Clinical phenotypes and genetic features of epilepsy children with MBD5 gene variants / 中华儿科杂志

Objective: To summarize the phenotypes of epilepsy in patients with MBD5 gene variants. Methods: A total of 9 epileptic patients, who were treated in the Department of Pediatrics, Peking University First Hospital from July 2016 to September 2021 and detected with MBD5 gene pathogenic variants, were enrolled. The features of clinical manifestations, electroencephalogram (EEG), and neuroimaging were analyzed retrospectively. Results: Among 9 patients, 6 were male and 3 were female. Age at seizure onset ranged from 5 to 89 months. Multiple seizure types were observed, including generalized tonic clonic seizures (GTCS) in 7 patients, myoclonic seizures in 5 patients, focal seizures in 5 patients, atypical absence seizures in 3 patients, atonic seizures in 2 patients, myoclonus absence seizures in 1 patient, epileptic spasms in 1 patient, and tonic seizures in 1 patient. There were 8 patients with multiple seizure types, 2 patients with sensitivity to fever and 5 patients with clustering of seizures. Two patients had a history of status epilepticus. All patients had developmental delay before seizure onset. Nine patients had obvious language delay, and 6 patients had autism-like manifestations. Five patients had slow background activity in EEG. Interictal EEG showed abnormal discharges in 9 patients. Brain magnetic resonance imaging (MRI) was normal in all patients. A total of 9 epileptic patients carried MBD5 gene variants, all of them were de novo variants. There were MBD5 gene overall heterozygous deletion in 1 patient, large fragment deletions including MBD5 gene in 3 patients and single nucleotide variations (c.300C>A/p.C100X, c.1775delA/p.N592Tfs*29, c.1759C>T/p.Q587X, c.150_151del/p.Lys51Asnfs*6, c.113+1G>C) in 5 patients. The age at last follow-up ranged from 2 years and 9 months to 11 years and 11 months. At the last follow-up, 2 patients were seizure-free for more than 11 months to 4 years 6 months, 7 patients still had seizures. Conclusions: The initial seizure onset in patients with MBD5 gene variants usually occurs in infancy. Most patients have multiple seizure types. The seizures may be fever sensitive and clustered. Developmental delays, language impairments, and autistic behaviors are common. MBD5 gene variants include single nucleotide variations and fragment deletions. Epilepsy associated with MBD5 gene variants is usually refractory.

Analysis of SCN1A gene variants among patients with Dravet syndrome / 中华医学遗传学杂志

OBJECTIVE@#To analyze the clinical features and genetic variants in two patients with Dravet syndrome (DS).@*METHODS@#Peripheral blood samples of the children and their parents were collected for the extraction of genomic DNA and high-throughput sequencing. Suspected variants were confirmed by Sanger sequencing.@*RESULTS@#By high-throughput sequencing, the two children were found to respectively harbor a c.2135delC frameshifting variant in exon 12 and a c.1522G>T nonsense variant in exon 10 of the SCN1A gene. Both variants were predicted to be pathogenic by bioinformatic analysis. Based on the American College of Medical Genetics and Genomics standards and guidelines, the c.2135delC and c.1522G>A variants of the SCN1A gene were predicted to be pathogenic (PVS1+ PS2+ PM2+ PP3).@*CONCLUSION@#The variants of the SCN1A gene probably underlay the DS in the patients. Above finding has enriched the variant spectrum and enabled genetic counseling for their families.

Encefalopatías epilépticas determinadas genéticamente / Genetically determined epileptic encephalopathies

Las encefalopatías epilépticas es un grupo de síndromes epilépticos caracterizados por el deterioro cognitivo más allá de lo esperado debido a la actividad epiléptica. Se caracterizan por presentar resistencia farmacológica grave, electroencefalogramas profundamente anormales, inicio en la niñez temprana, deterioro neurocognitivo, fenotipo variable y resonancia magnética de cerebro usualmente normal. Frecuentemente estos síndromes están genéticamente determinados. Su diagnóstico correcto y oportuno puede contribuir y guiar el consejo médico y terapia adecuada, influyendo así en el pronóstico a corto, mediano y largo plazo. En este artículo se revisan los hallazgos electroencefalográficos, genéticos y opciones terapéuticas más recomendadas, facilitando así la conducta clínica. Las encefalopatías epilépticas incluidas en este artículos abarcan los síndromes de Ohtahara, encefalopatia mioclónica temprana, epilepsia focal migratoria de la infancia, West, Dravet, estado mioclónico en encefalopatías no progresivas, Doose, Lennox-Gastaut, Landau-Kleffner y epilepsia con espiga-onda continuas durante el sueño de onda lenta.

Epileptic encephalopathies is a group of epileptic syndromes characterized by progressive cognitive impairment beyond the expected for the epilepsy activity. They are characterized by severe pharmaco-resistant epilepsy, severely abnormal electroencephalograms, early-age onset, neurocognitve impairment, variable phenotype and usually normal brain MRI. These syndromes are usually genetically determined. A correct and timely diagnosis could help and guide the medical counselling and the correct therapeutic approach improving the short, medium and long term outcomes. In this article we review the electroencephalographic and genetic findings along with the most recommended therapeutic options facilitating the clinical management. We include the following epileptic encephalopathy syndromes: Ohtahara, early myoclonic encephalopathy, epilepsy of infancy with migrating focal seizures, West, Dravet, non-progressive myoclonic status, Doose, Lennox-Gastaut, Landau-Kleffner and continuous spike-wave during sleep epilepsy.

¿Crisis febriles complejas o síndrome de Dravet?: Descripción de 3 casos clínicos / Complex febrile Seizures or Dravet syndrome?: Description of 3 case reports

Introduction: Dravet syndrome (DS) is one of the most intractable forms of epilepsy that begins in infancy. This syndrome is characterized by beginning with complex febrile seizures (FS) in a healthy infant and progresses to refractory epilepsy with psychomotor regression. The detection of a SCN1A mutation encoding the sodium channel can confirm the diagnosis. Objective: To report 3 confirmed cases of genetically DS. Case reports: We describe 3 girls diagnosed with complex FS that started when they were between 2 and 7 months old. FS were frequent, hemi generalized and myoclonic associated with recurrent febrile status epilepticus (SE). Despite FS and SE recurrence, the psychomotor development, electrophysiological studies and magnetic resonance imaging (MRI) of the brain were normal. After a year, they developed afebrile seizures progressing to refractory epilepsy with developmental regression. A molecular study detected SCN1A mutation confirming DS. The specific antiepileptic treatment and prevention of febrile episodes allowed partial control of epilepsy with some recovery of psychomotor skills. Conclusions: The high frequency complex FS associated with recurrent SE in a previously healthy infant should alert about the possibility of DS. Molecular diagnostics helps us to establish a drugs and non-drug therapies treatment, as well as long-term prognosis and genetic counseling.

Introducción: El Síndrome de Dravet (SD) es una de las formas más intratables de epilepsia que debuta en lactantes con convulsiones febriles (CF) complejas recurrentes que evolucionan posteriormente a epilepsia refractaria con regresión psicomotora. La detección de una mutación del canal de Sodio (SCN1A) permite certificar el diagnóstico. Objetivo: Reportar 3 casos de SD confirmados genéticamente. Casos clínicos: Se describen 3 niñas con diagnóstico de CF complejas iniciadas entre los 2 y 7 meses de edad. Las CF eran frecuentes, hemigeneralizadas, mioclónicas asociadas a status epilepticus (SE) febriles recurrentes. A pesar de la recurrencia de CF y SE, tanto el desarrollo psicomotor como los estudios electrofisiológicos y la resonancia magnética (RM) cerebral, fueron normales. Posterior al año iniciaron crisis afebriles que evolucionaron a epilepsia refractaria con regresión del desarrollo. El estudio molecular detectó la mutación SCN1A confirmando SD. El tratamiento antiepiléptico específico y la prevención de cuadros febriles permitieron un control parcial de la epilepsia con recuperación de algunas habilidades psicomotoras. Conclusiones: La alta frecuencia de CF complejas asociadas a SE recurrentes en un lactante previamente sano, debe alertar sobre la posibilidad de un SD. El diagnóstico molecular nos permite instaurar un tratamiento antiepiléptico y terapias no farmacológicas además de un pronóstico a largo plazo y consejería genética.

Gen SCN1A, Epilepsias Genéticas (Sindrome de DRAVET), Correlato Genotipo / Fenotipo / The SCN1A gene, congenital epilepsies (Dravet syndrome), genotype/phenotype correlations

Las mutaciones del Gen SCN1A están asociadas a varios síndromes epilépticos con presentaciones clínicas superpuestas y de variable severidad a saber: Epilepsia Severa Mioclonica de la Infancia o Síndrome de Dravet,Epilepsia Generalizada con Convulsiones Febriles Plus, formas más leves de Sindrome de Dravet, la Epilepsia Intratable con Convulsiones Generalizadas Tonico-Clonicas y raros casos de Migraña familiar. Todas estas formas clínicas representan el 90% de los casos de mutación del gen SCN1A; recientemente se han incluido la Epilepsia Focal y Generalizada Criptogenética, la Mioclónica–Astática, formas del Síndrome de Lennox-Gastaut y la forma severa de Epilepsia Multifocal Infantil (Epilepsia Migratoria o Multifocal Severa de la Infancia). El objetivo de la presentación de estos tres casos de Epilepsia Refractaria Precoz es enfatizar los Fenotipos variables en la evolución de la semiología convulsiva, y del compromiso cognitivo, asociado a genotipos variables (compromiso de alelos diferentes en el mismo Gen). Se debe sospechar compromiso del Gen SCN1A en toda Encefalopatía Epiléptica con convulsiones febriles de comienzo en el 1er año de vida repetidas, en muchas ocasiones, prolongadas o en ramilletes, refractarias al tratamiento médico, con neuroimagenes y EEG normales en el inicio del trastorno convulsivo aunque la regresión psicomotora ocurra años después o las mioclonias estén ausentes y en quienes la vulnerabilidad a la fiebre o a los estados infecciosos leves precipitan convulsiones

Mutations in the SCN1A gene are associated with different epi-lepsy syndromes with overlapping clinical presentations and of variable severity, such as severe myoclonic epilepsy in infancy or Dravet syndrome, generalized epilepsy with febrile seizures plus, milder forms of Dravet syndrome, refractory epilepsy with generalized tonic-clonic seizures, and rare cases of familial migraine. In 90% of all these clinical presentations SCN1A mutations are found. More recently, cryptogenic focal and ge-neralized epilepsy, myoclonic–astatic epilepsy, different types of Lennox-Gastaut syndrome, and the severe form of infantile multifocal epilepsy (migrating partial seizures or severe infanti-le multifocal epilepsy) have also been included. The aim of the presentation of these three cases of early refractory epilepsy was to emphasize the variable phenotypes in the evolution of seizure semiology and the cognitive involvement associated with variable genotypes (involvement of different alleles of the same gene). SCN1A-gene involvement should be suspected in the face of all epileptic encephalopathies...

Crisis febriles simples y complejas, epilepsia generalizada con crisis febriles plus, FIRES y nuevos síndromes / [Simple febrile seizure, complex seizure, generalized epilepsy with febrile seizure plus, FIRES and new syndromes].

Febrile seizures are the most common seizures in childhood. They have been observed in 2-5

of children before the age of 5, but in some populations this figure may increase to 15

. It is a common cause of pediatric hospital admissions and cause of anxiety for parents. Febrile seizures could be the first manifestation of epilepsy. About 13

of epileptic patients have a history of febrile seizure, and 30

have had recurrent febrile seizures. Their phenotypic characteristics allow, in the majority of cases, a classification of the seizure, an elaboration of a prognosis and to assume a specific therapeutic attitude. It is possible to describe a spectrum according to their severity, from the benign simple seizure to the more complex, febrile seizure plus, Dravet’syndrome, and FIRES. During the past decade, molecular genetic studies have contributed to the identification of genetic factors involved in febrile seizure and related disorders, making the necessity of a careful follow up of these patients in order to detect risk factors earlier. We have reviewed the medical literature to update current knowledge of febrile seizures, their prognosis and their relation to new epileptic syndromes.

Dravet's syndrome; a catastrophic epileptic syndrome

It was first described by Charlotte Dravet in 1978 and has been recognized as a syndrome by the International League Against Epilepsy since 1989. It starts in the first year of life frequently with febrile seizures [FS] in an, otherwise, normal infant. This is followed by refractory and mixed type of seizures. [Dravet's syndrome] [DS] previously named severe myoclonic epilepsy of infancy [SMEI], or epilepsy with polymorphic seizures. DS is caused by a mutation in the neuronal sodium channel gene, SCN1A, that is also mutated in generalized epilepsy with FS+ [GEFS+]

Patología médica ocasionada por repetidos de trinucleótidos / Medical pathology occasioned by trinucleotide repeat

Se han descrito diez enfermedades genéticas en donde la alteración es la expansión de repeticiones de trinucleótidos. Existen cuatro tipos de secuencias trinucleotídicas involucradas en expansiones. El tipo, posición en un gen y número de copias en los individuos afectados, varía según la enfermedad. Algunas de estas repeticiones expandibles están relacionadas con sitios frágiles en los cromosomas y cuando se encuentran expandidas existen 2000 o más copias de la secuencia. Otro tipo de secuencias repetidas se localiza en regiones codificadoras de genes relacionados con problemas neurodegenerativos, como el mal de Huntington, atrofia muscular espinobulbar o ataxia espinocerebral tipo 1, en donde presentan expansiones cortas de 60 a 90 copias del trinucleótido en el gen. La expansión continua de repetidos en estos padecimientos puede explicar la anticipación genetíca que caracteriza a estas enfermedades y existe una correlación entre la gravedad de la enfermedad y el número de repetidos. Recientemente se ha demostrado este tipo de expansión en secuencias mayores del tipo minisatélites: En un caso, está relacionada con la epilepsia tipo 1 y en la otra al sitio frágil 16B sensible a Distancia. Esta forma de herencia es importante por su relación con algunas de las enfermedades degenerativas más comunes en los humanos

Myoclonic epilepsy of late onset in trisomy 21

Pacientes com trissomia 21 (T21), com o passar dos anos, sao propensos a desenvolver crises epilépticas parciais concomitantes ao aparecimento de degeneraçao cerebral do tipo Alzheimer. Pacientes com T21 e demência parecem ter o risco maior de apresentarem crises epiléticas que outros pacientes com degeneraçao cerebral do tipo Alzheimer. O caso relatado é de um paciente com T21 com epilepsia de início tardio. A história clínica consiste de crises mioclônicas ao despertar. ocasionais crises generalizadas tônico-clônicas, demência e ponta onda generalizada no EEG. Demência do tipo Alzheimer familial é ligada ao cromossoma 21, bem como epilepsia mioclônica progressiva (tipo Unverricht-Lundborg) Isto sugere que este caso possa representar um tipo distinto de epilepsia mioclônica progressiva, ligado ao cromossoma 21.

Doença de Lafora: uma possibilidade diagnóstica das demências juvenis / Lafora's disease: a possible diagnosis of juvenile dementia

Cinco casos de doença de Lafora säo relatados, dando-se ênfase à seqüência de eventos clínicos que permitiram a suspeita do diagnóstico e o posterior método de comprovaçäo através de exames histopatológicos da pele e fígado. Todos os pacientes iniciaram o quadro clínico com diminuiçäo do rendimento escolar ou distúrbio de memória, a que se seguiram crise convulsivas e mioclonias. Ressalta-se o caráter familiar da doença, a idade de início entre os 12 e 16 anos e a impossibilidade de se atingir um controle adequado das crises, mesmo se utilizando múltiplos esquemas terapêuticos. Säo discutidos os diagnósticos diferenciais do ponto de vista clínico e laboratorial mostrando que casos que se apresentem com esta evoluçäo devem ser submetidos inicialmente a biópsia de pele e, se näo se lograr a caracterizaçäo dos corpos de Lafora nas glândulas sudoríparas, proceder-se-á ao exame do fígado, que foi positivo em quatro das cinco biópsias