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1.
Brain ; 142(8): 2303-2318, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31302675

RESUMO

Epilepsy is common in early childhood. In this age group it is associated with high rates of therapy-resistance, and with cognitive, motor, and behavioural comorbidity. A large number of genes, with wide ranging functions, are implicated in its aetiology, especially in those with therapy-resistant seizures. Identifying the more common single-gene epilepsies will aid in targeting resources, the prioritization of diagnostic testing and development of precision therapy. Previous studies of genetic testing in epilepsy have not been prospective and population-based. Therefore, the population-incidence of common genetic epilepsies remains unknown. The objective of this study was to describe the incidence and phenotypic spectrum of the most common single-gene epilepsies in young children, and to calculate what proportion are amenable to precision therapy. This was a prospective national epidemiological cohort study. All children presenting with epilepsy before 36 months of age were eligible. Children presenting with recurrent prolonged (>10 min) febrile seizures; febrile or afebrile status epilepticus (>30 min); or with clusters of two or more febrile or afebrile seizures within a 24-h period were also eligible. Participants were recruited from all 20 regional paediatric departments and four tertiary children's hospitals in Scotland over a 3-year period. DNA samples were tested on a custom-designed 104-gene epilepsy panel. Detailed clinical information was systematically gathered at initial presentation and during follow-up. Clinical and genetic data were reviewed by a multidisciplinary team of clinicians and genetic scientists. The pathogenic significance of the genetic variants was assessed in accordance with the guidelines of UK Association of Clinical Genetic Science (ACGS). Of the 343 patients who met inclusion criteria, 333 completed genetic testing, and 80/333 (24%) had a diagnostic genetic finding. The overall estimated annual incidence of single-gene epilepsies in this well-defined population was 1 per 2120 live births (47.2/100 000; 95% confidence interval 36.9-57.5). PRRT2 was the most common single-gene epilepsy with an incidence of 1 per 9970 live births (10.0/100 000; 95% confidence interval 5.26-14.8) followed by SCN1A: 1 per 12 200 (8.26/100 000; 95% confidence interval 3.93-12.6); KCNQ2: 1 per 17 000 (5.89/100 000; 95% confidence interval 2.24-9.56) and SLC2A1: 1 per 24 300 (4.13/100 000; 95% confidence interval 1.07-7.19). Presentation before the age of 6 months, and presentation with afebrile focal seizures were significantly associated with genetic diagnosis. Single-gene disorders accounted for a quarter of the seizure disorders in this cohort. Genetic testing is recommended to identify children who may benefit from precision treatment and should be mainstream practice in early childhood onset epilepsy.

2.
Am J Hum Genet ; 103(2): 305-316, 2018 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-30057029

RESUMO

Next-generation sequencing combined with international data sharing has enormously facilitated identification of new disease-associated genes and mutations. This is particularly true for genetically extremely heterogeneous entities such as neurodevelopmental disorders (NDDs). Through exome sequencing and world-wide collaborations, we identified and assembled 20 individuals with de novo variants in FBXO11. They present with mild to severe developmental delay associated with a range of features including short (4/20) or tall (2/20) stature, obesity (5/20), microcephaly (4/19) or macrocephaly (2/19), behavioral problems (17/20), seizures (5/20), cleft lip or palate or bifid uvula (3/20), and minor skeletal anomalies. FBXO11 encodes a member of the F-Box protein family, constituting a subunit of an E3-ubiquitin ligase complex. This complex is involved in ubiquitination and proteasomal degradation and thus in controlling critical biological processes by regulating protein turnover. The identified de novo aberrations comprise two large deletions, ten likely gene disrupting variants, and eight missense variants distributed throughout FBXO11. Structural modeling for missense variants located in the CASH or the Zinc-finger UBR domains suggests destabilization of the protein. This, in combination with the observed spectrum and localization of identified variants and the lack of apparent genotype-phenotype correlations, is compatible with loss of function or haploinsufficiency as an underlying mechanism. We implicate de novo missense and likely gene disrupting variants in FBXO11 in a neurodevelopmental disorder with variable intellectual disability and various other features.

3.
Epilepsia ; 59(7): 1372-1380, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29873813

RESUMO

OBJECTIVE: Sudden unexpected death in epilepsy (SUDEP) is a tragic and devastating event for which the underlying pathophysiology remains poorly understood; this study investigated whether abnormalities in heart rate variability (HRV) are linked to SUDEP in patients with epilepsy due to mutations in sodium channel (SCN) genes. METHODS: We retrospectively evaluated HRV in epilepsy patients using electroencephalographic studies to study the potential contribution of autonomic dysregulation to SUDEP risk. We extracted HRV data, in wakefulness and sleep, from 80 patients with drug-resistant epilepsy, including 40 patients with mutations in SCN genes and 40 control patients with non-SCN drug-resistant epilepsy. From the SCN group, 10 patients had died of SUDEP. We compared HRV between SUDEP and non-SUDEP groups, specifically studying awake HRV and sleep:awake HRV ratios. RESULTS: The SUDEP patients had the most severe autonomic dysregulation, showing lower awake HRV and either extremely high or extremely low ratios of sleep-to-awake HRV in a subgroup analysis. A secondary analysis comparing the SCN and non-SCN groups indicated that autonomic dysfunction was slightly worse in the SCN epilepsy group. SIGNIFICANCE: These findings suggest that autonomic dysfunction is associated with SUDEP risk in patients with epilepsy due to sodium channel mutations. The relationship of HRV to SUDEP merits further study; HRV may eventually have potential as a biomarker of SUDEP risk, which would allow for more informed counseling of patients and families, and also serve as a useful outcome measure for research aimed at developing therapies and interventions to reduce SUDEP risk.

4.
Hum Genet ; 2018 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-29740699

RESUMO

Many genetic causes of developmental delay and/or intellectual disability (DD/ID) are extremely rare, and robust discovery of these requires both large-scale DNA sequencing and data sharing. Here we describe a GeneMatcher collaboration which led to a cohort of 13 affected individuals harboring protein-altering variants, 11 of which are de novo, in MED13; the only inherited variant was transmitted to an affected child from an affected mother. All patients had intellectual disability and/or developmental delays, including speech delays or disorders. Other features that were reported in two or more patients include autism spectrum disorder, attention deficit hyperactivity disorder, optic nerve abnormalities, Duane anomaly, hypotonia, mild congenital heart abnormalities, and dysmorphisms. Six affected individuals had mutations that are predicted to truncate the MED13 protein, six had missense mutations, and one had an in-frame-deletion of one amino acid. Out of the seven non-truncating mutations, six clustered in two specific locations of the MED13 protein: an N-terminal and C-terminal region. The four N-terminal clustering mutations affect two adjacent amino acids that are known to be involved in MED13 ubiquitination and degradation, p.Thr326 and p.Pro327. MED13 is a component of the CDK8-kinase module that can reversibly bind Mediator, a multi-protein complex that is required for Polymerase II transcription initiation. Mutations in several other genes encoding subunits of Mediator have been previously shown to associate with DD/ID, including MED13L, a paralog of MED13. Thus, our findings add MED13 to the group of CDK8-kinase module-associated disease genes.

5.
Neuropharmacology ; 132: 3-19, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29037745

RESUMO

The genetic channelopathies are a broad collection of diseases. Many ion channel genes demonstrate wide phenotypic pleiotropy, but nonetheless concerted efforts have been made to characterise genotype-phenotype relationships. In this review we give an overview of the factors that influence genotype-phenotype relationships across this group of diseases as a whole, using specific individual channelopathies as examples. We suggest reasons for the limitations observed in these relationships. We discuss the role of ion channel variation in polygenic disease and highlight research that has contributed to unravelling the complex aetiological nature of these conditions. We focus specifically on the quest for modifying genes in inherited channelopathies, using the voltage-gated sodium channels as an example. Epilepsy related to genetic channelopathy is one area in which precision medicine is showing promise. We will discuss the successes and limitations of precision medicine in these conditions. This article is part of the Special Issue entitled 'Channelopathies.'


Assuntos
Canalopatias/genética , Animais , Canalopatias/metabolismo , Canalopatias/terapia , Humanos
6.
Epilepsia ; 58(11): 1807-1816, 2017 11.
Artigo em Inglês | MEDLINE | ID: mdl-28880996

RESUMO

OBJECTIVE: Dravet syndrome (DS) is a severe developmental and epileptic encephalopathy characterized by the onset of prolonged febrile and afebrile seizures in infancy, and evolving to drug-resistant epilepsy with accompanying cognitive, behavioral, and motor impairment. Most cases are now known to be caused by pathogenic variants in the sodium channel gene SCN1A, but several other genes have also been implicated. This review examines current understanding of the role of non-SCN1A genes in DS, and what is known about phenotypic similarities and differences. We discuss whether these are best thought of as minority causes of DS, or as similar but distinct conditions. METHODS: Based on a review of literature, a list of genes linked to DS was compiled and PubMed was searched for reports of DS-like phenotypes arising from variants in each. Online Mendelian Inheritance in Man (OMIM) was used to identify further reports relevant to each gene. RESULTS: Genes that have been reported to cause DS-like phenotypes include SCN2A, SCN8A, SCN9A, SCN1B, PCDH19, GABRA1, GABRG2, STXBP1, HCN1, CHD2, and KCNA2. Many of these genes, however, appear to be associated with their own, different, clinical picture. Other candidate genes for DS have been reported, but there is currently an insufficient body of literature to support their causative role. SIGNIFICANCE: Although most cases of DS arise from SCN1A variants, numerous other genes cause encephalopathies that are clinically similar. Increasingly, a tendency is noted to define newly described epileptic disorders primarily in genetic terms, with clinical features being linked to genotypes. As genetic diagnosis becomes more readily available, its potential to guide pathophysiologic understanding and therapeutic strategy cannot be ignored. Clinical assessment remains essential; the challenge now is to develop a gene-based taxonomy that complements traditional syndromic classifications, allowing elements of both to inform new approaches to treatment.


Assuntos
Epilepsias Mioclônicas/diagnóstico , Epilepsias Mioclônicas/genética , Mutação/genética , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Humanos , Canal de Sódio Disparado por Voltagem NAV1.2/genética , Canal de Sódio Disparado por Voltagem NAV1.6/genética , Fenótipo , Receptores de GABA-A/genética
7.
Neuropharmacology ; 2017 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-28757052

RESUMO

The Publisher regrets that this article is an accidental duplication of an article that has already been published, https://doi.org/10.1016/j.neuropharm.2017.10.013. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.

8.
Epilepsia ; 58(4): 565-575, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28166369

RESUMO

OBJECTIVE: The phenotype of seizure clustering with febrile illnesses in infancy/early childhood is well recognized. To date the only genetic epilepsy consistently associated with this phenotype is PCDH19, an X-linked disorder restricted to females, and males with mosaicism. The SMC1A gene, which encodes a structural component of the cohesin complex is also located on the X chromosome. Missense variants and small in-frame deletions of SMC1A cause approximately 5% of Cornelia de Lange Syndrome (CdLS). Recently, protein truncating mutations in SMC1A have been reported in five females, all of whom have been affected by a drug-resistant epilepsy, and severe developmental impairment. Our objective was to further delineate the phenotype of SMC1A truncation. METHOD: Female cases with de novo truncation mutations in SMC1A were identified from the Deciphering Developmental Disorders (DDD) study (n = 8), from postmortem testing of an affected twin (n = 1), and from clinical testing with an epilepsy gene panel (n = 1). Detailed information on the phenotype in each case was obtained. RESULTS: Ten cases with heterozygous de novo mutations in the SMC1A gene are presented. All 10 mutations identified are predicted to result in premature truncation of the SMC1A protein. All cases are female, and none had a clinical diagnosis of CdLS. They presented with onset of epileptic seizures between <4 weeks and 28 months of age. In the majority of cases, a marked preponderance for seizures to occur in clusters was noted. Seizure clusters were associated with developmental regression. Moderate or severe developmental impairment was apparent in all cases. SIGNIFICANCE: Truncation mutations in SMC1A cause a severe epilepsy phenotype with cluster seizures in females. These mutations are likely to be nonviable in males.


Assuntos
Proteínas de Ciclo Celular/genética , Proteínas Cromossômicas não Histona/genética , Epilepsia/genética , Mutação/genética , Convulsões/genética , Criança , Pré-Escolar , Eletroencefalografia , Epilepsia/complicações , Feminino , Heterozigoto , Humanos , Masculino , Convulsões/complicações
9.
Curr Opin Neurol ; 30(2): 193-199, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28212175

RESUMO

PURPOSE OF REVIEW: Epilepsy genetics is shifting from the academic pursuit of gene discovery to a clinical discipline based on molecular diagnosis and stratified medicine. We consider the latest developments in epilepsy genetics and review how gene discovery in epilepsy is influencing the clinical classification of epilepsy and informing new therapeutic approaches and drug discovery. RECENT FINDINGS: Recent studies highlighting the importance of mutation in GABA receptors, NMDA receptors, potassium channels, G-protein coupled receptors, mammalian target of rapamycin pathway and chromatin remodeling are discussed. Examples of precision medicine in epilepsy targeting gain-of-function mutations in KCNT1, GRIN2A, GRIN2D and SCN8A are presented. Potential reasons for the paucity of examples of precision medicine for loss-of-function mutations or in non-ion channel epilepsy genes are explored. We highlight how systems genetics and gene network analyses have suggested that pathways disrupted in epilepsy overlap with those of other neurodevelopmental traits including human cognition. We review how network-based computational approaches are now being applied to epilepsy drug discovery. SUMMARY: We are living in an unparalleled era of epilepsy gene discovery. Advances in clinical care from this progress are already materializing through improved clinical diagnosis and stratified medicine. The application of targeted drug repurposing based on single gene defects has shown promise for epilepsy arising from gain-of-function mutations in ion-channel subunit genes, but important barriers remain to translating these approaches to non-ion channel epilepsy genes and loss-of-function mutations. Gene network analysis offers opportunities to discover new pathways for epilepsy, to decipher epilepsy's relationship to other neurodevelopmental traits and to frame a new approach to epilepsy drug discovery.


Assuntos
Epilepsia/genética , Animais , Epilepsia/diagnóstico , Epilepsia/terapia , Estudos de Associação Genética , Humanos , Mutação , Fenótipo , Canais de Potássio/genética
10.
Childs Nerv Syst ; 33(2): 275-280, 2017 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-27848003

RESUMO

PURPOSE: We test the hypothesis that ventriculoperitoneal (VP) shunt insertion significantly increases contralateral positional plagiocephaly. METHODS: We reviewed 339 children who had a VP shunt inserted at Birmingham Children's Hospital between 2006 and 2013, noting laterality of shunt insertion and frontal or occipital position. We ascertained the presence of post-operative positional plagiocephaly using the cranial vault asymmetry index. Multinomial logistic regression modelling was used to examine relationships between plagiocephaly, shunt position, gender and age. Adjusted odds and risk ratios for effect of variables on plagiocephaly were calculated. RESULTS: Children with occipital VP shunts are at significant risk of developing contralateral positional plagiocephaly, particularly in the first 12 months of life. CONCLUSIONS: We recommend careful follow-up and advice regarding head positioning following surgery. There should be consideration for active monitoring to avoid plagiocephaly, including physiotherapy and health visitor interventions. Endoscopic third ventriculostomy in selected cases or anterior shunt placement could be considered. A larger national study would be of interest to evaluate the extent of an otherwise correctable problem.


Assuntos
Plagiocefalia não Sinostótica/cirurgia , Derivação Ventriculoperitoneal/métodos , Adolescente , Fatores Etários , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Recém-Nascido , Modelos Logísticos , Masculino , Estudos Retrospectivos , Fatores Sexuais , Resultado do Tratamento , Ventriculostomia
11.
Arch Dis Child ; 102(7): 639-643, 2017 07.
Artigo em Inglês | MEDLINE | ID: mdl-27986698

RESUMO

OBJECTIVE: To test whether different measuring techniques produce systematic differences in head size that could explain the large head circumferences found in Northern European children compared with the WHO standard. DESIGN: Cross-sectional observational study. SETTING: Scotland, UK. PATIENTS: Study 1: 68 healthy children aged 0.4-18 months from mother and baby groups and a medical students teaching session. Study 2: 81 children aged 0.4 to 25 months from hospital wards and neonatal follow-up clinics. INTERVENTIONS: Study 1: heads measured with plastic tape using both the WHO tight and UK loose technique. Study 2: heads measured using WHO research technique and a metal measuring tape and compared with routinely acquired measurements. MAIN OUTCOME MEASURES: Mean difference in head z-scores using WHO standard between the two methods. RESULTS: The tight technique resulted in a mean (95% CI) z-score difference of 0.41 (0.27 to 0.54, p<0.001) in study 1 and 0.44 (0.36 to 0.53, p<0.001) in study 2. However, the mean WHO measurements in the healthy infants still produced a mean z-score that was two-third of a centile space (0.54 SD (0.28 to 0.79) p<0.001) above the 50th centile. CONCLUSION: The WHO measurement techniques produced significantly lower measures of head size, but average healthy Scottish children still had larger heads than the WHO standard using this method.


Assuntos
Cabeça/anatomia & histologia , Cefalometria/métodos , Pré-Escolar , Estudos Transversais , Europa (Continente)/etnologia , Feminino , Gráficos de Crescimento , Humanos , Lactente , Recém-Nascido , Masculino , Valores de Referência , Escócia/etnologia
12.
J. pediatr. (Rio J.) ; 91(6,supl.1): S67-S77, nov.-dez. 2015. tab
Artigo em Inglês | LILACS | ID: lil-769802

RESUMO

Resumo Objetivos: Analisar a base de evidências atual para o diagnóstico e tratamento das epilepsias da infância e chamar a atenção para as lacunas atuais nessa base de evidências. O foco será os aspectos terapêuticos. A terminologia atual da Liga Internacional contra a Epilepsia (ILAE) será descrita e usada na discussão. A análise chamará a atenção para os recentes avanços em nosso entendimento e no tratamento das epilepsias da infância. Serão discutidas possíveis orientações futuras para as opções de pesquisa e tratamento. Fontes de dados: Trabalhos originais relevantes para o assunto foram obtidos da base de dados MedLine com termos relevantes do MeSH. Os trabalhos relevantes foram lidos e assimilados. Foi usada pesquisa de citações. Resumo dos dados: A epilepsia é uma das maiores causas da carga global de doenças. As epilepsias da infância representam um grupo heterogêneo de doenças. Uma abordagem multiaxial do diagnóstico deve ser feita antes da tomada de decisões de tratamento de qualquer paciente individual. Na maioria dos pacientes, o controle bem-sucedido das crises pode ser obtido com uma única medicação. Contudo, uma minoria significativa desenvolve doença refratária. A cirurgia de epilepsia pode curar um grupo cuidadosamente selecionado desses casos. Conclusões: Ainda existem lacunas significativas na base de evidências de tratamento em diversas áreas de epilepsia da infância. Devem ser envidados esforços multicêntricos concertados para tentar fechar essas lacunas. Uma abordagem médica personalizada pode ajudar a reduzir a proporção de casos refratários de epilepsia da infância no futuro.


Abstract Objectives: To review the current evidence base for the diagnosis and management of the childhood epilepsies and to draw attention to the current gaps in this evidence base. The focus will be on therapeutic aspects. Current International League Against Epilepsy (ILAE) terminology will be described and used throughout the discussion. The review will draw attention to recent advances that have been made in both our understanding and treatment of the childhood epilepsies. Potential future directions for research and treatment options will be discussed. Sources: Original articles relevant to the subject were obtained from the MedLine database using pertinent MeSH terms. Relevant papers were read and assimilated. Citation searching was used. Summary of the findings: Epilepsy is a major cause of global disease burden. Childhood epilepsies are a heterogeneous group of conditions. A multi-axial diagnostic approach should be taken prior to making treatment and management decisions for any individual patient. For the majority of patients, successful control of seizures can be achieved with a single medication. However, a significant minority develops refractory disease. Epilepsy surgery can provide cure for a carefully selected group of these cases. Conclusions: There remain significant gaps the evidence base for treatment in several areas of childhood epilepsy. Concerted multi-center efforts should be made to try to close these gaps. A personalized medicine approach may help to reduce the proportion of refectory cases of childhood epilepsy in future.


Assuntos
Criança , Pré-Escolar , Humanos , Anticonvulsivantes/uso terapêutico , Epilepsia/diagnóstico , Epilepsia/tratamento farmacológico , Eletroencefalografia/métodos , Medicina Baseada em Evidências/tendências
13.
J Pediatr (Rio J) ; 91(6 Suppl 1): S67-77, 2015 Nov-Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26354872

RESUMO

OBJECTIVES: To review the current evidence base for the diagnosis and management of the childhood epilepsies and to draw attention to the current gaps in this evidence base. The focus will be on therapeutic aspects. Current International League Against Epilepsy (ILAE) terminology will be described and used throughout the discussion. The review will draw attention to recent advances that have been made in both our understanding and treatment of the childhood epilepsies. Potential future directions for research and treatment options will be discussed. SOURCES: Original articles relevant to the subject were obtained from the MedLine database using pertinent MeSH terms. Relevant papers were read and assimilated. Citation searching was used. SUMMARY OF THE FINDINGS: Epilepsy is a major cause of global disease burden. Childhood epilepsies are a heterogeneous group of conditions. A multi-axial diagnostic approach should be taken prior to making treatment and management decisions for any individual patient. For the majority of patients, successful control of seizures can be achieved with a single medication. However, a significant minority develops refractory disease. Epilepsy surgery can provide cure for a carefully selected group of these cases. CONCLUSIONS: There remain significant gaps the evidence base for treatment in several areas of childhood epilepsy. Concerted multi-center efforts should be made to try to close these gaps. A personalized medicine approach may help to reduce the proportion of refractory cases of childhood epilepsy in future.


Assuntos
Anticonvulsivantes/uso terapêutico , Epilepsia/diagnóstico , Epilepsia/tratamento farmacológico , Criança , Pré-Escolar , Eletroencefalografia/métodos , Medicina Baseada em Evidências/tendências , Humanos
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