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6.
Neurology ; 92(11): e1238-e1249, 2019 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-30737342

RESUMO

OBJECTIVE: The aim of this study was to expand the spectrum of epilepsy syndromes related to STX1B, encoding the presynaptic protein syntaxin-1B, and establish genotype-phenotype correlations by identifying further disease-related variants. METHODS: We used next-generation sequencing in the framework of research projects and diagnostic testing. Clinical data and EEGs were reviewed, including already published cases. To estimate the pathogenicity of the variants, we used established and newly developed in silico prediction tools. RESULTS: We describe 17 new variants in STX1B, which are distributed across the whole gene. We discerned 4 different phenotypic groups across the newly identified and previously published patients (49 patients in 23 families): (1) 6 sporadic patients or families (31 affected individuals) with febrile and afebrile seizures with a benign course, generally good drug response, normal development, and without permanent neurologic deficits; (2) 2 patients with genetic generalized epilepsy without febrile seizures and cognitive deficits; (3) 13 patients or families with intractable seizures, developmental regression after seizure onset and additional neuropsychiatric symptoms; (4) 2 patients with focal epilepsy. More often, we found loss-of-function mutations in benign syndromes, whereas missense variants in the SNARE motif of syntaxin-1B were associated with more severe phenotypes. CONCLUSION: These data expand the genetic and phenotypic spectrum of STX1B-related epilepsies to a diverse range of epilepsies that span the International League Against Epilepsy classification. Variants in STX1B are protean and contribute to many different epilepsy phenotypes, similar to SCN1A, the most important gene associated with fever-associated epilepsies.

8.
Am J Med Genet A ; 2018 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-30244534

RESUMO

De novo mutations of the TRIM8 gene, which codes for a tripartite motif protein, have been identified using whole exome sequencing (WES) in two patients with epileptic encephalopathy (EE), but these reports were not sufficient to conclude that TRIM8 was a novel gene responsible for EE. Here we report four additional patients presenting with EE and de novo truncating mutations of TRIM8 detected by WES, and give further details of the patient previously reported by the Epi4K consortium. Epilepsy of variable severity was diagnosed in children aged 2 months to 3.5 years of age. All patients had developmental delay of variable severity with no or very limited language, often associated with behavioral anomalies and unspecific facial features or MRI brain abnormalities. The phenotypic variability observed in these patients appeared related to the severity of the epilepsy. One patient presented pharmacoresistant EE with regression, recurrent infections and nephrotic syndrome, compatible with the brain and kidney expression of TRIM8. Interestingly, all mutations were located at the highly conserved C-terminus section of TRIM8. This collaborative study confirms that TRIM8 is a novel gene responsible for EE, possibly associated with nephrotic syndrome. This report brings new evidence on the pathogenicity of TRIM8 mutations and highlights the value of data-sharing to delineate the phenotypic characteristics and biological basis of extremely rare disorders.

9.
Epilepsia ; 59(9): 1635-1642, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30098010

RESUMO

Genomic findings are emerging rapidly in 2 large, closely related epilepsy research consortia: the Epilepsy Phenome/Genome Project and Epi4K. Disclosure of individual results to participants in genomic research is increasingly viewed as an ethical obligation, but strategies for return of results were not included in the design of these consortia, raising complexities in establishing criteria for which results to offer, determining participant preferences, managing the large number of sites involved, and covering associated costs. Here, we describe the challenges faced, alternative approaches considered, and progress to date. Experience from these 2 consortia illustrates the importance, for genomic research in epilepsy and other disorders, of including a specific plan for return of results in the study design, with financial support for obtaining clinical confirmation and providing ongoing support for participants. Participant preferences for return of results should be established at the time of enrollment, and methods for allowing future contacts with participants should be included. In addition, methods should be developed for summarizing meaningful, comprehensible information about findings in the aggregate that participants can access in an ongoing way.

10.
Cell ; 174(3): 505-520, 2018 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-30053424

RESUMO

Although gene discovery in neuropsychiatric disorders, including autism spectrum disorder, intellectual disability, epilepsy, schizophrenia, and Tourette disorder, has accelerated, resulting in a large number of molecular clues, it has proven difficult to generate specific hypotheses without the corresponding datasets at the protein complex and functional pathway level. Here, we describe one path forward-an initiative aimed at mapping the physical and genetic interaction networks of these conditions and then using these maps to connect the genomic data to neurobiology and, ultimately, the clinic. These efforts will include a team of geneticists, structural biologists, neurobiologists, systems biologists, and clinicians, leveraging a wide array of experimental approaches and creating a collaborative infrastructure necessary for long-term investigation. This initiative will ultimately intersect with parallel studies that focus on other diseases, as there is a significant overlap with genes implicated in cancer, infectious disease, and congenital heart defects.

11.
Epilepsia ; 59(1): 37-66, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29247482

RESUMO

The most common forms of acquired epilepsies arise following acute brain insults such as traumatic brain injury, stroke, or central nervous system infections. Treatment is effective for only 60%-70% of patients and remains symptomatic despite decades of effort to develop epilepsy prevention therapies. Recent preclinical efforts are focused on likely primary drivers of epileptogenesis, namely inflammation, neuron loss, plasticity, and circuit reorganization. This review suggests a path to identify neuronal and molecular targets for clinical testing of specific hypotheses about epileptogenesis and its prevention or modification. Acquired human epilepsies with different etiologies share some features with animal models. We identify these commonalities and discuss their relevance to the development of successful epilepsy prevention or disease modification strategies. Risk factors for developing epilepsy that appear common to multiple acute injury etiologies include intracranial bleeding, disruption of the blood-brain barrier, more severe injury, and early seizures within 1 week of injury. In diverse human epilepsies and animal models, seizures appear to propagate within a limbic or thalamocortical/corticocortical network. Common histopathologic features of epilepsy of diverse and mostly focal origin are microglial activation and astrogliosis, heterotopic neurons in the white matter, loss of neurons, and the presence of inflammatory cellular infiltrates. Astrocytes exhibit smaller K+ conductances and lose gap junction coupling in many animal models as well as in sclerotic hippocampi from temporal lobe epilepsy patients. There is increasing evidence that epilepsy can be prevented or aborted in preclinical animal models of acquired epilepsy by interfering with processes that appear common to multiple acute injury etiologies, for example, in post-status epilepticus models of focal epilepsy by transient treatment with a trkB/PLCγ1 inhibitor, isoflurane, or HMGB1 antibodies and by topical administration of adenosine, in the cortical fluid percussion injury model by focal cooling, and in the albumin posttraumatic epilepsy model by losartan. Preclinical studies further highlight the roles of mTOR1 pathways, JAK-STAT3, IL-1R/TLR4 signaling, and other inflammatory pathways in the genesis or modulation of epilepsy after brain injury. The wealth of commonalities, diversity of molecular targets identified preclinically, and likely multidimensional nature of epileptogenesis argue for a combinatorial strategy in prevention therapy. Going forward, the identification of impending epilepsy biomarkers to allow better patient selection, together with better alignment with multisite preclinical trials in animal models, should guide the clinical testing of new hypotheses for epileptogenesis and its prevention.


Assuntos
Lesões Encefálicas/complicações , Modelos Animais de Doenças , Epilepsia/etiologia , Pesquisa Médica Translacional , Animais , Lesões Encefálicas/classificação , Humanos
12.
PLoS Genet ; 13(11): e1007104, 2017 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-29186148

RESUMO

Trio exome sequencing has been successful in identifying genes with de novo mutations (DNMs) causing epileptic encephalopathy (EE) and other neurodevelopmental disorders. Here, we evaluate how well a case-control collapsing analysis recovers genes causing dominant forms of EE originally implicated by DNM analysis. We performed a genome-wide search for an enrichment of "qualifying variants" in protein-coding genes in 488 unrelated cases compared to 12,151 unrelated controls. These "qualifying variants" were selected to be extremely rare variants predicted to functionally impact the protein to enrich for likely pathogenic variants. Despite modest sample size, three known EE genes (KCNT1, SCN2A, and STXBP1) achieved genome-wide significance (p<2.68×10-6). In addition, six of the 10 most significantly associated genes are known EE genes, and the majority of the known EE genes (17 out of 25) originally implicated in trio sequencing are nominally significant (p<0.05), a proportion significantly higher than the expected (Fisher's exact p = 2.33×10-17). Our results indicate that a case-control collapsing analysis can identify several of the EE genes originally implicated in trio sequencing studies, and clearly show that additional genes would be implicated with larger sample sizes. The case-control analysis not only makes discovery easier and more economical in early onset disorders, particularly when large cohorts are available, but also supports the use of this approach to identify genes in diseases that present later in life when parents are not readily available.


Assuntos
Epilepsia/genética , Mutação , Estudos de Casos e Controles , Análise Mutacional de DNA , Feminino , Genes Dominantes , Estudo de Associação Genômica Ampla , Humanos , Masculino , Proteínas Munc18/genética , Canal de Sódio Disparado por Voltagem NAV1.2/genética , Proteínas do Tecido Nervoso/genética , Canais de Potássio/genética , Sequenciamento Completo do Exoma
13.
Am J Hum Genet ; 101(4): 516-524, 2017 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-28942967

RESUMO

Exome sequencing has readily enabled the discovery of the genetic mutations responsible for a wide range of diseases. This success has been particularly remarkable in the severe epilepsies and other neurodevelopmental diseases for which rare, often de novo, mutations play a significant role in disease risk. Despite significant progress, the high genetic heterogeneity of these disorders often requires large sample sizes to identify a critical mass of individuals with disease-causing mutations in a single gene. By pooling genetic findings across multiple studies, we have identified six individuals with severe developmental delay (6/6), refractory seizures (5/6), and similar dysmorphic features (3/6), each harboring a de novo mutation in PPP3CA. PPP3CA encodes the alpha isoform of a subunit of calcineurin. Calcineurin encodes a calcium- and calmodulin-dependent serine/threonine protein phosphatase that plays a role in a wide range of biological processes, including being a key regulator of synaptic vesicle recycling at nerve terminals. Five individuals with de novo PPP3CA mutations were identified among 4,760 trio probands with neurodevelopmental diseases; this is highly unlikely to occur by chance (p = 1.2 × 10-8) given the size and mutability of the gene. Additionally, a sixth individual with a de novo mutation in PPP3CA was connected to this study through GeneMatcher. Based on these findings, we securely implicate PPP3CA in early-onset refractory epilepsy and further support the emerging role for synaptic dysregulation in epilepsy.


Assuntos
Calcineurina/genética , Epilepsia/genética , Mutação , Transtornos do Neurodesenvolvimento/genética , Transmissão Sináptica/fisiologia , Adolescente , Adulto , Calcineurina/metabolismo , Criança , Pré-Escolar , Estudos de Coortes , Epilepsia/patologia , Exoma/genética , Feminino , Humanos , Lactente , Recém-Nascido , Síndrome de Lennox Gastaut/patologia , Masculino , Transtornos do Neurodesenvolvimento/patologia , Análise de Sequência de DNA , Índice de Gravidade de Doença , Espasmos Infantis/genética , Espasmos Infantis/patologia , Adulto Jovem
14.
Hum Genet ; 136(7): 821-834, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-28393272

RESUMO

Pathogenic variants in genes encoding subunits of the spliceosome are the cause of several human diseases, such as neurodegenerative diseases. The RNA splicing process is facilitated by the spliceosome, a large RNA-protein complex consisting of small nuclear ribonucleoproteins (snRNPs), and many other proteins, such as heterogeneous nuclear ribonucleoproteins (hnRNPs). The HNRNPU gene (OMIM *602869) encodes the heterogeneous nuclear ribonucleoprotein U, which plays a crucial role in mammalian development. HNRNPU is expressed in the fetal brain and adult heart, kidney, liver, brain, and cerebellum. Microdeletions in the 1q44 region encompassing HNRNPU have been described in patients with intellectual disability (ID) and other clinical features, such as seizures, corpus callosum abnormalities (CCA), and microcephaly. Recently, pathogenic HNRNPU variants were identified in large ID and epileptic encephalopathy cohorts. In this study, we provide detailed clinical information of five novels and review two of the previously published individuals with (likely) pathogenic de novo variants in the HNRNPU gene including three non-sense and two missense variants, one small intragenic deletion, and one duplication. The phenotype in individuals with variants in HNRNPU is characterized by early onset seizures (6/7), severe ID (6/6), severe speech impairment (6/6), hypotonia (6/7), and central nervous system (CNS) (5/6), cardiac (4/6), and renal abnormalities (3/4). In this study, we broaden the clinical and mutational HNRNPU-associated spectrum, and demonstrate that heterozygous HNRNPU variants cause epilepsy, severe ID with striking speech impairment and variable CNS, cardiac, and renal anomalies.


Assuntos
Epilepsia/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo U/genética , Heterozigoto , Deficiência Intelectual/genética , Idade de Início , Agenesia do Corpo Caloso/genética , Sistema Nervoso Central/anormalidades , Sistema Nervoso Central/patologia , Deleção Cromossômica , Cromossomos Humanos Par 1 , Epilepsia/diagnóstico , Feminino , Variação Genética , Humanos , Lactente , Deficiência Intelectual/diagnóstico , Rim/anormalidades , Masculino , Microcefalia/diagnóstico , Microcefalia/genética , Hipotonia Muscular/diagnóstico , Hipotonia Muscular/genética , Fenótipo , Processamento de RNA , Ribonucleoproteínas Nucleares Pequenas/genética , Convulsões/diagnóstico , Convulsões/genética
16.
Neurology ; 86(16): 1543-51, 2016 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-27009262

RESUMO

There is urgent need for clinical trials of novel interventions to reduce the burden of acute ischemic stroke. A key impediment to such trials is slow recruitment. Since obtaining written informed consent in the setting of acute stroke is especially challenging, some experts have endorsed relaxing the requirement for informed consent by permitting verbal consent or waivers to facilitate recruitment. This systematic review of 36 randomized controlled trials of acute interventions for ischemic stroke assesses whether alternatives to written informed consent are associated with increased recruitment rates. After the exclusion of 2 outlier trials that differed from other trials in conduct and interventions studied, no association was observed on univariable analysis (8.9 participants/month in trials requiring written consent vs 6.1 participants/month in trials with alternatives, p = 0.43) or multivariable analysis (when adjusting for the number of centers, number of countries, and exclusions based on modified Rankin Scale scores). Alternatives to written informed consent in acute stroke trials may enable trial designs that would not be feasible otherwise. However, we did not find evidence that, within traditional trial designs, such alternatives are associated with faster recruitment.


Assuntos
Consentimento Livre e Esclarecido , Seleção de Pacientes , Ensaios Clínicos Controlados Aleatórios como Assunto/métodos , Acidente Vascular Cerebral , Humanos , Acidente Vascular Cerebral/terapia
17.
Epilepsy Behav ; 55: 174-7, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26803428

RESUMO

Psychogenic nonepileptic seizures (PNES) are relatively common, accounting for 5-40% of visits to tertiary epilepsy centers. Inpatient video-electroencephalogram (vEEG) monitoring is the gold standard for diagnosis, but additional positive predictive tools are necessary given vEEG's relatively scarce availability. In this study, we investigated if the number of patient-reported allergies distinguishes between PNES and epilepsy. Excessive allergy-reporting, like PNES, may reflect somatization. Using electronic medical records, ICD-9 codes, and text-identification algorithms to search EEG reports, we identified 905 cases of confirmed PNES and 5187 controls with epilepsy but no PNES. Patients with PNES averaged more self-reported allergies than patients with epilepsy alone (1.93 vs. 1.00, p<0.001). Compared to those with no allergies, each additional allergy linearly increased the percentage of patients with PNES by 2.98% (R(2)=0.71) such that with ≥12 allergies, 12/28 patients (42.8%) had PNES compared to 349/3368 (11.6%) of the population with no allergies (odds ratio=6.49). This relationship remained unchanged with logistic regression analysis. We conclude that long allergy lists may help identify patients with PNES. We hypothesize that a tendency to inaccurately self-report allergies reflects a maladaptive externalization of psychologic distress and that a similar mechanism may be responsible for PNES in some patients with somatic symptom disorder.


Assuntos
Epilepsia/diagnóstico , Hipersensibilidade/complicações , Transtornos Psicofisiológicos/diagnóstico , Adolescente , Adulto , Diagnóstico Diferencial , Eletroencefalografia , Registros Eletrônicos de Saúde , Epilepsia/complicações , Epilepsia/psicologia , Feminino , Humanos , Classificação Internacional de Doenças , Masculino , Pessoa de Meia-Idade , Transtornos Psicofisiológicos/complicações , Transtornos Psicofisiológicos/psicologia , Estudos Retrospectivos , Adulto Jovem
19.
Epilepsia ; 56(11): 1696-9, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26497638

RESUMO

Advances in epilepsy genetics have been rapid, and it is challenging for clinicians on the ground to keep pace with these advances. The International League Against Epilepsy (ILAE) Genetics Commission has thus crafted a new Genetic Literacy series targeted at busy clinicians. Our goal is to help provide a concise, accessible resource on epilepsy genetics for the busy, on-the-ground clinician so that he/she can apply that knowledge at point-of-care to help patients. This new series is grounded in educational theories and evidence to ensure that learning is effective and efficient. We hope that by promoting and encouraging continuing medical education in epilepsy genetics, this eventually translates to better patient management and therefore better patient health outcomes.


Assuntos
Competência Clínica/normas , Epilepsia/genética , Testes Genéticos/normas , Alfabetização em Saúde/normas , Epilepsia/diagnóstico , Testes Genéticos/tendências , Alfabetização em Saúde/tendências , Humanos , Sistemas Automatizados de Assistência Junto ao Leito/normas , Sistemas Automatizados de Assistência Junto ao Leito/tendências
20.
Curr Biol ; 25(17): R742-6, 2015 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-26325130

RESUMO

Our cognitive abilities emerge from the coordinated activity of neurons in the brain. The average human brain contains 86 billion neurons that are richly interconnected through synapses, contact points for electrochemical communication. Patterns of synaptic connectivity create functional ensembles of neurons, called neural circuits, which mediate information processing in the brain. Neural circuits can be deconstructed further into basic motifs ('microcircuits') involving feedforward and feedback connections between different types of neurons that exert excitatory or inhibitory influence. At each level of neural circuitry, the opposing forces of excitation and inhibition are normally held in balance through a variety of homeostatic mechanisms.


Assuntos
Epilepsia/etiologia , Epilepsia/fisiopatologia , Neurônios/fisiologia , Sinapses/fisiologia , Encéfalo , Humanos
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