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1.
BMC Psychiatry ; 24(1): 23, 2024 01 04.
Artigo em Inglês | MEDLINE | ID: mdl-38177999

RESUMO

BACKGROUND: Many rare genetic neurodevelopmental disorders (RGNDs) are characterized by intellectual disability (ID), severe cognitive and behavioral impairments, potentially diagnosed as a comorbid autism spectrum disorder or attention-deficit hyperactivity disorder. Quality of life is often impaired due to irritability, aggression and self-injurious behavior, generally refractory to standard therapies. There are indications from previous (case) studies and patient reporting that cannabidiol (CBD) may be an effective treatment for severe behavioral manifestations in RGNDs. However, clear evidence is lacking and interventional research is challenging due to the rarity as well as the heterogeneity within and between disease groups and interindividual differences in treatment response. Our objective is to examine the effectiveness of CBD on severe behavioral manifestations in three RGNDs, including Tuberous Sclerosis Complex (TSC), mucopolysaccharidosis type III (MPS III), and Fragile X syndrome (FXS), using an innovative trial design. METHODS: We aim to conduct placebo-controlled, double-blind, block-randomized, multiple crossover N-of-1 studies with oral CBD (twice daily) in 30 patients (aged ≥ 6 years) with confirmed TSC, MPS III or FXS and severe behavioral manifestations. The treatment is oral CBD up to a maximum of 25 mg/kg/day, twice daily. The primary outcome measure is the subscale irritability of the Aberrant Behavior Checklist. Secondary outcome measures include (personalized) patient-reported outcome measures with regard to behavioral and psychiatric outcomes, disease-specific outcome measures, parental stress, seizure frequency, and adverse effects of CBD. Questionnaires will be completed and study medication will be taken at the participants' natural setting. Individual treatment effects will be determined based on summary statistics. A mixed model analysis will be applied for analyzing the effectiveness of the intervention per disorder and across disorders combining data from the individual N-of-1 trials. DISCUSSION: These N-of-1 trials address an unmet medical need and will provide information on the effectiveness of CBD for severe behavioral manifestations in RGNDs, potentially generating generalizable knowledge at an individual-, disorder- and RGND population level. TRIAL REGISTRATION: EudraCT: 2021-003250-23, registered 25 August 2022, https://www.clinicaltrialsregister.eu/ctr-search/trial/2021-003250-23/NL .


Assuntos
Transtorno do Espectro Autista , Canabidiol , Síndrome do Cromossomo X Frágil , Mucopolissacaridoses , Esclerose Tuberosa , Humanos , Canabidiol/uso terapêutico , Síndrome do Cromossomo X Frágil/complicações , Síndrome do Cromossomo X Frágil/tratamento farmacológico , Esclerose Tuberosa/complicações , Esclerose Tuberosa/tratamento farmacológico , Transtorno do Espectro Autista/tratamento farmacológico , Qualidade de Vida , Resultado do Tratamento , Mucopolissacaridoses/induzido quimicamente , Mucopolissacaridoses/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto
2.
Epilepsy Behav ; 146: 109361, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37523795

RESUMO

OBJECTIVE: Our study aimed to describe the prevalence and characteristics of gastrointestinal and eating problems in Dravet syndrome (DS) and other SCN1A-related seizure disorders and to determine the association between the occurrence of gastrointestinal and eating problems and core features of DS. METHODS: Gastrointestinal and eating problems were assessed with a questionnaire in a Dutch cohort of participants with an SCN1A-related seizure disorder. Associations between the number of gastrointestinal and eating problems and core features of DS, seizure severity, level of intellectual disability, impaired mobility, behavioral problems, and use of anti-seizure medication, were explored by multivariate ordinal regression analyses. Symptoms were divided into the categories dysphagia-related, behavioral, and gastrointestinal, and were assessed separately. RESULTS: One hundred sixty-nine participants with an SCN1A-related seizure disorder, of whom 118 (69.8%) with DS and 51 (30.2%) with Generalized Epilepsy with Febrile Seizures Plus / Febrile Seizures (GEFS+/FS), the non-DS phenotype, were evaluated. Gastrointestinal and eating problems were highly prevalent in DS participants, 50.8% had more than three symptoms compared to 3.9% of non-DS participants. Of participants with DS, 17.8% were fully or partly fed by a gastric tube. Within the three different symptom categories, the most prevalent dysphagia-related symptom was drooling (60.7%), distraction during mealtimes (61.4%) the most prevalent behavioral symptom, and constipation and loss of appetite (both 50.4%) the most prevalent gastrointestinal symptoms. DS participants who use a wheelchair (odds ratio (OR) 4.9 95%CI (1.9-12.8) compared to walking without aid), who use ≥3 anti-seizure medications (ASM) (OR 5.9 95%CI (1.9-18.2) compared to <3 ASM) and who have behavioral problems (OR 3.0 95%CI (1.1-8.1) compared to no behavioral problems) had more gastrointestinal and eating problems. CONCLUSION: Gastrointestinal and eating problems are frequently reported symptoms in DS. Distinguishing between symptom categories will lead to tailored management of patients at risk, will improve early detection, and enable a timely referral to a dietitian, behavioral expert, and/or speech therapist, ultimately aiming to improve the quality of life of both patients and caregivers.


Assuntos
Transtornos de Deglutição , Epilepsias Mioclônicas , Epilepsia , Humanos , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Qualidade de Vida , Transtornos de Deglutição/epidemiologia , Transtornos de Deglutição/etiologia , Mutação , Epilepsia/complicações , Epilepsia/epidemiologia , Epilepsia/diagnóstico , Epilepsias Mioclônicas/diagnóstico
3.
AJNR Am J Neuroradiol ; 41(8): 1532-1537, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32732273

RESUMO

BACKGROUND AND PURPOSE: Cerebral MR imaging in infants is usually performed with a field strength of up to 3T. In adults, a growing number of studies have shown added diagnostic value of 7T MR imaging. 7T MR imaging might be of additional value in infants with unexplained seizures, for example. The aim of this study was to investigate the feasibility of 7T MR imaging in infants. We provide information about the safety preparations and show the first MR images of infants at 7T. MATERIALS AND METHODS: Specific absorption rate levels during 7T were simulated in Sim4life using infant and adult models. A newly developed acoustic hood was used to guarantee hearing protection. Acoustic noise damping of this hood was measured and compared with the 3T Nordell hood and no hood. In this prospective pilot study, clinically stable infants, between term-equivalent age and the corrected age of 3 months, underwent 7T MR imaging immediately after their standard 3T MR imaging. The 7T scan protocols were developed and optimized while scanning this cohort. RESULTS: Global and peak specific absorption rate levels in the infant model in the centered position and 50-mm feet direction did not exceed the levels in the adult model. Hearing protection was guaranteed with the new hood. Twelve infants were scanned. No MR imaging-related adverse events occurred. It was feasible to obtain good-quality imaging at 7T for MRA, MRV, SWI, single-shot T2WI, and MR spectroscopy. T1WI had lower quality at 7T. CONCLUSIONS: 7T MR imaging is feasible in infants, and good-quality scans could be obtained.


Assuntos
Recém-Nascido , Lactente , Imageamento por Ressonância Magnética/instrumentação , Imageamento por Ressonância Magnética/métodos , Estudos de Viabilidade , Feminino , Humanos , Masculino , Projetos Piloto , Estudos Prospectivos
4.
Neuropathol Appl Neurobiol ; 46(2): 142-159, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31183875

RESUMO

AIM: Matrix metalloproteinases (MMPs) and their endogenous tissue inhibitors (TIMPs) control proteolysis within the extracellular matrix (ECM) of the brain. Dysfunction of this enzymatic system due to brain inflammation can disrupt the blood-brain barrier (BBB) and has been implicated in the pathogenesis of epilepsy. However, this has not been extensively studied in the epileptogenic human brain. METHODS: We investigated the expression and cellular localization of major MMPs (MMP2, MMP3, MMP9 and MMP14) and TIMPs (TIMP1, TIMP2, TIMP3 and TIMP4) using quantitative real-time polymerase chain reaction (RT-PCR) and immunohistochemistry in resected epileptogenic brain tissue from patients with tuberous sclerosis complex (TSC), a severe neurodevelopmental disorder characterized by intractable epilepsy and prominent neuroinflammation. Furthermore, we determined whether anti-inflammatory microRNAs, miR146a and miR147b, which can regulate gene expression at the transcriptional level, could attenuate dysregulated MMP and TIMP expression in TSC tuber-derived astroglial cultures. RESULTS: We demonstrated higher mRNA and protein expression of MMPs and TIMPs in TSC tubers compared to control and perituberal brain tissue, particularly in dysmorphic neurons and giant cells, as well as in reactive astrocytes, which was associated with BBB dysfunction. More importantly, IL-1ß-induced dysregulation of MMP3, TIMP2, TIMP3 and TIMP4 could be rescued by miR146a and miR147b in tuber-derived TSC cultures. CONCLUSIONS: This study provides evidence of dysregulation of the MMP/TIMP proteolytic system in TSC, which is associated with BBB dysfunction. As dysregulated MMP and TIMP expression can be ameliorated in vitro by miR146a and miR147b, these miRNAs deserve further investigation as a novel therapeutic approach.


Assuntos
Metaloproteinases da Matriz/metabolismo , MicroRNAs/metabolismo , Esclerose Tuberosa/metabolismo , Encéfalo/metabolismo , Encéfalo/patologia , Pré-Escolar , Humanos , Masculino , Inibidores Teciduais de Metaloproteinases/metabolismo , Esclerose Tuberosa/patologia , Células Tumorais Cultivadas
5.
Neuropathol Appl Neurobiol ; 46(6): 546-563, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-31869431

RESUMO

AIMS: Oxidative stress is evident in resected epileptogenic brain tissue of patients with developmental brain malformations related to mammalian target of rapamycin activation: tuberous sclerosis complex (TSC) and focal cortical dysplasia type IIb (FCD IIb). Whether chronic activation of anti-oxidant pathways is beneficial or contributes to pathology is not clear. METHODS: We investigated oxidative stress markers, including haem oxygenase 1, ferritin and the inflammation associated microRNA-155 in surgically resected epileptogenic brain tissue of TSC (n = 10) and FCD IIb (n = 8) patients and in a TSC model (Tsc1GFAP-/- mice) using immunohistochemistry, in situ hybridization, real-time quantitative PCR and immunoblotting. Using human foetal astrocytes we performed an in vitro characterization of the anti-oxidant response to acute and chronic oxidative stress and evaluated overexpression of the disease-relevant pro-inflammatory microRNA-155. RESULTS: Resected TSC or FCD IIb tissue displayed higher expression of oxidative stress markers and microRNA-155. Tsc1GFAP-/- mice expressed more microRNA-155 and haem oxygenase 1 in the brain compared to wild-type, preceding the typical development of spontaneous seizures in these animals. In vitro, chronic microRNA-155 overexpression induced haem oxygenase 1, iron regulatory elements and increased susceptibility to oxidative stress. Overexpression of iron regulatory genes was also detected in patients with TSC, FCD IIb and Tsc1GFAP-/- mice. CONCLUSION: Our results demonstrate that early and sustained activation of anti-oxidant signalling and dysregulation of iron metabolism are a pathological hallmark of FCD IIb and TSC. Our findings suggest novel therapeutic strategies aimed at controlling the pathological link between both processes.


Assuntos
Antioxidantes/metabolismo , Epilepsia/metabolismo , Ferro/metabolismo , Malformações do Desenvolvimento Cortical/complicações , Malformações do Desenvolvimento Cortical/metabolismo , Redes e Vias Metabólicas , Animais , Células Cultivadas , Encefalite/genética , Encefalite/metabolismo , Epilepsia/complicações , Epilepsia/genética , Feminino , Ferritinas/metabolismo , Proteína Glial Fibrilar Ácida/genética , Heme Oxigenase-1/metabolismo , Humanos , Masculino , Malformações do Desenvolvimento Cortical/genética , Malformações do Desenvolvimento Cortical do Grupo I/genética , Malformações do Desenvolvimento Cortical do Grupo I/metabolismo , Camundongos , Camundongos Knockout , MicroRNAs/genética , Estresse Oxidativo , Esclerose Tuberosa/genética , Esclerose Tuberosa/metabolismo
6.
Eur J Neurol ; 26(6): 856-864, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30223294

RESUMO

BACKGROUND AND PURPOSE: Juvenile myoclonic epilepsy (JME) is a common epilepsy syndrome for which treatment response is generally assumed to be good. We aimed to determine the prevalence and prognostic risk factors for refractoriness of JME. METHODS: We systematically searched PubMed and EMBASE and included 43 eligible studies, reporting seizure outcome after antiepileptic drug (AED) treatment in JME cohorts. We defined refractory JME as persistence of any seizure despite AED treatment and performed a random-effects meta-analysis to assess the prevalence of refractory JME and of seizure recurrence after AED withdrawal in individuals with well-controlled seizures. Studies reporting potential prognostic risk factors in relation to seizure outcome were included for subsequent meta-analysis of risk factors for refractoriness. RESULTS: Overall, 35% (95% confidence interval, 29-41%) of individuals (n = 3311) were refractory. There was marked heterogeneity between studies. Seizures recurred in 78% (95% confidence interval, 52-94%) of individuals who attempted to withdraw from treatment after a period of seizure freedom (n = 246). Seizure outcome by publication year suggested that prognosis did not improve over time. Meta-analysis suggested six variables as prognostic factors for refractoriness, i.e. having three seizure types, absence seizures, psychiatric comorbidities, earlier age at seizure onset, history of childhood absence epilepsy and praxis-induced seizures. CONCLUSION: One-third of people with JME were refractory, which is a higher prevalence than expected. Risk factors were identified and can be used to guide treatment and counselling of people with JME.


Assuntos
Epilepsia Mioclônica Juvenil/epidemiologia , Anticonvulsivantes/uso terapêutico , Humanos , Epilepsia Mioclônica Juvenil/tratamento farmacológico , Epilepsia Mioclônica Juvenil/etiologia , Prevalência , Prognóstico , Fatores de Risco
7.
Genet Med ; 21(4): 1008-1014, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30166628

RESUMO

PURPOSE: Developmental and epileptic encephalopathies (DEEs) are severe clinical conditions characterized by stagnation or decline of cognitive and behavioral abilities preceded, accompanied or followed by seizures. Because DEEs are clinically and genetically heterogeneous, next-generation sequencing, especially exome sequencing (ES), is becoming a first-tier strategy to identify the molecular etiologies of these disorders. METHODS: We combined ES analysis and international data sharing. RESULTS: We identified 11 unrelated individuals with DEE and de novo heterozygous truncating variants in the interferon regulatory factor 2-binding protein-like gene (IRF2BPL). The 11 individuals allowed for delineation of a consistent neurodevelopmental disorder characterized by mostly normal initial psychomotor development followed by severe global neurological regression and epilepsy with nonspecific electroencephalogram (EEG) abnormalities and variable central nervous system (CNS) anomalies. IRF2BPL, also known as enhanced at puberty protein 1 (EAP1), encodes a transcriptional regulator containing a C-terminal RING-finger domain common to E3 ubiquitin ligases. This domain is required for its repressive and transactivating transcriptional properties. The variants identified are expected to encode a protein lacking the C-terminal RING-finger domain. CONCLUSIONS: These data support the causative role of truncating IRF2BPL variants in pediatric neurodegeneration and expand the spectrum of transcriptional regulators identified as molecular factors implicated in genetic developmental and epileptic encephalopathies.


Assuntos
Proteínas de Transporte/genética , Epilepsia/genética , Transtornos do Neurodesenvolvimento/genética , Proteínas Nucleares/genética , Convulsões/genética , Adolescente , Adulto , Sistema Nervoso Central/diagnóstico por imagem , Sistema Nervoso Central/patologia , Criança , Eletroencefalografia , Epilepsia/diagnóstico por imagem , Epilepsia/fisiopatologia , Feminino , Heterozigoto , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Transtornos do Neurodesenvolvimento/diagnóstico por imagem , Transtornos do Neurodesenvolvimento/fisiopatologia , Fenótipo , Convulsões/diagnóstico por imagem , Convulsões/fisiopatologia , Sequenciamento do Exoma , Adulto Jovem
8.
J Mol Neurosci ; 59(4): 464-70, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27122151

RESUMO

In tuberous sclerosis complex (TSC), overexpression of numerous genes associated with inflammation has been observed. Among different proinflammatory cytokines, interleukin-1ß (IL-1ß) has been shown to be significantly involved in epileptogenesis and maintenance of seizures. Recent evidence indicates that IL-1ß gene expression can be regulated by DNA methylation of its promoter. In the present study, we hypothesized that hypomethylation in the promoter region of the IL-1ß gene may underlie its overexpression observed in TSC brain tissue. Bisulfite sequencing was used to study the methylation status of the promoter region of the IL-1ß gene in TSC and control samples. We identified hypomethylation in the promoter region of the IL-1ß gene in TSC samples. IL-1ß is overexpressed in tubers, and gene expression is correlated with promoter hypomethylation at CpG and non-CpG sites. Our results provide the first evidence of epigenetic modulation of the IL-1ß signaling in TSC. Thus, strategies that target epigenetic alterations could offer new therapeutic avenues to control the persistent activation of interleukin-1ß-mediated inflammatory signaling in TSC brain.


Assuntos
Metilação de DNA , Interleucina-1beta/metabolismo , Regiões Promotoras Genéticas , Esclerose Tuberosa/metabolismo , Adolescente , Encéfalo/metabolismo , Estudos de Casos e Controles , Criança , Ilhas de CpG , Epigênese Genética , Feminino , Humanos , Interleucina-1beta/genética , Masculino , Esclerose Tuberosa/genética , Regulação para Cima
9.
Glia ; 64(6): 1066-82, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27014996

RESUMO

Tuberous sclerosis complex (TSC) is a genetic disease presenting with multiple neurological symptoms including epilepsy, mental retardation, and autism. Abnormal activation of various inflammatory pathways has been observed in astrocytes in brain lesions associated with TSC. Increasing evidence supports the involvement of microRNAs in the regulation of astrocyte-mediated inflammatory response. To study the role of inflammation-related microRNAs in TSC, we employed real-time PCR and in situ hybridization to characterize the expression of miR21, miR146a, and miR155 in TSC lesions (cortical tubers and subependymal giant cell astrocytomas, SEGAs). We observed an increased expression of miR21, miR146a, and miR155 in TSC tubers compared with control and perituberal brain tissue. Expression was localized in dysmorphic neurons, giant cells, and reactive astrocytes and positively correlated with IL-1ß expression. In addition, cultured human astrocytes and SEGA-derived cell cultures were used to study the regulation of the expression of these miRNAs in response to the proinflammatory cytokine IL-1ß and to evaluate the effects of overexpression or knockdown of miR21, miR146a, and miR155 on inflammatory signaling. IL-1ß stimulation of cultured glial cells strongly induced intracellular miR21, miR146a, and miR155 expression, as well as miR146a extracellular release. IL-1ß signaling was differentially modulated by overexpression of miR155 or miR146a, which resulted in pro- or anti-inflammatory effects, respectively. This study provides supportive evidence that inflammation-related microRNAs play a role in TSC. In particular, miR146a and miR155 appear to be key players in the regulation of astrocyte-mediated inflammatory response, with miR146a as most interesting anti-inflammatory therapeutic candidate.


Assuntos
Astrócitos/metabolismo , Astrocitoma/metabolismo , MicroRNAs/metabolismo , Esclerose Tuberosa/metabolismo , Adolescente , Adulto , Astrocitoma/patologia , Encéfalo/metabolismo , Técnicas de Cultura de Células , Células Cultivadas , Criança , Pré-Escolar , Humanos , Lactente , Pessoa de Meia-Idade , Neurônios/metabolismo , Transdução de Sinais/fisiologia , Adulto Jovem
10.
Epilepsy Res ; 91(1): 84-93, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20656459

RESUMO

Adhesion molecule on glia (AMOG) mediates neuronal migration during development and ion homeostasis. Recently, AMOG has been identified as a regulator of the Pi3K-mTOR signaling pathway. In the present study, we investigated the expression pattern of AMOG in human cortex during development and in focal malformations of cortical development. In the developing human cortex, AMOG expression was detected in the cortical plate at 13 gestational weeks and increased in later gestational ages. In adult human control cortex, a diffuse immunoreactivity pattern was observed for AMOG in the grey matter. In the white matter, AMOG was expressed in perivascular astrocytes. In focal cortical dysplasia (n=6) and cortical tubers (n=6), the diffuse AMOG expression pattern was reduced in the grey matter. However, AMOG immunoreactivity was observed in reactive astrocytes and strong perisomatic staining was detected in balloon and giant cells. Double-labeling showed co-localization of AMOG with the precursor cell marker CD34 and phosphorylated S6, used as a marker of mTOR activation. The AMOG expression pattern, with altered cellular distribution, observed in malformations of cortical development suggests that AMOG might contribute to the abnormal cortical development via mTOR activation. Whether dysfunction of AMOG might influence the ionic and osmotic regulation, contributing to neuronal hyperexcitability, deserves further investigation.


Assuntos
Adenosina Trifosfatases/biossíntese , Proteínas de Transporte de Cátions/biossíntese , Moléculas de Adesão Celular Neuronais/biossíntese , Córtex Cerebral/embriologia , Córtex Cerebral/metabolismo , Regulação da Expressão Gênica no Desenvolvimento , Malformações do Desenvolvimento Cortical/metabolismo , Adenosina Trifosfatases/genética , Adenosina Trifosfatases/metabolismo , Adolescente , Adulto , Antígenos CD34/genética , Antígenos CD34/metabolismo , Proteínas de Transporte de Cátions/genética , Proteínas de Transporte de Cátions/metabolismo , Moléculas de Adesão Celular Neuronais/genética , Moléculas de Adesão Celular Neuronais/metabolismo , Córtex Cerebral/anormalidades , Criança , Pré-Escolar , Ativação Enzimática/genética , Feminino , Feto/enzimologia , Feto/metabolismo , Feto/patologia , Humanos , Lactente , Masculino , Malformações do Desenvolvimento Cortical/genética , Malformações do Desenvolvimento Cortical/patologia , Proteínas Quinases S6 Ribossômicas/genética , Proteínas Quinases S6 Ribossômicas/metabolismo , Transdução de Sinais/genética , Serina-Treonina Quinases TOR/metabolismo , Serina-Treonina Quinases TOR/fisiologia , Adulto Jovem
11.
Neurology ; 70(12): 916-23, 2008 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-18032744

RESUMO

OBJECTIVE: In patients with tuberous sclerosis complex (TSC), associations between tuber number, infantile spasms, and cognitive impairment have been proposed. We hypothesized that the tuber/brain proportion (TBP), the proportion of the total brain volume occupied by tubers, would be a better determinant of seizures and cognitive function than the number of tubers. We investigated tuber load, seizures, and cognitive function and their relationships. METHODS: Tuber number and TBP were characterized on three-dimensional fluid-attenuated inversion recovery MRI with an automated tuber segmentation program. Seizure histories and EEG recordings were obtained. Intelligence equivalents were determined and an individual cognition index (a marker of cognition that incorporated multiple cognitive domains) was calculated. RESULTS: In our sample of 61 patients with TSC, TBP was inversely related to the age at seizure onset and to the intelligence equivalent and tended to be inversely related to the cognition index. Further, a younger age at seizure onset or a history of infantile spasms was related to lower intelligence and lower cognition index. In a multivariable analysis, only age at seizure onset and cognition index were related. CONCLUSIONS: Our systematic analysis confirms proposed relationships between tuber load, epilepsy and cognitive function in tuberous sclerosis complex (TSC), but also indicates that tuber/brain proportion is a better predictor of cognitive function than tuber number and that age at seizure onset is the only independent determinant of cognitive function. Seizure control should be the principal neurointervention in patients with TSC.


Assuntos
Encéfalo/patologia , Transtornos Cognitivos/patologia , Espasmos Infantis/patologia , Esclerose Tuberosa/complicações , Esclerose Tuberosa/patologia , Adolescente , Adulto , Idade de Início , Encéfalo/fisiopatologia , Criança , Pré-Escolar , Transtornos Cognitivos/fisiopatologia , Eletroencefalografia , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Lactente , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Deficiência Intelectual/fisiopatologia , Testes de Inteligência , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Valor Preditivo dos Testes , Prognóstico , Índice de Gravidade de Doença , Espasmos Infantis/genética , Espasmos Infantis/fisiopatologia , Esclerose Tuberosa/genética
12.
Neurology ; 70(12): 908-15, 2008 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-18032745

RESUMO

OBJECTIVE: The purpose of this study was to systematically analyze the associations between different TSC1 and TSC2 mutations and the neurologic and cognitive phenotype in patients with tuberous sclerosis complex (TSC). METHODS: Mutation analysis was performed in 58 patients with TSC. Epilepsy variables, including EEG, were classified. A cognition index was determined based on a comprehensive neuropsychological assessment. On three-dimensional fluid-attenuated inversion recovery MR images, an automated tuber segmentation program detected and calculated the number of tubers and the proportion of total brain volume occupied by tubers (tuber/brain proportion [TBP]). RESULTS: As a group, patients with a TSC2 mutation had earlier age at seizure onset, lower cognition index, more tubers, and a greater TBP than those with a TSC1 mutation, but the ranges overlapped considerably. Familial cases were older at seizure onset and had a higher cognition index than nonfamilial cases. Patients with a mutation deleting or directly inactivating the tuberin GTPase activating protein (GAP) domain had more tubers and a greater TBP than those with an intact GAP domain. Patients with a truncating TSC1 or TSC2 mutation differed from those with nontruncating mutations in seizure types only. CONCLUSIONS: Although patients with a TSC1 mutation are more likely to have a less severe neurologic and cognitive phenotype than those with a TSC2 mutation, the considerable overlap between both aspects of the phenotype implies that prediction of the neurologic and cognitive phenotypes in individuals with tuberous sclerosis complex should not be based on their particular TSC1 or TSC2 mutation.


Assuntos
Transtornos Cognitivos/genética , Epilepsia/genética , Predisposição Genética para Doença/genética , Esclerose Tuberosa/genética , Proteínas Supressoras de Tumor/genética , Adolescente , Adulto , Idade de Início , Criança , Pré-Escolar , Análise Mutacional de DNA , Feminino , Testes Genéticos , Genótipo , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Mutação/genética , Testes Neuropsicológicos , Fenótipo , Valor Preditivo dos Testes , Prognóstico , Estrutura Terciária de Proteína/genética , Esclerose Tuberosa/complicações , Esclerose Tuberosa/fisiopatologia , Proteína 1 do Complexo Esclerose Tuberosa , Proteína 2 do Complexo Esclerose Tuberosa
13.
Seizure ; 16(5): 445-53, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17412615

RESUMO

INTRODUCTION: Epilepsy associated with tuberous sclerosis complex (TSC) is drug resistant in more than half of the patients. Epilepsy surgery may be an alternative treatment option, if the epileptogenic tuber can be identified reliably and if seizure reduction is not at the expense of cognitive or other functions. We report the pre-surgical identification of the epileptogenic tuber and post-surgical outcome of patients with TSC in The Netherlands. METHODS: Twenty-five patients underwent the pre-surgical evaluation of the Dutch Comprehensive Epilepsy Surgery Programme, including a detailed seizure history, interictal and ictal video EEG registrations, 3D FLAIR MRI scans and neuropsychological testing. Suitability of the candidates was decided in consensus. Seizure outcome, scored with the Engel classification, and cognition were reassessed at fixed post-surgery intervals. RESULTS: Epilepsy surgery was performed in six patients. At follow-up, four patients had Engel classification 1, two had classification 4. Improved development and behaviour was perceived by the parents of two patients. Epilepsy surgery was not performed in 19 patients because seizures were not captured, ictal onset zones could not be localised or were multiple, interictal EEG, video EEG and MEG results were not concordant, or seizure burden had diminished during decision making. A higher cognition index was found in the surgical patients compared to the non-surgical candidates. CONCLUSIONS: Epilepsy surgery can be performed safely and successfully in patients in whom semiology, interictal EEG, ictal EEG, MEG and the location of tubers are concordant. In other cases the risk of surgery should be weighed against the chance of seizure relief and in case of children subsequent impact on neurodevelopment.


Assuntos
Epilepsia/complicações , Epilepsia/cirurgia , Procedimentos Neurocirúrgicos/métodos , Resultado do Tratamento , Esclerose Tuberosa/complicações , Adolescente , Adulto , Criança , Pré-Escolar , Eletroencefalografia/métodos , Feminino , Seguimentos , Humanos , Imageamento por Ressonância Magnética , Magnetoencefalografia , Masculino , Países Baixos/epidemiologia , Testes Neuropsicológicos , Estudos Retrospectivos
14.
Neurology ; 67(12): 2224-6, 2006 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-17190949

RESUMO

Establishing an etiologic diagnosis in adults with refractory epilepsy and intellectual disability is challenging. We analyzed the phenotype of 14 adults with severe myoclonic epilepsy of infancy. This phenotype comprised heterogeneous seizure types with nocturnal generalized tonic-clonic seizures predominating, mild to severe intellectual disability, and variable motor abnormalities. The diagnosis was suggested by a characteristic evolution of clinical findings in the first years of life. Ten had mutations in SCN1A and one in GABRG2.


Assuntos
Epilepsias Mioclônicas/diagnóstico , Epilepsias Mioclônicas/genética , Proteínas do Tecido Nervoso/genética , Canais de Sódio/genética , Adolescente , Adulto , Diagnóstico Diferencial , Feminino , Predisposição Genética para Doença/genética , Testes Genéticos/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , Canal de Sódio Disparado por Voltagem NAV1.1 , Fenótipo
15.
Neurology ; 63(7): 1293-5, 2004 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-15477556

RESUMO

In a tuberous sclerosis patient with a mutation in the TSC1 tumor suppressor gene, no second-hit mutation was found in a resected cortical tuber. Tuber giant cells showed predominantly nuclear hamartin, cytosolic tuberin, and hyperphosphorylation of S6. Differential accumulation of hamartin and tuberin in separate cellular compartments of giant cells may prevent formation of the hamartin-tuberin complex, resulting in increased S6 phosphorylation. These data provide an alternative mechanism for tuberogenesis.


Assuntos
Proteínas do Tecido Nervoso/metabolismo , Proteínas Repressoras/metabolismo , Proteína S6 Ribossômica/metabolismo , Esclerose Tuberosa/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Córtex Cerebral/metabolismo , Criança , Epilepsia/etiologia , Epilepsia/metabolismo , Feminino , Mutação em Linhagem Germinativa , Humanos , Técnicas Imunoenzimáticas , Fosforilação , Mutação Puntual , Esclerose Tuberosa/complicações , Esclerose Tuberosa/genética , Proteína 1 do Complexo Esclerose Tuberosa , Proteína 2 do Complexo Esclerose Tuberosa , Proteínas Supressoras de Tumor/genética
18.
Clin Neurophysiol ; 113(7): 1025-9, 2002 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-12088695

RESUMO

OBJECTIVES: This study was performed to assess the extent of functional involvement of the affected hemisphere in Sturge Weber syndrome in comparison with the uninvolved hemisphere. To this end beta activity in the electroencephalogram (EEG) was measured, both before and after administration of diazepam intravenously (i.v.). METHODS: In 9 patients asymmetry in beta band activity was studied before and after diazepam administration. Several beta bands and asymmetry parameters were calculated. beta band asymmetries were compared with structural abnormalities (magnetic resonance imaging, MRI). RESULTS: Total beta activity was reduced in the involved hemisphere in all patients after diazepam administration. In 3 patients functional abnormalities were found in brain regions that were structurally intact. CONCLUSIONS: Decreased diazepam-enhanced beta activity in the EEG is a sensitive criterion of functional abnormality. In patients with subtle structural abnormalities diazepam-enhanced EEG may have added value in diagnosing functional involvement and in monitoring disease progression in patients.


Assuntos
Anticonvulsivantes , Ritmo beta/efeitos dos fármacos , Diazepam , Imageamento por Ressonância Magnética , Síndrome de Sturge-Weber/diagnóstico , Adolescente , Anticonvulsivantes/administração & dosagem , Encéfalo/patologia , Criança , Pré-Escolar , Diazepam/administração & dosagem , Feminino , Lateralidade Funcional/fisiologia , Humanos , Lactente , Injeções Intravenosas , Masculino , Síndrome de Sturge-Weber/patologia
19.
Pediatr Neurol ; 23(4): 361-3, 2000 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11068173

RESUMO

We report an infant whose clinical condition deteriorated acutely at 1 month of age because of a subarachnoid hemorrhage with an intracerebellar hematoma. Computed tomographic angiography revealed an aneurysm of the left posterior inferior cerebellar artery. Because of the critical condition of the child and her very young age, the decision to perform surgery was based solely on the computed tomographic angiography findings.


Assuntos
Aneurisma Intracraniano/diagnóstico por imagem , Hemorragia Subaracnóidea/diagnóstico por imagem , Angiografia Cerebral/métodos , Feminino , Humanos , Lactente , Aneurisma Intracraniano/cirurgia , Hemorragia Subaracnóidea/cirurgia , Tomografia Computadorizada por Raios X
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