, Auteur ; Jiong QIN, Auteur ; Valentin SANDER, Auteur ; Matthias SAUTER, Auteur ; Seema SHAH, Auteur ; Yukitoshi TAKAHASHI, Auteur ; Renaud TOURAINE, Auteur ; Sotiris YOUROUKOS, Auteur ; Bernard ZONNENBERG, Auteur ; J Chris KINGSWOOD, Auteur ; Anna C. JANSEN, Auteur ; TOSCA CONSORTIUM AND TOSCA INVESTIGATORS, Auteur Langues : Anglais (eng) Mots-clés : Autism Spectrum Disorder/epidemiology/etiology  Checklist  Cognitive Dysfunction  Feasibility Studies  Female  Humans  Male  Tuberous Sclerosis/complications/epidemiology  Asd  Cluster analysis  Factor analysis  Natural TAND clusters  Neuropsychiatric  Registry  Tand  Tosca  Tuberous sclerosis complex  AM, SY, MPB, BZ, and ACJ received honoraria and travel support from Novartis. VC  received personal fees for consulting  lecture fees and travel from Actelion,  Bayer, Biogen Idec, Boehringer Ingelheim, Gilead, GSK, MSD, Novartis, Pfizer,  Roche, and Sanofi  grants from Actelion, Boehringer Ingelheim, GSK, Pfizer, and  Roche  and personal fees for developing educational material from Boehringer  Ingelheim and Roche. PJdV has been on the steering group of the EXIST-1, 2, and 3  studies sponsored by Novartis and co-PI on two investigator-initiated studies  part-funded by Novartis. RN received grant support, paid to her institution, from  Eisai and lecture fees from Nutricia, Eisai, Advicenne, and GW Pharma. YT  received personal fees from Novartis for lecture and for copyright of referential  figures from the journals and grant from the Japanese government for intractable  epilepsy research. SJ was partly financed by the EC Seventh Framework Programme  (FP7/2007-2013  EPISTOP, grant agreement no. 602391), the Polish Ministerial  funds for science (years 2013–2018) for the implementation of international  co-financed project, and the grant EPIMARKER of the Polish National Center for  Research and Development No. STRATEGMED3/306306/4/2016. JCK, PC, CH, JAL, and JQ  received research grants from Novartis. RM and SS are employees of Novartis. LD’A  was an employee of Novartis at the time of manuscript concept approval. VS  reported no conflict of interest. Index. décimale : PER Périodiques Résumé : BACKGROUND: Tuberous sclerosis complex (TSC)-associated neuropsychiatric disorders (TAND) have unique, individual patterns that pose significant challenges for diagnosis, psycho-education, and intervention planning. A recent study suggested that it may be feasible to use TAND Checklist data and data-driven methods to generate natural TAND clusters. However, the study had a small sample size and data from only two countries. Here, we investigated the replicability of identifying natural TAND clusters from a larger and more diverse sample from the TOSCA study. METHODS: As part of the TOSCA international TSC registry study, this embedded research project collected TAND Checklist data from individuals with TSC. Correlation coefficients were calculated for TAND variables to generate a correlation matrix. Hierarchical cluster and factor analysis methods were used for data reduction and identification of natural TAND clusters. RESULTS: A total of 85 individuals with TSC (female:male, 40:45) from 7 countries were enrolled. Cluster analysis grouped the TAND variables into 6 clusters: a scholastic cluster (reading, writing, spelling, mathematics, visuo-spatial difficulties, disorientation), a hyperactive/impulsive cluster (hyperactivity, impulsivity, self-injurious behavior), a mood/anxiety cluster (anxiety, depressed mood, sleep difficulties, shyness), a neuropsychological cluster (attention/concentration difficulties, memory, attention, dual/multi-tasking, executive skills deficits), a dysregulated behavior cluster (mood swings, aggressive outbursts, temper tantrums), and an autism spectrum disorder (ASD)-like cluster (delayed language, poor eye contact, repetitive behaviors, unusual use of language, inflexibility, difficulties associated with eating). The natural clusters mapped reasonably well onto the six-factor solution generated. Comparison between cluster and factor solutions from this study and the earlier feasibility study showed significant similarity, particularly in cluster solutions. CONCLUSIONS: Results from this TOSCA research project in an independent international data set showed that the combination of cluster analysis and factor analysis may be able to identify clinically meaningful natural TAND clusters. Findings were remarkably similar to those identified in the earlier feasibility study, supporting the potential robustness of these natural TAND clusters. Further steps should include examination of larger samples, investigation of internal consistency, and evaluation of the robustness of the proposed natural clusters. En ligne : https://dx.doi.org/10.1186/s11689-020-09327-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=573 [article] Natural clusters of tuberous sclerosis complex (TSC)-associated neuropsychiatric disorders (TAND): new findings from the TOSCA TAND research project [texte imprimé] / Petrus J. DE VRIES, Auteur ; Elena BELOUSOVA, Auteur ; Mirjana P. BENEDIK, Auteur ; Tom CARTER, Auteur ; Vincent COTTIN, Auteur ; Paolo CURATOLO, Auteur ; Lisa D'AMATO, Auteur ; Guillaume BEURE D'AUGÈRES, Auteur ; José C. FERREIRA, Auteur ; Martha FEUCHT, Auteur ; Carla FLADROWSKI, Auteur ; Christoph HERTZBERG, Auteur ; Sergiusz JOZWIAK, Auteur ; John A. LAWSON, Auteur ; Alfons MACAYA, Auteur ; Ruben MARQUES, Auteur ; Rima NABBOUT, Auteur ; Finbar O'CALLAGHAN, Auteur ; Jiong QIN, Auteur ; Valentin SANDER, Auteur ; Matthias SAUTER, Auteur ; Seema SHAH, Auteur ; Yukitoshi TAKAHASHI, Auteur ; Renaud TOURAINE, Auteur ; Sotiris YOUROUKOS, Auteur ; Bernard ZONNENBERG, Auteur ; J Chris KINGSWOOD, Auteur ; Anna C. JANSEN, Auteur ; TOSCA CONSORTIUM AND TOSCA INVESTIGATORS, Auteur. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 12 (2020) Mots-clés : Autism Spectrum Disorder/epidemiology/etiology  Checklist  Cognitive Dysfunction  Feasibility Studies  Female  Humans  Male  Tuberous Sclerosis/complications/epidemiology  Asd  Cluster analysis  Factor analysis  Natural TAND clusters  Neuropsychiatric  Registry  Tand  Tosca  Tuberous sclerosis complex  AM, SY, MPB, BZ, and ACJ received honoraria and travel support from Novartis. VC  received personal fees for consulting  lecture fees and travel from Actelion,  Bayer, Biogen Idec, Boehringer Ingelheim, Gilead, GSK, MSD, Novartis, Pfizer,  Roche, and Sanofi  grants from Actelion, Boehringer Ingelheim, GSK, Pfizer, and  Roche  and personal fees for developing educational material from Boehringer  Ingelheim and Roche. PJdV has been on the steering group of the EXIST-1, 2, and 3  studies sponsored by Novartis and co-PI on two investigator-initiated studies  part-funded by Novartis. RN received grant support, paid to her institution, from  Eisai and lecture fees from Nutricia, Eisai, Advicenne, and GW Pharma. YT  received personal fees from Novartis for lecture and for copyright of referential  figures from the journals and grant from the Japanese government for intractable  epilepsy research. SJ was partly financed by the EC Seventh Framework Programme  (FP7/2007-2013  EPISTOP, grant agreement no. 602391), the Polish Ministerial  funds for science (years 2013–2018) for the implementation of international  co-financed project, and the grant EPIMARKER of the Polish National Center for  Research and Development No. STRATEGMED3/306306/4/2016. JCK, PC, CH, JAL, and JQ  received research grants from Novartis. RM and SS are employees of Novartis. LD’A  was an employee of Novartis at the time of manuscript concept approval. VS  reported no conflict of interest. Index. décimale : PER Périodiques Résumé : BACKGROUND: Tuberous sclerosis complex (TSC)-associated neuropsychiatric disorders (TAND) have unique, individual patterns that pose significant challenges for diagnosis, psycho-education, and intervention planning. A recent study suggested that it may be feasible to use TAND Checklist data and data-driven methods to generate natural TAND clusters. However, the study had a small sample size and data from only two countries. Here, we investigated the replicability of identifying natural TAND clusters from a larger and more diverse sample from the TOSCA study. METHODS: As part of the TOSCA international TSC registry study, this embedded research project collected TAND Checklist data from individuals with TSC. Correlation coefficients were calculated for TAND variables to generate a correlation matrix. Hierarchical cluster and factor analysis methods were used for data reduction and identification of natural TAND clusters. RESULTS: A total of 85 individuals with TSC (female:male, 40:45) from 7 countries were enrolled. Cluster analysis grouped the TAND variables into 6 clusters: a scholastic cluster (reading, writing, spelling, mathematics, visuo-spatial difficulties, disorientation), a hyperactive/impulsive cluster (hyperactivity, impulsivity, self-injurious behavior), a mood/anxiety cluster (anxiety, depressed mood, sleep difficulties, shyness), a neuropsychological cluster (attention/concentration difficulties, memory, attention, dual/multi-tasking, executive skills deficits), a dysregulated behavior cluster (mood swings, aggressive outbursts, temper tantrums), and an autism spectrum disorder (ASD)-like cluster (delayed language, poor eye contact, repetitive behaviors, unusual use of language, inflexibility, difficulties associated with eating). The natural clusters mapped reasonably well onto the six-factor solution generated. Comparison between cluster and factor solutions from this study and the earlier feasibility study showed significant similarity, particularly in cluster solutions. CONCLUSIONS: Results from this TOSCA research project in an independent international data set showed that the combination of cluster analysis and factor analysis may be able to identify clinically meaningful natural TAND clusters. Findings were remarkably similar to those identified in the earlier feasibility study, supporting the potential robustness of these natural TAND clusters. Further steps should include examination of larger samples, investigation of internal consistency, and evaluation of the robustness of the proposed natural clusters. En ligne : https://dx.doi.org/10.1186/s11689-020-09327-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=573

Specific pattern of maturation and differentiation in the formation of cortical tubers in tuberous sclerosis omplex (TSC): evidence from layer-specific marker expression / A. MUHLEBNER in Journal of Neurodevelopmental Disorders, 8-1 (December 2016)  

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 8-1 (December 2016) . - p.9 Titre : Specific pattern of maturation and differentiation in the formation of cortical tubers in tuberous sclerosis omplex (TSC): evidence from layer-specific marker expression Type de document : texte imprimé Auteurs : A. MUHLEBNER, Auteur ; Anand IYER, Auteur ; Jackelien VAN SCHEPPINGEN, Auteur ; Jasper ANINK, Auteur ; Floor E. JANSEN, Auteur ; Tim J. VEERSEMA, Auteur ; Kees P. BRAUN, Auteur ; Wim G.M. SPLIET, Auteur ; Wim VAN HECKE, Auteur ; F. SOYLEMEZOGLU, Auteur ; Martha FEUCHT, Auteur ; Pavel KRSEK, Auteur ; Josef ZAMECNIK, Auteur ; Christian G. BIEN, Auteur ; Tilman POLSTER, Auteur ; Roland CORAS, Auteur ; I. BLUMCKE, Auteur ; Eleonora ARONICA, Auteur Article en page(s) : p.9 Langues : Anglais (eng) Mots-clés : Cortical layer markers  Epilepsy  Neuropathology  Neurosurgery  Tuberous sclerosis complex Index. décimale : PER Périodiques Résumé : BACKGROUND: Tuberous sclerosis complex (TSC) is a multisystem disorder that results from mutations in the TSC1 or TSC2 genes, leading to constitutive activation of the mammalian target of rapamycin (mTOR) signaling pathway. Cortical tubers represent typical lesions of the central nervous system (CNS) in TSC. The pattern of cortical layering disruption observed in brain tissue of TSC patients is not yet fully understood, and little is known about the origin and phenotype of individual abnormal cell types recognized in tubers. METHODS: In the present study, we aimed to characterize dysmorphic neurons (DNs) and giant cells (GCs) of cortical tubers using neocortical layer-specific markers (NeuN, SMI32, Tbr1, Satb2, Cux2, ER81, and RORbeta) and to compare the features with the histo-morphologically similar focal cortical dysplasia (FCD) type IIb. We studied a cohort of nine surgically resected cortical tubers, five FCD type IIb, and four control samples using immunohistochemistry and in situ hybridization. RESULTS: Cortical tuber displayed a prominent cell loss in all cortical layers. Moreover, we observed altered proportions of layer-specific markers within the dysplastic region. DNs, in both tubers and FCD type IIb, were found positive for different cortical layer markers, regardless of their laminar location, and their immunophenotype resembles that of cortical projection neurons. CONCLUSIONS: These findings demonstrate that, similar to FCD type IIb, cortical layering is markedly disturbed in cortical tubers of TSC patients. Distribution of these disturbances is comparable in all tubers and suggests a dysmaturation affecting early and late migratory patterns, with a more severe impairment of the late stage of maturation. En ligne : http://dx.doi.org/10.1186/s11689-016-9142-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=348 [article] Specific pattern of maturation and differentiation in the formation of cortical tubers in tuberous sclerosis omplex (TSC): evidence from layer-specific marker expression [texte imprimé] / A. MUHLEBNER, Auteur ; Anand IYER, Auteur ; Jackelien VAN SCHEPPINGEN, Auteur ; Jasper ANINK, Auteur ; Floor E. JANSEN, Auteur ; Tim J. VEERSEMA, Auteur ; Kees P. BRAUN, Auteur ; Wim G.M. SPLIET, Auteur ; Wim VAN HECKE, Auteur ; F. SOYLEMEZOGLU, Auteur ; Martha FEUCHT, Auteur ; Pavel KRSEK, Auteur ; Josef ZAMECNIK, Auteur ; Christian G. BIEN, Auteur ; Tilman POLSTER, Auteur ; Roland CORAS, Auteur ; I. BLUMCKE, Auteur ; Eleonora ARONICA, Auteur . - p.9. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 8-1 (December 2016) . - p.9 Mots-clés : Cortical layer markers  Epilepsy  Neuropathology  Neurosurgery  Tuberous sclerosis complex Index. décimale : PER Périodiques Résumé : BACKGROUND: Tuberous sclerosis complex (TSC) is a multisystem disorder that results from mutations in the TSC1 or TSC2 genes, leading to constitutive activation of the mammalian target of rapamycin (mTOR) signaling pathway. Cortical tubers represent typical lesions of the central nervous system (CNS) in TSC. The pattern of cortical layering disruption observed in brain tissue of TSC patients is not yet fully understood, and little is known about the origin and phenotype of individual abnormal cell types recognized in tubers. METHODS: In the present study, we aimed to characterize dysmorphic neurons (DNs) and giant cells (GCs) of cortical tubers using neocortical layer-specific markers (NeuN, SMI32, Tbr1, Satb2, Cux2, ER81, and RORbeta) and to compare the features with the histo-morphologically similar focal cortical dysplasia (FCD) type IIb. We studied a cohort of nine surgically resected cortical tubers, five FCD type IIb, and four control samples using immunohistochemistry and in situ hybridization. RESULTS: Cortical tuber displayed a prominent cell loss in all cortical layers. Moreover, we observed altered proportions of layer-specific markers within the dysplastic region. DNs, in both tubers and FCD type IIb, were found positive for different cortical layer markers, regardless of their laminar location, and their immunophenotype resembles that of cortical projection neurons. CONCLUSIONS: These findings demonstrate that, similar to FCD type IIb, cortical layering is markedly disturbed in cortical tubers of TSC patients. Distribution of these disturbances is comparable in all tubers and suggests a dysmaturation affecting early and late migratory patterns, with a more severe impairment of the late stage of maturation. En ligne : http://dx.doi.org/10.1186/s11689-016-9142-0 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=348

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