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

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

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

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

Public ISBD [article]  inJournal of Neurodevelopmental Disorders > 7-1 (December 2015) . - p.34 Titre : Sensory modulation disorders in childhood epilepsy Type de document : texte imprimé Auteurs : Jolien S. VAN CAMPEN, Auteur ; Floor E. JANSEN, Auteur ; Nienke J. KLEINRENSINK, Auteur ; M. JOELS, Auteur ; Kees P. BRAUN, Auteur ; Hilgo BRUINING, Auteur Article en page(s) : p.34 Langues : Anglais (eng) Mots-clés : Epilepsy  Excitation  Seizures  Sensory modulation Index. décimale : PER Périodiques Résumé : BACKGROUND: Altered sensory sensitivity is generally linked to seizure-susceptibility in childhood epilepsy but may also be associated to the highly prevalent problems in behavioral adaptation. This association is further suggested by the frequent overlap of childhood epilepsy with autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), conditions in which altered behavioral responses to sensory stimuli have been firmly established. A continuum of sensory processing defects due to imbalanced neuronal inhibition and excitation across these disorders has been hypothesizedthat may lead to common symptoms of inadequate modulation of behavioral responses to sensory stimuli. Here, we investigated the prevalence of sensory modulation disorders among children with epilepsy and their relation with symptomatology of neurodevelopmental disorders. METHODS: We used the Sensory Profile questionnaire to assess behavioral responses to sensory stimuli and categorize sensory modulation disorders in children with active epilepsy (aged 4-17 years). We related these outcomes to epilepsy characteristics and tested their association with comorbid symptoms of ASD (Social Responsiveness Scale) and ADHD (Strengths and Difficulties Questionnaire). RESULTS: Sensory modulation disorders were reported in 49 % of the 158 children. Children with epilepsy reported increased behavioral responses associated with sensory "sensitivity," "sensory avoidance," and "poor registration" but not "sensory seeking." Comorbidity of ASD and ADHD was associated with more severe sensory modulation problems, although 27 % of typically developing children with epilepsy also reported a sensory modulation disorder. CONCLUSIONS: Sensory modulation disorders are an under-recognized problem in children with epilepsy. The extent of the modulation difficulties indicates a substantial burden on daily functioning and may explain an important part of the behavioral distress associated with childhood epilepsy. En ligne : http://dx.doi.org/10.1186/s11689-015-9130-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=348 [article] Sensory modulation disorders in childhood epilepsy [texte imprimé] / Jolien S. VAN CAMPEN, Auteur ; Floor E. JANSEN, Auteur ; Nienke J. KLEINRENSINK, Auteur ; M. JOELS, Auteur ; Kees P. BRAUN, Auteur ; Hilgo BRUINING, Auteur . - p.34. Langues : Anglais (eng) in Journal of Neurodevelopmental Disorders > 7-1 (December 2015) . - p.34 Mots-clés : Epilepsy  Excitation  Seizures  Sensory modulation Index. décimale : PER Périodiques Résumé : BACKGROUND: Altered sensory sensitivity is generally linked to seizure-susceptibility in childhood epilepsy but may also be associated to the highly prevalent problems in behavioral adaptation. This association is further suggested by the frequent overlap of childhood epilepsy with autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), conditions in which altered behavioral responses to sensory stimuli have been firmly established. A continuum of sensory processing defects due to imbalanced neuronal inhibition and excitation across these disorders has been hypothesizedthat may lead to common symptoms of inadequate modulation of behavioral responses to sensory stimuli. Here, we investigated the prevalence of sensory modulation disorders among children with epilepsy and their relation with symptomatology of neurodevelopmental disorders. METHODS: We used the Sensory Profile questionnaire to assess behavioral responses to sensory stimuli and categorize sensory modulation disorders in children with active epilepsy (aged 4-17 years). We related these outcomes to epilepsy characteristics and tested their association with comorbid symptoms of ASD (Social Responsiveness Scale) and ADHD (Strengths and Difficulties Questionnaire). RESULTS: Sensory modulation disorders were reported in 49 % of the 158 children. Children with epilepsy reported increased behavioral responses associated with sensory "sensitivity," "sensory avoidance," and "poor registration" but not "sensory seeking." Comorbidity of ASD and ADHD was associated with more severe sensory modulation problems, although 27 % of typically developing children with epilepsy also reported a sensory modulation disorder. CONCLUSIONS: Sensory modulation disorders are an under-recognized problem in children with epilepsy. The extent of the modulation difficulties indicates a substantial burden on daily functioning and may explain an important part of the behavioral distress associated with childhood epilepsy. En ligne : http://dx.doi.org/10.1186/s11689-015-9130-9 Permalink : https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=348

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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