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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.
Epileptic Disord ; 21(S1): 5-12, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31149900

RESUMO

Five pediatric and adult neurologists with clinical and research interests in Encephalopathy related to Status Epilepticus during slow Sleep (ESES) express their opinions on definition, diagnostic assessment and terminology that may be considered for this condition. The aim of this "debate" is to identify aspects in which there is a shared opinion and areas where there are still controversies in the classification and suggest areas which demand further studies and research.

3.
Epileptic Disord ; 21(S1): 88-96, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31180329

RESUMO

We investigated whether Encephalopathy related to Status Epilepticus during slow Sleep (ESES) in childhood was associated with progressive intellectual decline. Participants were identified from the caseload of a single paediatric neurosciences centre and EEG department. A retrospective review of overnight sleep EEG reports (n=2200) over a five-year period identified twenty-two children as having the neurophysiological characteristics of ESES. All had repeat neuropsychological assessment using the WISC-III (UK) and/or WPPSI-R (UK). There was a statistically significant reduction in Full-Scale IQ and Performance IQ across a mean and median time interval of two years. Around a third of the participants showed a clinically significant regression in intellectual functioning evidenced by =>12-point reduction in IQ. These patients were not distinguishable from the rest of the cohort in terms of clinical history, imaging or duration of ESES. The reduction in IQ reflected reduced processing speed, working memory and overall cognitive efficiency. Children with a history of ESES require close monitoring in order to support educational planning and provide families with accurate information about prognosis.

4.
Eur J Paediatr Neurol ; 23(1): 3, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30642533
5.
Seizure ; 64: 45-49, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30554130

RESUMO

PURPOSE: To evaluate the clinical utility of the ambulatory electroencephalogram (AEEG) in children. METHOD: Data from 199 consecutive referrals for a paediatric AEEG were reviewed retrospectively. Information was gathered on various aspects of the referral process, the characteristics of the children referred and the reasons for referral. Clinical utility was calculated as the percentage of cases in which the investigation provided useful information with respect to the question asked of the test. RESULTS: The AEEG was useful in 64.8% cases overall. In 51.4% of cases the reason for referral was to capture events, however the test was only useful in 42.6% of these. The most common reason for an unsuccessful investigation was failure to capture events (55.6%). Suspected encephalopathy with status epilepticus during sleep (ESES) was the indication in a substantial number of cases (38.6%), and the investigation was useful in most of these (97.5%). Technical issues were only responsible for 7 (9.7%) of unsuccessful studies. CONCLUSION: The paediatric AEEG was useful in two thirds of patients. Failure to capture events appears to be the most significant limiting factor. The AEEG is very useful in investigating suspected ESES.


Assuntos
Eletroencefalografia/normas , Epilepsia/diagnóstico , Monitorização Ambulatorial/normas , Sono/fisiologia , Estado Epiléptico/diagnóstico , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos , Adulto Jovem
6.
J Med Genet ; 55(12): 803-813, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30287594

RESUMO

BACKGROUND: Progressive encephalopathy, hypsarrhythmia and optic atrophy (PEHO) has been described as a clinically distinct syndrome. It has been postulated that it is an autosomal recessive condition. However, the aetiology is poorly understood, and the genetic basis of the condition has not been fully elucidated. Our objective was to discover if PEHO syndrome is a single gene disorder. METHOD: Children with PEHO and PEHO-like syndrome were recruited. Clinical, neurological and dysmorphic features were recorded; EEG reports and MRI scans were reviewed. Where possible, exome sequencing was carried out first to seek mutations in known early infantile developmental and epileptic encephalopathy (DEE) genes and then to use an agnostic approach to seek novel candidate genes. We sought intra-interfamilial phenotypic correlations and genotype-phenotype correlations when pathological mutations were identified. RESULTS: Twenty-three children were recruited from a diverse ethnic background, 19 of which were suitable for inclusion. They were similar in many of the core and the supporting features of PEHO, but there was significant variation in MRI and ophthalmological findings, even between siblings with the same mutation. A pathogenic genetic variant was identified in 15 of the 19 children. One further girl's DNA failed analysis, but her two affected sisters shared confirmed variants. Pathogenic variants were identified in seven different genes. CONCLUSIONS: We found significant clinical and genetic heterogeneity. Given the intrafamily variation demonstrated, we question whether the diagnostic criteria for MRI and ophthalmic findings should be altered. We also question whether PEHO and PEHO-like syndrome represent differing points on a clinical spectrum of the DEE. We conclude that PEHO and PEHO-like syndrome are clinically and genetically diverse entities-and are phenotypic endpoints of many severe genetic encephalopathies.

7.
Lancet Child Adolesc Health ; 2(10): 691-693, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30236370
8.
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.

9.
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.

10.
N Engl J Med ; 378(20): 1888-1897, 2018 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-29768152

RESUMO

BACKGROUND: Cannabidiol has been used for treatment-resistant seizures in patients with severe early-onset epilepsy. We investigated the efficacy and safety of cannabidiol added to a regimen of conventional antiepileptic medication to treat drop seizures in patients with the Lennox-Gastaut syndrome, a severe developmental epileptic encephalopathy. METHODS: In this double-blind, placebo-controlled trial conducted at 30 clinical centers, we randomly assigned patients with the Lennox-Gastaut syndrome (age range, 2 to 55 years) who had had two or more drop seizures per week during a 28-day baseline period to receive cannabidiol oral solution at a dose of either 20 mg per kilogram of body weight (20-mg cannabidiol group) or 10 mg per kilogram (10-mg cannabidiol group) or matching placebo, administered in two equally divided doses daily for 14 weeks. The primary outcome was the percentage change from baseline in the frequency of drop seizures (average per 28 days) during the treatment period. RESULTS: A total of 225 patients were enrolled; 76 patients were assigned to the 20-mg cannabidiol group, 73 to the 10-mg cannabidiol group, and 76 to the placebo group. During the 28-day baseline period, the median number of drop seizures was 85 in all trial groups combined. The median percent reduction from baseline in drop-seizure frequency during the treatment period was 41.9% in the 20-mg cannabidiol group, 37.2% in the 10-mg cannabidiol group, and 17.2% in the placebo group (P=0.005 for the 20-mg cannabidiol group vs. placebo group, and P=0.002 for the 10-mg cannabidiol group vs. placebo group). The most common adverse events among the patients in the cannabidiol groups were somnolence, decreased appetite, and diarrhea; these events occurred more frequently in the higher-dose group. Six patients in the 20-mg cannabidiol group and 1 patient in the 10-mg cannabidiol group discontinued the trial medication because of adverse events and were withdrawn from the trial. Fourteen patients who received cannabidiol (9%) had elevated liver aminotransferase concentrations. CONCLUSIONS: Among children and adults with the Lennox-Gastaut syndrome, the addition of cannabidiol at a dose of 10 mg or 20 mg per kilogram per day to a conventional antiepileptic regimen resulted in greater reductions in the frequency of drop seizures than placebo. Adverse events with cannabidiol included elevated liver aminotransferase concentrations. (Funded by GW Pharmaceuticals; GWPCARE3 ClinicalTrials.gov number, NCT02224560 .).


Assuntos
Anticonvulsivantes/administração & dosagem , Canabidiol/administração & dosagem , Síndrome de Lennox Gastaut/tratamento farmacológico , Convulsões/prevenção & controle , Adolescente , Adulto , Anticonvulsivantes/efeitos adversos , Anticonvulsivantes/uso terapêutico , Canabidiol/efeitos adversos , Criança , Pré-Escolar , Relação Dose-Resposta a Droga , Método Duplo-Cego , Quimioterapia Combinada , Humanos , Síndrome de Lennox Gastaut/complicações , Masculino , Pessoa de Meia-Idade , Razão de Chances , Transaminases/sangue , Adulto Jovem
11.
Epileptic Disord ; 20(2): 77-87, 2018 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-29620013

RESUMO

The International League against Epilepsy (ILAE) published in the April 2017 edition of Epilepsia three companion articles on the classification of seizures and the epilepsies. These represent a long-awaited update on the original 1981 and 1989 publications and provide a modern descriptive template. The new classification presents three levels of terminology, involving seizure types, epilepsy types, and syndromes. In this fourth paper, we present an interpretation of these new concepts for people with epilepsy and those who care for them, as well as for young medical doctors not specialized in epilepsy and nurses. Our goal in writing this paper is to ensure that everyone is speaking and understanding the same language, which is fundamental to the optimal management of people with epilepsy.


Assuntos
Epilepsia/classificação , Convulsões/classificação , Cuidadores , Humanos , Médicos , Terminologia como Assunto
14.
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
15.
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
16.
Neurology ; 89(12): 1202-1203, 2017 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-28842451
17.
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.

19.
Epilepsy Behav ; 70(Pt A): 104-109, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28431364

RESUMO

We reviewed the current literature with respect to the humanistic and financial burdens of Dravet Syndrome (DS) on the caregivers of children with DS, in order to (1) identify key unanswered questions or gaps in knowledge that need to be addressed and then, based on these knowledge gaps, (2) propose a research agenda for the scientific community to address in the coming decade. The findings support the conclusion that caring for a child with DS is associated with significant humanistic burden and direct costs. However, due in part to the paucity of studies, as well as the lack of measures of specific burden domains, there remains much that is not known regarding the burden of caregiving for children with DS. To address the significant knowledge gaps in this area, research is needed that will: (1) identify the specific domains of caregivers' lives that are impacted by caring for a child with DS; (2) identify or, if needed, develop measures of caregiving impact in this area; (3) identify the factors that influence DS caregiving burden; (4) develop and evaluate the efficacy of treatments for reducing the negative impact of DS and its comorbidities on DS caregivers; (5) quantify the direct medical costs associated with DS and DS comorbidities and identify the factors that influence these costs; and (6) quantify and fully explore the indirect costs of DS. Research that addresses these goals will provide the empirical foundation needed for improving the quality of life of children with DS and their families.


Assuntos
Pesquisa Biomédica/economia , Cuidadores/economia , Cuidadores/psicologia , Efeitos Psicossociais da Doença , Epilepsias Mioclônicas/economia , Família/psicologia , Pesquisa Biomédica/tendências , Criança , Previsões , Humanos , Qualidade de Vida/psicologia
20.
Epilepsia ; 58(4): 511, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28276059
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