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1.
Epilepsia ; 65(5): 1275-1284, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38411300

RESUMO

OBJECTIVE: In pregnancy, it is important to balance the risks of uncontrolled epileptic seizures to the mother and fetus against the potential teratogenic effects of antiseizure medications. Data are limited on pregnancy outcomes among patients taking lacosamide (LCM), particularly when taken as monotherapy. The objective of this analysis was to evaluate the pregnancy outcomes of LCM-exposed pregnancies. METHODS: This analysis included all reports in the UCB Pharma pharmacovigilance database of exposure to LCM during pregnancy from spontaneous sources (routine clinical settings) or solicited reports from interventional clinical studies and noninterventional postmarketing studies. Prospective and retrospective reports were analyzed separately. RESULTS: At the data cutoff (August 31, 2021), there were 202 prospective pregnancy cases with maternal exposure to LCM and known outcomes. Among these cases, 44 (21.8%) patients received LCM monotherapy and 158 (78.2%) received LCM polytherapy. Most patients received LCM during the first trimester (LCM monotherapy: 39 [88.6%]; LCM polytherapy: 143 [90.5%]). From the prospective pregnancy cases with maternal LCM exposure, there were 204 reported outcomes (two twin pregnancies occurred in the polytherapy group). The proportion of live births was 84.1% (37/44) in patients who received LCM as monotherapy, and 76.3% (122/160) for LCM polytherapy. The overall proportion of abortions (for any reason) was 15.9% (7/44) with LCM monotherapy, and 22.5% (36/160) with LCM polytherapy. Congenital malformations were reported in 2.3% (1/44) of known pregnancy outcomes with maternal exposure to LCM monotherapy, and 6.9% (11/160) with polytherapy. SIGNIFICANCE: Our preliminary data do not raise major concerns on the use of LCM during pregnancy. Most pregnancies with LCM exposure resulted in healthy live births, and no new safety issues were identified. These findings should be interpreted with caution, as additional data are needed to fully evaluate the safety profile of LCM in pregnancy.


Assuntos
Anticonvulsivantes , Epilepsia , Lacosamida , Complicações na Gravidez , Resultado da Gravidez , Humanos , Gravidez , Feminino , Lacosamida/efeitos adversos , Lacosamida/uso terapêutico , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/uso terapêutico , Adulto , Complicações na Gravidez/tratamento farmacológico , Complicações na Gravidez/epidemiologia , Resultado da Gravidez/epidemiologia , Epilepsia/tratamento farmacológico , Estudos Prospectivos , Estudos Retrospectivos , Farmacovigilância , Anormalidades Induzidas por Medicamentos/epidemiologia , Anormalidades Induzidas por Medicamentos/etiologia , Adulto Jovem , Recém-Nascido
2.
Epilepsia ; 63(12): 3111-3121, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36082520

RESUMO

OBJECTIVE: Existing gene panels were developed to understand the etiology of epilepsy, and further benefits will arise from an effective pharmacogenomics panel for personalizing therapy and achieving seizure control. Our study assessed the cost-effectiveness of a pharmacogenomics panel for patients with drug-resistant epilepsy, compared with usual care. METHODS: A cost-utility analysis was employed using a discrete event simulation model. The microsimulation model aggregated the costs and benefits of genetically guided treatment versus usual care for 5000 simulated patients. The 10-year model combined data from various sources including genomic databases on prevalence of variants, population-level pharmaceutical claims on antiseizure medications, published long-term therapy retention rates, patient-level cost data, and systematic reviews. Incremental cost per quality-adjusted life-year (QALY) gained was computed. Deterministic and probabilistic sensitivity analyses were undertaken to address uncertainty in model parameters. RESULTS: The mean cost of the genetically guided treatment option was AU$98 199 compared with AU$95 386 for usual care. Corresponding mean QALYs were 4.67 compared with 4.28 for genetically guided and usual care strategies, respectively. The incremental cost per QALY gained was AU$7381. In probabilistic sensitivity analyses, the incremental cost per QALY gained was AU$6321 (95% uncertainty interval = AU$3604-AU$9621), with a 100% likelihood of being cost-effective in the Australian health care system. The most influential drivers of the findings were the monthly health care costs associated with reduced seizures, costs when seizures continued, and the quality-of-life estimates under genetically guided and usual care strategies. SIGNIFICANCE: This early economic evaluation of a pharmacogenomics panel to guide treatment for drug-resistant epilepsy could potentially be cost-effective in the Australian health care system. Clinical trial evidence is necessary to confirm these findings.


Assuntos
Epilepsia , Qualidade de Vida , Humanos , Análise Custo-Benefício , Austrália , Convulsões
3.
Ann Neurol ; 75(5): 782-7, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24585383

RESUMO

We recently identified DEPDC5 as the gene for familial focal epilepsy with variable foci and found mutations in >10% of small families with nonlesional focal epilepsy. Here we show that DEPDC5 mutations are associated with both lesional and nonlesional epilepsies, even within the same family. DEPDC5-associated malformations include bottom-of-the-sulcus dysplasia (3 members from 2 families), and focal band heterotopia (1 individual). DEPDC5 negatively regulates the mammalian target of rapamycin (mTOR) pathway, which plays a key role in cell growth. The clinicoradiological phenotypes associated with DEPDC5 mutations share features with the archetypal mTORopathy, tuberous sclerosis, raising the possibility of therapies targeted to this pathway.


Assuntos
Encéfalo/anormalidades , Epilepsias Parciais/diagnóstico , Epilepsias Parciais/genética , Mutação/genética , Proteínas Repressoras/genética , Serina-Treonina Quinases TOR/genética , Adulto , Criança , Feminino , Proteínas Ativadoras de GTPase , Humanos , Masculino , Linhagem , Adulto Jovem
4.
Front Glob Womens Health ; 5: 1363470, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38933454

RESUMO

Epilepsy, is a serious neurological condition, characterized by recurring, unprovoked seizures and affects over 50 million people worldwide. Epilepsy has an equal prevalence in males and females, and occurs throughout the life span. Women with epilepsy (WWE) present with unique challenges due to the cyclical fluctuation of sex steroid hormone concentrations during their life course. These shifts in sex steroid hormones and their metabolites are intricately intertwined with seizure susceptibility and affect epilepsy during the life course of women in a complex manner. Here we present a review encompassing neurosteroids-steroids that act on the brain regardless of their site of synthesis in the body; the role of neurosteroids in women with epilepsy through their life-course; exogenous neurosteroid trials; and future research directions. The focus of this review is on progesterone and its derived neurosteroids, given the extensive basic research that supports their role in modulating neuronal excitability.

5.
Sci Rep ; 14(1): 7717, 2024 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-38565608

RESUMO

Despite the significant advances in understanding the genetic architecture of epilepsy, many patients do not receive a molecular diagnosis after genomic testing. Re-analysing existing genomic data has emerged as a potent method to increase diagnostic yields-providing the benefits of genomic-enabled medicine to more individuals afflicted with a range of different conditions. The primary drivers for these new diagnoses are the discovery of novel gene-disease and variants-disease relationships; however, most decisions to trigger re-analysis are based on the passage of time rather than the accumulation of new knowledge. To explore how our understanding of a specific condition changes and how this impacts re-analysis of genomic data from epilepsy patients, we developed Vigelint. This approach combines the information from PanelApp and ClinVar to characterise how the clinically relevant genes and causative variants available to laboratories change over time, and this approach to five clinical-grade epilepsy panels. Applying the Vigelint pipeline to these panels revealed highly variable patterns in new, clinically relevant knowledge becoming publicly available. This variability indicates that a more dynamic approach to re-analysis may benefit the diagnosis and treatment of epilepsy patients. Moreover, this work suggests that Vigelint can provide empirical data to guide more nuanced, condition-specific approaches to re-analysis.


Assuntos
Epilepsia , Humanos , Epilepsia/diagnóstico , Epilepsia/genética , Genômica , Testes Genéticos
6.
N Engl J Med ; 363(14): 1335-40, 2010 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-20879882

RESUMO

De novo mutations are a cause of sporadic disease, but little is known about the developmental timing of such mutations. We studied concordant and discordant monozygous twins with de novo mutations in the sodium channel α1 subunit gene (SCN1A) causing Dravet's syndrome, a severe epileptic encephalopathy. On the basis of our findings and the literature on mosaic cases, we conclude that de novo mutations in SCN1A may occur at any time, from the premorula stage of the embryo (causing disease in the subject) to adulthood (with mutations in the germ-line cells of parents causing disease in offspring).


Assuntos
Epilepsias Mioclônicas/genética , Mutação , Proteínas do Tecido Nervoso/genética , Canais de Sódio/genética , Gêmeos Monozigóticos/genética , Adulto , Feminino , Mutação da Fase de Leitura , Marcadores Genéticos , Mutação em Linhagem Germinativa , Humanos , Lactente , Mutagênese , Canal de Sódio Disparado por Voltagem NAV1.1 , Reação em Cadeia da Polimerase , Análise de Sequência de DNA , Fatores de Tempo
7.
Stem Cell Res ; 60: 102673, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35074713

RESUMO

In this paper, we describe the generation and validation of human induced pluripotent stem cell (hiPSC) lines from peripheral blood mononuclear cells (PBMCs) from 6 epilepsy patients using a non-integrative Sendai virus vector. These human cellular models will enable patient-specific drug screening to improve outcomes for individuals with this disorder.


Assuntos
Epilepsia , Células-Tronco Pluripotentes Induzidas , Diferenciação Celular , Reprogramação Celular , Avaliação Pré-Clínica de Medicamentos , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Leucócitos Mononucleares , Vírus Sendai
8.
J Clin Med ; 11(14)2022 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-35888005

RESUMO

BACKGROUND: The genomic era has led to enormous progress in clinical care and a multi-disciplinary team (MDT) approach is imperative for integration of genomics into epilepsy patient care. METHODS: The MDT approach involved patient selection, genomic testing choice, variant discussions and return of results. Genomics analysis included cytogenomic testing and whole exome sequencing (WES). Neurologist surveys were undertaken at baseline and after genomic testing to determine if genomic diagnoses would alter their management, and if there was a change in confidence in genomic testing and neurologist perceptions of the MDT approach. RESULTS: The total diagnostic yield from all genomic testing was 17% (11/66), with four diagnoses from cytogenomic analyses. All chromosomal microarray (CMA) diagnoses were in patients seen by adult neurologists. Diagnostic yield for WES was 11% (7/62). The most common gene with pathogenic variants was DCX, reported in three patients, of which two were mosaic. The genomic diagnosis impacted management in 82% (9/11). There was increased confidence with integrating genomics into clinical care (Pearson chi square = 83, p = 0.004) and qualitative comments were highly supportive of the MDT approach. CONCLUSIONS: We demonstrated diagnostic yield from genomic testing, and the impact on management in a cohort with drug-resistant epilepsy. The MDT approach increased confidence in genomic testing and neurologists valued the input from this approach. The utility of CMA was demonstrated in epilepsy patients seen by adult neurologists as was the importance of considering mosaicism for previously undiagnosed patients.

9.
Am J Hum Genet ; 82(3): 673-84, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18308289

RESUMO

Action myoclonus-renal failure syndrome (AMRF) is an autosomal-recessive disorder with the remarkable combination of focal glomerulosclerosis, frequently with glomerular collapse, and progressive myoclonus epilepsy associated with storage material in the brain. Here, we employed a novel combination of molecular strategies to find the responsible gene and show its effects in an animal model. Utilizing only three unrelated affected individuals and their relatives, we used homozygosity mapping with single-nucleotide polymorphism chips to localize AMRF. We then used microarray-expression analysis to prioritize candidates prior to sequencing. The disorder was mapped to 4q13-21, and microarray-expression analysis identified SCARB2/Limp2, which encodes a lysosomal-membrane protein, as the likely candidate. Mutations in SCARB2/Limp2 were found in all three families used for mapping and subsequently confirmed in two other unrelated AMRF families. The mutations were associated with lack of SCARB2 protein. Reanalysis of an existing Limp2 knockout mouse showed intracellular inclusions in cerebral and cerebellar cortex, and the kidneys showed subtle glomerular changes. This study highlights that recessive genes can be identified with a very small number of subjects. The ancestral lysosomal-membrane protein SCARB2/LIMP-2 is responsible for AMRF. The heterogeneous pathology in the kidney and brain suggests that SCARB2/Limp2 has pleiotropic effects that may be relevant to understanding the pathogenesis of other forms of glomerulosclerosis or collapse and myoclonic epilepsies.


Assuntos
Cromossomos Humanos Par 4/genética , Genes Recessivos , Glomerulonefrite/genética , Proteínas de Membrana Lisossomal/genética , Epilepsias Mioclônicas Progressivas/genética , Receptores Depuradores/genética , Animais , Córtex Cerebelar/patologia , Mapeamento Cromossômico , Expressão Gênica , Ligação Genética , Genótipo , Glomerulonefrite/patologia , Humanos , Camundongos , Camundongos Knockout , Epilepsias Mioclônicas Progressivas/patologia , Análise de Sequência com Séries de Oligonucleotídeos
10.
Stem Cell Res ; 56: 102564, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34649201

RESUMO

Epilepsy is a common neurological disorder characterized by seizures. Unfortunately, 30-40% of all epilepsy patients are resistant to at least two or more anti-seizure medications. Attempts to treat these patients and prevent further seizures necessitates multiple drug trials for the patient. Here we describe the generation and validation of induced pluripotent stem cell (iPSC) lines from peripheral blood mononuclear cells (PBMCs) from 3 drug responsive and 3 drug resistant patients, using a non-integrative Sendai virus vector. These lines can be used to generate 2D and 3D patient-specific human cellular models that will enable personalised drug screening and pharmacogenomic studies.


Assuntos
Epilepsia , Células-Tronco Pluripotentes Induzidas , Preparações Farmacêuticas , Diferenciação Celular , Reprogramação Celular , Epilepsia/tratamento farmacológico , Humanos , Leucócitos Mononucleares
11.
Pharmacogenomics ; 22(4): 225-234, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33666520

RESUMO

Evaluating genes involved in the pharmacodynamics and pharmacokinetics of epilepsy drugs is critical to better understand pharmacoresistant epilepsy. We reviewed the pharmacogenetics literature on six antiseizure medicines (carbamazepine, perampanel, lamotrigine, levetiracetam, sodium valproate and zonisamide) and compared the genes found with those present on epilepsy gene panels using a functional annotation pathway analysis. Little overlap was found between the two gene lists; pharmacogenetic genes are mainly involved in detoxification processes, while epilepsy panel genes are involved in cell signaling and gene expression. Our work provides support for a specific pharmacoresistant epilepsy gene panel to assist antiseizure medicine selection, enabling personalized approaches to treatment. Future efforts will seek to include this panel in genomic analyses of pharmacoresistant patients, to determine clinical utility and patient treatment responses.


Assuntos
Epilepsia Resistente a Medicamentos/tratamento farmacológico , Epilepsia Resistente a Medicamentos/genética , Farmacogenética , Anticonvulsivantes/uso terapêutico , Humanos
12.
Epilepsy Res ; 156: 106163, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31310899

RESUMO

OBJECTIVE: The aetiology of self-limited epilepsy with centro-temporal spikes (SECTS) remains controversial and a strong genetic basis has long been presumed. The discordant monozygotic twin (MZ) model controls for shared genetic and environmental factors, enabling focus on the potential role of the non-shared environment. METHODS: DNA methylation data was acquired from DNA extracted from three discordant MZ twin pairs, from both new born blood spots before epilepsy onset, and blood samples taken after epilepsy onset. An epigenome-wide analysis was performed, using the Illumina Infinium EPIC array. Differentially methylated regions (DMR) were identified using the bumphunter package in R. Comparative analyses were undertaken at the two different time points as well as a combined analysis independent of time. RESULTS: Many of the top DMR-associated genes have previously been described in neurodevelopmental disorders. The LYPD8 gene was associated with a top-ranked DMR both at birth and across the two time points. CONCLUSION: We have demonstrated the novel utility of the longitudinal, discordant MZ twin model, to facilitate a deeper appreciation of the complex neurobiology of SECTS. The genetic architecture of SECTS is complex and is likely to involve an interplay between genes and environment, in part mediated by epigenetics.


Assuntos
Metilação de DNA/genética , Epigênese Genética/genética , Epilepsia/genética , Criança , Meio Ambiente , Feminino , Estudo de Associação Genômica Ampla , Humanos , Masculino , Gêmeos Monozigóticos/genética
13.
Epigenomics ; 11(8): 951-968, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31166810

RESUMO

Aim: Epilepsy is a common neurological disorder characterized by recurrent seizures. We performed epigenetic analyses between and within 15 monozygotic (MZ) twin pairs discordant for focal or generalized epilepsy. Methods: DNA methylation analysis was performed using Illumina Infinium MethylationEPIC arrays, in blood and buccal samples. Results: Differentially methylated regions between epilepsy types associated with PM20D1 and GFPT2 genes in both tissues. Within MZ discordant twin pairs, differentially methylated regions associated with OTX1 and ARID5B genes for generalized epilepsy and TTC39C and DLX5 genes for focal epilepsy. Conclusion: This is the first epigenome-wide association study, utilizing the discordant MZ co-twin model, to deepen our understanding of the neurobiology of epilepsy.


Assuntos
Epigênese Genética , Epilepsia/genética , Genoma Humano/genética , Gêmeos Monozigóticos/genética , Adulto , Idoso , Estudos de Coortes , Metilação de DNA , Epigenômica , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Adulto Jovem
14.
Epilepsia ; 49(9): 1546-54, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18435749

RESUMO

PURPOSE: To identify genes involved in idiopathic absence epilepsies by analyzing gene expression using a monozygotic (MZ) twin design. METHODS: Genome-wide gene expression in lymphoblastoid cell lines (LCLs) was determined using microarrays derived from five discordant and four concordant MZ twin pairs with idiopathic absence epilepsies and five unaffected MZ twin pairs. Gene expression was analyzed using three strategies: discordant MZ twins were compared as matched pairs, MZ twins concordant for epilepsy were compared to control MZ twins, and a singleton design of affected versus unaffected MZ twin individuals was used irrespective of twin pairing. An overlapping gene list was generated from these analyses. Dysregulation of genes recognized from the microarray experiment was validated using quantitative real time PCR (qRT-PCR) in the twin sample and in an independent sample of 18 sporadic absence cases and 24 healthy controls. RESULTS: Sixty-five probe sets were identified from the three combined microarray analysis strategies. Sixteen genes were chosen for validation and nine of these genes confirmed by qRT-PCR in the twin sample. Differential expression for EGR1 (an immediate early gene) and RCN2 (coding for the calcium-binding protein Reticulocalbin 2) were reconfirmed by qRT-PCR in the independent sample. DISCUSSION: Using a unique sample of discordant MZ twins, our study identified genes with altered expression, which suggests novel mechanisms in idiopathic absence epilepsy. Dysregulation of EGR1 and RCN2 is implicated in idiopathic absence epilepsy.


Assuntos
Proteínas de Ligação ao Cálcio/genética , Proteína 1 de Resposta de Crescimento Precoce/genética , Epilepsia Tipo Ausência/diagnóstico , Epilepsia Tipo Ausência/genética , Expressão Gênica/genética , Gêmeos Monozigóticos/genética , Adulto , Anticonvulsivantes/uso terapêutico , Linhagem Celular Tumoral/patologia , Epilepsia Tipo Ausência/tratamento farmacológico , Feminino , Humanos , Masculino , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Ácido Valproico/uso terapêutico
15.
Twin Res Hum Genet ; 11(6): 634-40, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19016620

RESUMO

Adverse events during the perinatal period have traditionally been thought to contribute to the risk of febrile seizures although an association has not been found in large epidemiological studies. Disease-discordant twins provide a means to assess the role of non-shared environmental factors while matching for confounding factors and avoiding difficulties of epidemiological studies in singletons. This study aimed to examine the association of obstetric events and febrile seizures in a community-based twin study. Twenty-one twin pairs discordant for febrile seizures were ascertained from a community-based twin register. Obstetric events were scored using the McNeil-Sjöström Scale for Obstetric Complications and expressed as a summary score (OC score). The frequency of individual obstetric events in affected and unaffected twins, the within-pair differences in OC scores and other markers of perinatal risk including birthweight, birth order and Apgar scores were examined. No significant difference was found in the frequency of individual obstetric events, nor in OC scores between affected and unaffected twins. No differences in birth weight, birth order, 1- or 5-minute Apgar scores were observed. Our results confirm previous findings that obstetric events are not associated with the risk of febrile seizures.


Assuntos
Complicações na Gravidez/genética , Convulsões Febris/genética , Gêmeos/genética , Adolescente , Criança , Pré-Escolar , Feminino , Hospitais Comunitários , Humanos , Lactente , Masculino , Gravidez , Sistema de Registros , Fatores de Risco
16.
Neurology ; 89(12): 1210-1219, 2017 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-28842445

RESUMO

OBJECTIVE: Following our original description of generalized epilepsy with febrile seizures plus (GEFS+) in 1997, we analyze the phenotypic spectrum in 409 affected individuals in 60 families (31 new families) and expand the GEFS+ spectrum. METHODS: We performed detailed electroclinical phenotyping on all available affected family members. Genetic analysis of known GEFS+ genes was carried out where possible. We compared our phenotypic and genetic data to those published in the literature over the last 19 years. RESULTS: We identified new phenotypes within the GEFS+ spectrum: focal seizures without preceding febrile seizures (16/409 [4%]), classic genetic generalized epilepsies (22/409 [5%]), and afebrile generalized tonic-clonic seizures (9/409 [2%]). Febrile seizures remains the most frequent phenotype in GEFS+ (178/409 [44%]), followed by febrile seizures plus (111/409 [27%]). One third (50/163 [31%]) of GEFS+ families tested have a pathogenic variant in a known GEFS+ gene. CONCLUSION: As 37/409 (9%) affected individuals have focal epilepsies, we suggest that GEFS+ be renamed genetic epilepsy with febrile seizures plus rather than generalized epilepsy with febrile seizures plus. The phenotypic overlap between GEFS+ and the classic generalized epilepsies is considerably greater than first thought. The clinical and molecular data suggest that the 2 major groups of generalized epilepsies share genetic determinants.


Assuntos
Epilepsias Parciais/fisiopatologia , Epilepsia Generalizada/fisiopatologia , Convulsões Febris/fisiopatologia , Adolescente , Adulto , Idade de Início , Criança , Pré-Escolar , Epilepsias Parciais/genética , Epilepsia Generalizada/genética , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Convulsões Febris/genética , Adulto Jovem
17.
Clin Neurophysiol ; 114(9): 1738-43, 2003 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-12948804

RESUMO

OBJECTIVE: To characterize the electroencephalographic (EEG) findings in patients with Kufs disease, the adult autosomal recessive form of neuronal ceroid-lipofuscinosis. METHODS: We reviewed the EEG findings in 5 patients with biopsy-proven Kufs disease from our institution and 14 case reports of Kufs disease in the literature. The criteria used for patient inclusion were clinical evidence of a progressive neurodegenerative disorder, biopsy-proven evidence of Kufs disease, and EEG recordings during the course of the illness. RESULTS: One patient had phenotype A with generalized atypical spike and slow wave complexes and marked photoparoxysmal responses, particularly at low flash frequencies. Three patients had phenotype B with generalized slowing. One patient in the miscellaneous category showed focal sharp and spike waves and quasi-periodic slow waves maximal over anterior regions of the head. Review of the literature identified 14 case reports that met the inclusion criteria. CONCLUSIONS: The inheritance, mechanism, and manifestations of Kufs disease are not well understood. EEG findings may guide clinicians toward a confirmatory pathological diagnosis and distinguish various phenotypes of this disorder. SIGNIFICANCE: The EEG may assist in the diagnosis of Kufs disease.


Assuntos
Eletroencefalografia , Lipofuscinoses Ceroides Neuronais/fisiopatologia , Adulto , Biópsia , Córtex Cerebral , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Lipofuscinoses Ceroides Neuronais/classificação , Lipofuscinoses Ceroides Neuronais/diagnóstico , Testes Neuropsicológicos
18.
Epileptic Disord ; 6(2): 89-95, 2004 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-15246953

RESUMO

AIMS: Scalp-EEG interictal epileptiform discharges (IEDs) may be less predictive of the outcome of frontal lobe epilepsy surgery than of temporal lobe epilepsy surgery. We identified factors associated with the location of scalp-EEG IEDs in intractable frontal lobe epilepsy. METHODS: Ten factors were assessed in a retrospective review of 53 patients with either concordant (frontal lobe seizure focus) or discordant (generalized or outside frontal seizure focus) IED or both, who had excellent surgical outcomes. The Fisher exact test and the Wilcoxon rank sum test determined statistically significant associations. RESULTS: Thirty-six patients (68%) had concordant IED, 24 (45%) discordant IED, and 17 (32%) both. Younger age at onset was significantly associated with discordant IED (mean, 7.5 years versus 17 years for patients without discordant IED; P < 0.01), whereas duration of epilepsy was not. Seizure foci at the frontal convexity were associated with concordant IED. About 72% of patients with a convexity seizure focus had concordant IED, compared with only 33% of patients with mesial frontal foci having concordant IED (P = 0.06). CONCLUSIONS: Early seizure onset in intractable frontal lobe epilepsy is associated with IEDs discordant with seizure focus. Frontal convexity seizure foci are more likely than mesial frontal seizure foci to be associated with concordant discharges.


Assuntos
Eletroencefalografia , Epilepsia do Lobo Frontal/diagnóstico , Adolescente , Adulto , Criança , Diagnóstico Diferencial , Epilepsia do Lobo Frontal/cirurgia , Feminino , Seguimentos , Humanos , Masculino , Procedimentos Neurocirúrgicos/métodos , Estudos Retrospectivos , Couro Cabeludo , Índice de Gravidade de Doença , Cirurgia Vídeoassistida
19.
Neurology ; 83(12): 1042-8, 2014 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-25107880

RESUMO

OBJECTIVE: Analysis of twins with epilepsy to explore the genetic architecture of specific epilepsies, to evaluate the applicability of the 2010 International League Against Epilepsy (ILAE) organization of epilepsy syndromes, and to integrate molecular genetics with phenotypic analyses. METHODS: A total of 558 twin pairs suspected to have epilepsy were ascertained from twin registries (69%) or referral (31%). Casewise concordance estimates were calculated for epilepsy syndromes. Epilepsies were then grouped according to the 2010 ILAE organizational scheme. Molecular genetic information was utilized where applicable. RESULTS: Of 558 twin pairs, 418 had confirmed seizures. A total of 534 twin individuals were affected. There were higher twin concordance estimates for monozygotic (MZ) than for dizygotic (DZ) twins for idiopathic generalized epilepsies (MZ = 0.77; DZ = 0.35), genetic epilepsy with febrile seizures plus (MZ = 0.85; DZ = 0.25), and focal epilepsies (MZ = 0.40; DZ = 0.03). Utilizing the 2010 ILAE scheme, the twin data clearly demonstrated genetic influences in the syndromes designated as genetic. Of the 384 tested twin individuals, 10.9% had mutations of large effect in known epilepsy genes or carried validated susceptibility alleles. CONCLUSIONS: Twin studies confirm clear genetic influences for specific epilepsies. Analysis of the twin sample using the 2010 ILAE scheme strongly supported the validity of grouping the "genetic" syndromes together and shows this organizational scheme to be a more flexible and biologically meaningful system than previous classifications. Successful selected molecular testing applied to this cohort is the prelude to future large-scale next-generation sequencing of epilepsy research cohorts. Insights into genetic architecture provided by twin studies provide essential data for optimizing such approaches.


Assuntos
Epilepsias Parciais/genética , Epilepsia Generalizada/genética , Convulsões Febris/genética , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética , Estudos de Coortes , Epilepsia/genética , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Síndrome
20.
Epilepsy Res ; 105(1-2): 103-9, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23522981

RESUMO

PURPOSE: Febrile seizures (FS) are the most common seizure syndrome. A strong genetic component has been well established through family and twin studies; however, such studies have not examined the genetics of different FS types (simple, complex, febrile status epilepticus) and sub-syndromes (true FS, febrile seizures plus (FS+), 'FS with later epilepsy'). Here we used a community-based twin sample to analyze genetic factors within different FS subtypes and FS syndromes. METHODS: Twin pairs were ascertained from the twin database of the Epilepsy Research Centre. A retrospective chart review was conducted and follow-up attempted for all subjects. Casewise concordance values were calculated for the different subgroups and intra-pair variation was analyzed. KEY FINDINGS: One hundred and seventy-nine twin pairs with FS were identified. Overall casewise concordance for FS in monozygotic (MZ) twins (0.62) was greater than in dizygotic (DZ) twins (0.16, p<0.0001). A greater concordance amongst MZ pairs than DZ twin pairs was also observed for all FS subtypes and FS sub-syndromes, particularly in twins with FS+. Within concordant MZ pairs, we did not observe the co-occurrence of FS and FS+. SIGNIFICANCE: These results suggest a strong genetic contribution to different FS subtypes and sub-syndromes. They also support the existence of distinct genetic factors for different FS subtypes and sub-syndromes, especially FS+. This information is important for the strategic planning of next generation sequencing studies of febrile seizures.


Assuntos
Doenças em Gêmeos/genética , Convulsões Febris/genética , Gêmeos Dizigóticos/genética , Gêmeos Monozigóticos/genética , Criança , Pré-Escolar , Doenças em Gêmeos/diagnóstico , Doenças em Gêmeos/epidemiologia , Feminino , Seguimentos , Humanos , Lactente , Masculino , Sistema de Registros , Estudos Retrospectivos , Convulsões Febris/diagnóstico , Convulsões Febris/epidemiologia
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