Tratamientos empleados para el síndrome de Dravet / Treatments used for Dravet syndrome / Tratamentos usados para a síndrome de Dravet

Se estima que el síndrome de Dravet (SD) es una encefalopatía epiléptica y de desarrollo grave, que ocurre en 1 de cada 15000 nacidos vivos. Se caracteriza por una epilepsia resistente a los medicamentos que se presenta en el primer año de vida con convulsiones prolongadas acompañadas de fiebre o cambios de temperatura, a menudo de naturaleza hemiclónica, seguidas de convulsiones no provocadas de diversos tipos. Objetivo. Describir los tratamientos empleados para el Síndrome de Dravet. Metodología. Se realizó una revisión sistemática. Para ello, se ejecutó una búsqueda en múltiples bases de datos, como Pubmed, Dialnet, Sciencedirect, Scielo y Scopus. La búsqueda se limitó a los artículos publicados desde el año 2017 hasta el 2022. Después de recopilar los artículos, se aplicaron varios criterios de filtrado para asegurarse de que sólo se incluyeran aquellos estudios que eran pertinentes para el análisis. Conclusión. Los tratamientos actuales, como los medicamentos antiepilépticos, las dietas cetogénicas y la estimulación nerviosa, han demostrado ser efectivos para reducir la frecuencia y la gravedad de las convulsiones en los pacientes. Es importante que los pacientes y sus cuidadores trabajen en conjunto con un equipo médico para lograr la mejor gestión posible de la enfermedad. Aunque no se dispone de una cura definitiva para el Síndrome de Dravet, los avances médicos continúan proporcionando esperanza y opciones de tratamiento a los pacientes y sus familias.

Dravet syndrome (DS) is estimated to be a severe developmental and epileptic encephalopathy, occurring in 1 in 15000 live births. It is characterized by drug-resistant epilepsy presenting in the first year of life with prolonged seizures accompanied by fever or temperature changes, often hemiclonic in nature, followed by unprovoked seizures of various types. Objective. To describe the treatments used for Dravet syndrome. Methodology. A systematic review was performed. For this purpose, a search was carried out in multiple databases, such as Pubmed, Dialnet, Sciencedirect, Scielo and Scopus. The search was limited to articles published from 2017 to 2022. After collecting the articles, several filtering criteria were applied to ensure that only those studies that were relevant to the analysis were included. Conclusion. Current treatments, such as antiepileptic drugs, ketogenic diets, and nerve stimulation, have been shown to be effective in reducing the frequency and severity of seizures in patients. It is important that patients and their caregivers work together with a medical team to achieve the best possible management of the disease. Although there is no definitive cure for Dravet syndrome, medical advances continue to provide hope and treatment options for patients and their families.

Estima-se que a síndrome de Dravet (SD) seja uma encefalopatia epiléptica e de desenvolvimento grave, que ocorre em 1 a cada 15.000 nascidos vivos. Caracteriza-se por epilepsia resistente a medicamentos que se apresenta no primeiro ano de vida com convulsões prolongadas acompanhadas de febre ou alterações de temperatura, muitas vezes de natureza hemiclônica, seguidas de convulsões não provocadas de vários tipos. Objetivo. Descrever os tratamentos usados para a síndrome de Dravet. Metodologia. Foi realizada uma revisão sistemática. Para isso, foi realizada uma pesquisa em vários bancos de dados, como Pubmed, Dialnet, Sciencedirect, Scielo e Scopus. A pesquisa foi limitada a artigos publicados de 2017 a 2022. Após a coleta dos artigos, vários critérios de filtragem foram aplicados para garantir que apenas os estudos relevantes para a análise fossem incluídos. Conclusão. Os tratamentos atuais, como medicamentos antiepilépticos, dietas cetogênicas e estimulação nervosa, demonstraram ser eficazes na redução da frequência e da gravidade das convulsões nos pacientes. É importante que os pacientes e seus cuidadores trabalhem em conjunto com uma equipe médica para obter o melhor controle possível da doença. Embora não haja uma cura definitiva para a Síndrome de Dravet, os avanços médicos continuam a oferecer esperança e opções de tratamento para os pacientes e suas famílias.

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.

Mutación en el gen SCN9Aasociado con el síndrome de Dravet: presentación de un caso pediátrico / Mutation in the SCN9A Gene Associated with Dravet Syndrome: A Pediatric Case Report / Mutação no gene SCN9A associada à síndrome de Dravet: relato de um caso pediátrico

Introducción:el síndrome de Dravet, también conocido como epilepsia mioclónica grave de la infancia, corresponde a una encefalopatía epiléptica resistente a fármacos que inicia generalmente en el primer año de vida. Se caracteriza por crisis epilépticas que suelen tener múltiples desencadenantes; el más asociado es la presencia de episodios febriles previos. Se considera una enfermedad rara, debido a su baja incidencia y prevalencia. Presentación del caso: niño de 10 años de edad con un cuadro de epilepsia de origen estructural, asociada con un retraso en el neurodesarrollo y anomalías craneofaciales meno-res, con antecedente de cardiopatía congénita no corregida, colpocefalia y agenesia del cuerpo calloso. Debido a la persistencia de las crisis convulsivas y su consiguiente resistencia farmacológica, se le rea-lizó un exoma genético que evidenció una mutación del gen SCN9. Discusión: el síndrome de Dravet debe ser sospechado en todo paciente menor de un año que tenga crisis convulsivas a repetición asociadas con episodios febriles cuantificados. Aproximadamente, entre el 70 % y el 85 % de los pacientes con el diagnóstico de síndrome de Dravet presenta una mutación en el gen SCN1A, por lo que mutaciones en otros genes que codifican para canales de sodio, ubicados en el mismo cromosoma, como el SCN9A, podrían contribuir de forma multifactorial a dicha entidad

Introduction: Dravet syndrome, also known as severe myoclonic epilepsy in infancy, is a drug resistant epileptic encephalopathy that usually begins in the first year of life. It is characterized by the presence of epileptic seizures that usually have multiple triggers; the most currently associated is the presence of previous febrile episodes. It is considered as a rare disease due to its low incidence and prevalence. Case presentation: We reported the case of a ten-year-old boy with structural epilepsy associated with a neuro-developmental delay and minor craniofacial anomalies. He had a history of uncorrected congenital heart disease, colpocephaly, and agenesis of the corpus callosum. Due to the persistence of seizures secondary to drug resistance, it was decided to perform a genetic exome that evidenced a mutation of the SCN9A gene. Conclusions: Dravet syndrome should be suspected in all patients under one year of age who have recu-rrent seizures associated with fever that does not respond to medication and modifies its presentation. Approximately 70%−85% of the patients diagnosed with Dravet syndrome have a mutation in the SCN1A gene; therefore, mutations in other genes that encode sodium channels located on the same chromosome, such as SCN9A, could contribute in a multifactorial way.

Introdução: a síndrome de Dravet, também conhecida como epilepsia mioclônica grave da infância, corresponde a uma encefalopatia epiléptica resistente a medicamentos que geralmente se inicia no primeiro ano de vida. É caracterizada pela presença de crises epilépticas que costumam ter múltiplos detonantes, sendo que o mais associado atualmente é a presença de episódios febris prévios. É conside-rada uma doença rara devido à sua baixa incidência e prevalência. Apresentação do caso: é apresentado o caso de um menino de 10 anos de idade com quadro de epilepsia de origem estrutural, associada a atraso no desenvolvimento neurológico e pequenas anomalias craniofaciais; com histórico de cardio-patia congênita não corrigida, colpocefalia e agenesia do corpo caloso. Devido à persistência das crises epilépticas e consequente resistência farmacológica, optou-se pela realização de um exoma genético que apresenta uma mutação do gene SCN9. Discussão: a síndrome de Dravet deve ser suspeitada em todos os pacientes com menos de um ano de idade que apresentam convulsões repetidas associadas a episódios febris quantificados. Aproximadamente 70 a 85% dos pacientes com diagnóstico de síndrome de Dravet apresentam mutação no gene SCN1A, portanto mutações em outros genes que codificam canais de sódio, localizados no mesmo cromossomo, como o SCN9A, poderiam contribuir de forma multifatorial para essa entidade

Lipofuscinosis ceroidea neuronal 6 (enfermedad Kufs tipo A): Reporte de caso en Colombia / Neuronal ceroid lipofuscinosis 6 (Kufs disease Type A): Case report from Colombia

RESUMEN INTRODUCCIÓN: Las lipofuscinosis ceroideas neuronales (CLN) son un grupo de enfermedades neurodegenerativas de inicio generalmente en la infancia, caracterizadas por acumulación intracelular de material de almacenamiento autofluorescente. En la última década se han identificado 14 formas de CLN con mutaciones en 13 genes (CLN1-CLN14), en la CLN9 no se ha identificado aún el gen. Los pacientes con mutaciones en el gen CLN6 localizado en el cromosoma 15q21-23 presentan tres tipos de variantes clínicas: CLN6 infantil tardía, con presentación entre 18 meses a 8 años, las variantes Kufs tipo A y Kufs tipo B de inicio en adolescentes y adultos. REPORTE DE CASO: Se presenta el caso de un paciente con epilepsia generalizada de inicio en la edad adulta, que ingresa a valoración en primera ocasión, con resonancia magnética cerebral con atrofia cortical leve; la enfermedad se inició a los 14 años con déficit cognitivo lentamente progresivo, sin compromiso visual; con posterior identificación genética de una variante patogénica en el gen CLN6, con un conjunto de la variante clínica Kufs tipo A de lipofuscinosis ceroidea neuronal 6 (CLN6). DISCUSIÓN: Este es el primer reporte de CLN6 con variante clínica Kufs tipo A en Colombia. Con el advenimiento de técnicas genéticas se pueden hacer diagnósticos específicos de CLN6, a partir de la clínica y sospecha diagnóstica; utilizando métodos no invasivos.

ABSTRACT INTRODUCTION: Neuronal ceroid lipofuscinosis (CLN) is a group of neurodegenerative diseases generally with onset in childhood, characterized by intracellular accumulation of autofluorescent storage material. In the last decade, 14 forms of CLN have been identified with mutations in 13 genes (CLN1-CLN14), in CLN9 the gene has not yet been identified. Patients with mutations in the CLN6 gene located on chromosome 15q21-23 present three types of clinical variants: late childhood CLN6, presenting between 18 months to 8 years, the Kufs type A and Kufs type B variants of onset in adolescents and adults. CASE REPORT: We present the case of a male patient with generalized epilepsy of onset in adulthood, who was admitted for evaluation the first time, with brain magnetic resonance imaging with mild cortical atrophy; he started at age 14 with slowly progressive cognitive deficit, without visual compromise; with subsequent genetic identification of a pathogenic variant in the CLN6 gene, jointly presenting the clinical variant Kufs type A of neuronal ceroid lipofuscinosis 6 (CLN6). DISCUSSION: This is the first report of CLN6 with Kufs type A clinical variant in Colombia. With the advent of genetic techniques, specific diagnoses of CLN6 can be made, based on the clinical and suspected diagnoses; using non-invasive methods.

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.

A los diecisiete años desaparecen del EEG las polipuntas y polipunta ondas: a propósito del síndrome de Lance-Adams / At the seventeen years they disappear from the EEG The little and little waves: About the Lance-Adams syndrome

Objetivo: la inesperada ausencia del signo de polipunta o de polipunta onda (PPO) en el electroencefalograma (EEG) de dos casos, de 29 y 51 años, respectivamente, del Síndrome Lance Adams (SLA), que hemos visto y publicado con anterioridad, nos motivó a investigar la edad cuando este signo tiende a extinguirse, dejando de ser obligatorio para diagnosticar SLA a pacientes de edad madura. Métodos: de una muestra de 7137 trazados se incluyeron 6939, tras excluir 198 por referimientos no identificables. Estos EEG del Centro de Rehabilitación y el Centro Médico de la Universidad Central del Este (UCE), fueron realizados con electroencefalógrafos Nervus y Cadwell, de manera respectiva. Se revisaron buscando la presencia de PPO para estudiar la edad, la patología sospechada en cada indicación y el género de los pacientes. Resultados: PPO fue encontrada en 293 casos: 4.22 % de la muestra total. En 272 habría ocurrido antes de los 17 años, con la gráfica mostrando una elevación inicial máxima a las nueve. En cambio, de los 18 a los 65 solo apareció la PPO en 18 casos. 14 pacientes mostraron supresión de paroxismo o patrones de electro depresión sin PPO. Conclusión: la polipunta/polipunta onda prácticamente desaparece a los 17 años, a mayor edad, por lo tanto, el signo PPO deja de ser obligatorio para el diagnóstico del SLA en pacientes mayores. Es más frecuente en epilépticos y en varones

Objective: Unexpected absence of polyspike/polyspike & wave sign (PPW) in the EEG of our 29 and 51-year old published cases of Lance Adams Syndrome (LAS), prompted us to investigate the age when this sign may nearly disappear. This in order of considering it not obligatory for late LAS diagnosis. Methods: Inclusion consisted of a sample of 7137 recordings performed at the Rehabilitation Center and the Universidad Central del Este's (UCE) teaching clinic (Nervus and Cadwell respectively). Excluded were 198 for unidentifiable indications. PPW was searched in order to study patient's age, suspected pathology plus gender. Results: PPW was found in 293cases: 4.22% of the total sample: in 275.it occurred before the age of 17 with curve showing an initial tip at nine while between 18 and 65 only 18 cases showed it. Incidentally 14 patients showed Burst suppression or electro-decrement patterns without PPW. The most common indication pathology was Epilepsy followed by learning disability. Finally it was more frequent in 176(63.9%) male vs. 113(36.1%) in female cases: ratio 1.56 to 1. however not significant for the gender ratio in the total EEG sample is 1.55 to 1. Conclusion: PPW nearly disappears after the age of seventeen, perhaps explaining rarity in advanced aged SLA. It is more frequent in Epilepsy EEG indications and in the male

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.

Acute Tubular Necrosis associated with the Ketogenic Diet in a Child with Intractable Epilepsy

The ketogenic diet (KD) has been used as an effective antiepileptic therapy for intractable childhood epilepsy. However, various adverse effects have been reported with use of the KD. We report a case of a child who developed acute tubular necrosis subsequent to therapy with KD. A 5-year-old girl had myoclonic epilepsy with developmental delay. She was under the treatment with antiepileptic drugs since the age of 3 months and on the KD during the past 18 months. Proteinuria persisted intermittently with the initiation of the KD and subsequently increased in the past 2 months. She was admitted with intermittent mild fever, vomiting, and lethargy for the past 3–4 weeks. At the time of admission, she presented with hypertriglyceridemia, heavy proteinuria, renal Fanconi syndrome, and acute kidney injury. Renal sonography showed a marked increase in the size and parenchymal echogenicity of both kidneys. A renal biopsy revealed acute tubular necrosis accompanied by early interstitial fibrosis. After the withdrawal of the KD and supportive therapy, without changing other anticonvulsants and their dosages, improvement of renal function was observed. Proteinuria had disappeared after 1 month and kidney size returned to normal after 8 months. It is hypothesized that the KD can induce and/or aggravate the renal tubulointerstitial injury in some patients who are under the treatment with anticonvulsants.

Neurological impairment of the monozygotic twins with congenital infection presumed by Zika virus: Case report / Comprometimento neurológico de gêmeas monozigóticas com infecção congênita presumida pelo Zika vírus: Relato de caso

Abstract Introduction: the increase in the incidence of congenital microcephaly in Brazil has been associated to the Zika virus outbreak. This case report aimed to describe the neurological impairment of monozygotic twins presumably due to an intrauterine infection by Zika virus during the Brazilian outbreak in 2015. Case description: The monozygotic twins born at term with severe congenital microcephaly were taken to the Outpatient Pediatric Service of a University Hospital. The 17-yearold mother, primigravida, lives in the Northeast region of Brazil, has a normal body mass index, no family history of microcephaly, no clinical history of viral diseases, or exposure to drugs and/or radiation during pregnancy. Serological tests for toxoplasmosis, rubella, syphilis, cytomegalovirus and HIV were negative at the prenatal evaluation and the obstetrical ultrasounds showed a monochorionic, diamniotic twin pregnancy without any evidence of neurological abnormalities. In the post-natal, the imaging of the skull, was evidenced of a great neurological impairment in one of the twins, who, in addition to presenting cerebral calcifications, gliosis and subependymal cysts, also had ventriculomegaly with hydrocephalus of supratentorial predominance and more pronounced cerebral atrophy compared to the other twin. Both presented delayed neuropsychomotor development. Discussion: distinct neurological alterations in the monochorionic twins with an infection presumed by Zika virus may raise the hypothesis of the existence of predisposing factors or protection against this viral agent.

Resumo Introdução: o aumento da incidência de microcefalia congênita no Brasil tem sido associado à epidemia do zika vírus. Este relato objetivou descrever o comprometimento neurológico de gêmeas monozigóticas presumidamente infectadas intra-útero pelo zika vírus durante a epidemia brasileira de 2015. Descrição do caso: gêmeas monozigóticas, nascidas a termo, com microcefalia congênita severa, foram encaminhadas ao serviço ambulatorial de Pediatria do Hospital Universitário. Genitora de 17 anos, residente na região Nordeste do Brasil, primigesta, índice de massa corpórea normal, sem história familiar de microcefalia ou relato de história clínica de doenças virais e de exposição a drogas e/ou radiação durante a gestação. Na avaliação médica pré-natal, as sorologias para toxoplasmose, rubéola, sífilis, citomegalovírus e HIV foram negativas e as ultrassonografias obstétricas revelaram gestação gemelar mono-coriônica diamniótica, sem evidências de anormalidades neurológicas. Os exames de imagem do crânio pós-natais evidenciaram maior comprometimento neurológico em uma das geme-lares, que além de apresentar calcificações cerebrais, gliose e cistos subependimários, também portava ventriculomegalia acentuada com hidrocefalia de predomínio supratentorial e atrofia cerebral mais pronunciada em relação à outra gemelar. Ambas apresentaram atraso de desenvolvimento neuropsicomotor. Discussão: alterações neurológicas distintas em gêmeas monocoriônicas com infecção presumida por zika vírus podem suscitar a hipótese da existência de fatores de predisposição ou de proteção contra esse agente viral.

A "Triple Trouble" Case of Facioscapulohumeral Muscular Dystrophy Accompanied by Peripheral Neuropathy and Myoclonic Epilepsy / 中华医学杂志(英文版)

<p><b>Background</b>Facioscapulohumeral muscular dystrophy (FSHD) is characterized by asymmetric muscular deficit of facial, shoulder-girdle muscles, and descending to lower limb muscles, but it exists in several extramuscular manifestations or overlapping syndromes. Herein, we report a "complex disease plus" patient with FSHD1, accompanied by peripheral neuropathy and myoclonic epilepsy.</p><p><b>Methods</b>Standard clinical assessments, particular auxiliary examination, histological analysis, and molecular analysis were performed through the new Comprehensive Clinical Evaluation Form, pulsed-field gel electrophoresis-based Southern blot, Multiplex Ligation-dependent Probe Amplification (MLPA), whole exome sequencing (WES), and targeted methylation sequencing.</p><p><b>Results</b>The patient presented with mild facial weakness, humeral poly-hill sign, scapular winging, peroneal weakness, drop foot, pes cavus, and myoclonic epilepsy. Furthermore, electrophysiology revealed severely demyelinated and axonal injury. The muscle and nerve biopsy revealed broadly fiber Type II grouping atrophy and myelinated nerve fibers that significantly decreased with thin myelinated fibers and onion bulbs changes. Generalized sharp and sharp-slow wave complexes on electroencephalography support the diagnosis toward myoclonic epilepsy. In addition, molecular testing demonstrated a co-segregated 20-kb 4q35-EcoRI fragment and permissive allele A, which corresponded with D4Z4 hypomethylation status in the family. Both the patient's mother and brother only presented the typical FSHD but lacked overlapping syndromes. However, no mutations for hereditary peripheral neuropathy and myoclonic epilepsy were discovered by MLPA and WES.</p><p><b>Conclusions</b>The present study described a "tripe trouble" with FSHD, peripheral neuropathy, and myoclonic epilepsy, adding the spectrum of overlapping syndromes and contributing to the credible diagnosis of atypical phenotype. It would provide a direct clue on medical care and genetic counseling.</p>

Report on the External Quality Assessment Scheme for Molecular Diagnostics in Korea (2017)

Quality control for genetic analysis has become more important with a drastic increase in testing volume and clinical demands. The molecular diagnostics division of the Korean Association of Quality Assurance for Clinical Laboratory conducted two trials in 2017 on the basis of molecular diagnostics surveys, involving 53 laboratories. The molecular diagnostics surveys included 37 tests: gene rearrangement tests for leukemia (BCR-ABL1, PML-RARA, AML1-ETO, and TEL-AML1), genetic tests for Janus kinase 2, FMS-like tyrosine kinase 3-internal tandem duplication, FMS-like tyrosine kinase 3-tyrosine kinase domain, nucleophosmin, cancer-associated genes (KRAS, EGFR, KIT, and BRAF), hereditary breast and ovarian cancer genes (BRCA1 and BRCA2), Li-Fraumeni syndrome (TP53), Wilson disease (ATP7B), achondroplasia (FGFR3), hearing loss and deafness (GJB2), Avellino (TGFBI), multiple endocrine neoplasia 2 (RET), Huntington disease, spinocerebellar ataxia, spinal and bulbar muscular atrophy, mitochondrial encephalopathy with lactic acidosis and stroke-like episodes, myoclonic epilepsy ragged red fibre, Leber hereditary optic neuropathy, Prader-raderd Angelman syndrome, Duchenne muscular dystrophy, spinal muscular atrophy, fragile X syndrome, apolipoprotein E genotyping, methylenetetrahydrofolate reductase genotyping, and ABO genotyping. Molecular genetic surveys revealed excellent results for most participants. The external quality assessment program for genetic analysis in 2017 proved useful for continuous education and the evaluation of quality improvement.

Levetiracetam como terapia adjuvante em pacientes com epilepsia mioclônica juvenil resistentes à monoterapia / Levetiracetam as adjuvant therapy in patients with juvenile myoclonic epilepsy resistant to monotherapy

CONTEXTO: A epilepsia é uma doença cerebral crônica caracterizada pela recorrência de crises epilépticas não provocadas. Conforme Protocolo Clínico e Diretrizes Terapêuticas (PCDT) vigente do Ministério da Saúde (MS), o tratamento disponível no Sistema Único de Saúde (SUS) inclui os agentes antiepilépticos fenobarbital, fenitoína, primidona, topiramato, lamotrigina, carbamazepina e valproato de sódio. As epilepsias idiopáticas generalizadas são classificadas como síndromes epilépticas. A EMJ é a mais comum dentre as síndromes da adolescência e uma das mais frequentemente diagnosticadas. A maioria dos pacientes com EMJ apresentam bom controle do quadro clínico com a utilização do valproato de sódio em monoterapia, mas na falha ou impossibilidade de seu uso, fármacos como a lamotrigina e o levetiracetam podem ser utilizados. TECNOLOGIA: levetiracetam (Keppra®). INDICAÇÃO: Terapia adjuvante, ou seja em associação com o valproato de sódio, em pacientes com epilepsia mioclônica juvenil (EMJ) resistentes à monoterapia. PERGUNTA: O uso do levetiracetam em regime de terapia adjuvante, é eficaz, seguro e custoefetivo em relação à continuação da monoterapia em pacientes com epilepsia mioclônica juvenil, resistentes a outros agentess antiepilépticos na perspectiva do SUS? EVIDÊNCIAS CIENTÍFICAS: A evidência da utilização do levetiracetam associado à tratamento prévio com um agente antiepiléptico para o tratamento da EMJ é baseada em um ensaio clínico duplo-cego que apresentou redução significante de 50% no número de dias por semana com crises convulsivas s (OR = 4,77; IC 95% 2,12 ­ 10,77; p<0,0001 e um maior número de pacientes, que receberam levetiracetam, apresentaram ausência total de crises durante o tratamento (16,7% dos pacientes, p = 0,03, vs 3,3 % do grupo que recebeu placebo). AVALIAÇÃO ECONÔMICA: Foi apresentado um modelo de custo-efetividade comparando a monoterapia com ácido valpróico ao tratamento adjuvante do levetiracetam (associado) ao ácido valpróico. Foi elaborado um modelo baseado primeiramente em uma árvore de decisão, seguido por um modelo de Markov. No caso-base a razão de custo-utilidade incremental (RCUI) foi de R$ 58.294 por ano de vida ajustada pela qualidade, que na análise de sensibilidade univariada variou entre R$ 22.119 e R$ 80.359. Avaliação de Impacto Orçamentário: Conforme as estimativas feitas pelo demandante o impacto orçamentário será de aproximadamente R$ 1,58 milhão no primeiro ano e de R$ 43,6 milhões nos primeiros 5 anos após a incorporação. Na análise de sensibilidade realizada o impacto orçamentário para os próximos 5 anos variou entre R$ 14,5 e R$ 87,3 milhões. EXPERIÊNCIA INTERNACIONAL: o levetiracetam é utilizado em terapia adjuvante para o tratamento de crises mioclônicas em agências como o National Institute for Health and Clinical Excellence (NICE) e Canadian Agency for Drugs and Technologies in Health (CADTH), de acordo com condições estabelecidas Discussão: A evidência do tratamento com levetiracetam em pacientes resistentes à monoterapia padrão, associado ao medicamento já utilizado, ocasionou em redução significante de pelo menos 50% no número de dias por semana com crises convulsivas e um maior número de pacientes apresentaram ausência total de crises convulsivas durante seu período de seguimento. Porém trata-se de evidência indireta e de baixa qualidade. Os estudos para essa indicação da tecnologia são escassos e há baixa probabilidade de novos estudos serem realizados. A avaliação econômica foi custo-efetiva na adição do levetiracetam ao medicamento previamente utilizado em monoterapia, em pacientes resistentes, com um impacto orçamentário de até R$ 87,3 milhões em 5 anos, de acordo com a análise de sensibilidade. A secretaria executiva da CONITEC estimou o número de pacientes, que considera mais adequada para o cálculo, que foi 7,8% maior que a população considerada na análise do demandante, o que levaria a um impacto orçamentário ainda maior. RECOMENDAÇÃO DA CONITEC: A CONITEC em sua 54ª reunião no dia 06 de abril de 2017, recomendou preliminarmente a incorporação no SUS do levetiracetam como terapia adjuvante em pacientes com epilepsia mioclônica juvenil resistentes à monoterapia, condicionada à redução de preço e consonância com a atualização do PCDT de Epilepsia. Consulta pública: Foi realizada a Consulta Pública nº 22/2017, entre os dias 25/04/2017 e 16/05/2017 e recebeu 105 contribuições, sendo 88 sobre experiência ou opinião e 17 técnicocientíficas. Todas as contribuições foram avaliadas quantitativamente e qualitativamente. Seu conteúdo não trouxe novas evidências e informações que pudessem modificar a recomendação inicial da CONITEC. DELIBERAÇÃO FINAL: Os membros da CONITEC presentes na 56ª reunião ordinária do plenário do dia 07/06/2017 deliberaram, por unanimidade, por recomendar a incorporação do levetiracetam para pacientes com epilepsia mioclônica juvenil (EMJ) resistentes à monoterapia, associando-o ao medicamento já utilizado, condicionado à negociação de preço e conforme Protocolo Clínico e Diretrizes Terapêuticas do Ministério da Saúde. Foi assinado o Registro de Deliberação nº 264/2017.(AU)

Síndrome de Kinsbourne: reporte de un caso / Síndrome de Kinsbourne: reporte de um caso / Kinsbourne syndrome: Report of a case

El síndrome de Kinsbourne, conocido también como “síndrome de opsoclonus-mioclonus” o “síndrome de los ojos danzantes”, es una enfermedad rara caracterizada por movimientos oculares rápidos, irregulares, multidireccionales (opsoclonus), movimientos mioclónicos en tronco, cara y/o extremidades y ataxia; se presenta entre los 6 y 36 meses de edad. Su etiología puede ser paraneoplásica (neuroblastoma), no paraneoplásica (infecciosa) o idiopática. Independientemente de la causa, se han utilizado inmunosupresores para reducir la formación de anticuerpos posiblemente involucrados en su fisiopatología. Presentamos el caso de una niña lactante de 21 meses con este síndrome secundario a un cuadro respiratorio viral. Tuvo ataxia, opsoclonus, mioclonías de miembros superiores, irritabilidad y alteración en el patrón de sueño. Se descartó el diagnóstico de neuroblastoma. El tratamiento inicial se hizo con pulsos de metilprednisolona seguida de prednisolona oral. Sus síntomas desaparecieron progresivamente y recuperó la marcha; actualmente está asintomática y sin secuelas. En estos pacientes se debe descartar siempre un síndrome paraneoplásico.

Kinsbourne syndrome, also known as “Opsoclonus-myoclonus syndrome” or “Dancing eyes syndrome” is a rare condition characterized by rapid, irregular, multi-directional eye movements (opsoclonus), myoclonic movements in the trunk, face and/or limbs and ataxia. It occurs in children aged between 6 and 36 months. Its etiology may be paraneoplasic (neuroblastoma), non-paraneoplasic (infectious processes) or idiopathic. Regardless of its etiology, immunosuppressive drugs have been used in order to reduce the formation of antibodies possibly involved in the pathophysiology. We report the case of a 21 month-old girl with this syndrome secondary to an infectious respiratory illness. She had ataxia, opsoclonus, upper limbs myoclonus, irritability and altered sleep pattern. Neuroblastoma was ruled out. Initial management was done with methylprednisolone pulses, followed by oral prednisolone. She had progressive clinical improvement, and is currently asymptomatic with no sequelae. In these patients a paraneoplasic syndrome should always be ruled out.

A síndrome de Kinsbourne, conhecida também como “síndrome de opsoclonus-mioclonus” a “síndrome dos olhos dançantes”, é uma doença rara caracterizada por movimentos oculares rápidos, irregulares, multidirecionais (opsoclonus), movimentos mioclônicos em tronco, cara e/ou extremidades e ataxia; se apresenta entre os 6 e 36 meses de idade. Sua etiologia pode ser paraneoplásica (neuroblastoma), não paraneoplásica (infecciosa) ou idiopática. Independentemente da causa, se há utilizado imunossupressores para reduzir a formação de anticorpos possivelmente envolvidos em sua fisiopatologia. Apresentamos o caso de uma criança lactante de 21 meses com esta síndrome secundária a um quadro respiratório viral. Teve ataxia, opsoclonus, mioclonias de membros superiores, irritabilidade e alteração no padrão de sono. Se descartou o diagnóstico de neuroblastoma. O tratamento inicial se fez com pulsos de metilprednisolona seguida de prednisolona oral. Seus sintomas desapareceram progressivamente e recuperou a marcha; atualmente está assintomática e sem sequelas. Nestes pacientes se deve descartar sempre uma síndrome paraneoplásico.

Analysis of SCN1A deletions or duplications in patients with Dravet syndrome / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To determine the type and frequency of SCN1A deletions and duplications among patients with Dravet syndrome (DS).</p><p><b>METHODS</b>For DS patients in which no mutations of the SCN1A gene were detected by PCR-DNA sequencing, SCN1A deletions and duplications were detected by multiplex ligation-dependent probe amplification (MLPA).</p><p><b>RESULTS</b>In 680 DS patients, 489 had SCN1A mutations identified by PCR-DNA sequencing. In 191 patients who were negative for the SCN1A PCR-DNA sequencing, 15 (15/191, 7.9%) were detected with heterozygous SCN1A deletions or duplications, which included 14 (14/15, 93.3%) SCN1A deletions and 1 SCN1A duplication. There were 13 types of mutations, including whole SCN1A deletions in 3 patients, partial SCN1A deletions in 11 patients and partial SCN1A duplications in one patient. By testing the parents, 14 mutations were found to be de novo. For the remaining case, no SCN1A deletion or duplication was found in the mother, while the father was not available.</p><p><b>CONCLUSION</b>Approximately 8% of Chinese patients who were negative for SCN1A mutation by PCR-sequencing have SCN1A deletions or duplications. The MLPA analysis should be considered as an important strategy for such patients. SCN1A deletions are more common than SCN1A duplications among DS patients, and the most common types are whole SCN1A deletions. The majority of SCN1A deletions or duplications are de novo.</p>

SCN1A Gene Mutation and Adaptive Functioning in 18 Vietnamese Children with Dravet Syndrome

BACKGROUND AND PURPOSE: Dravet syndrome is a rare and severe type of epilepsy in infants. The heterogeneity in the overall intellectual disability that these patients suffer from has been attributed to differences in genetic background and epilepsy severity. METHODS: Eighteen Vietnamese children diagnosed with Dravet syndrome were included in this study. SCN1A variants were screened by direct sequencing and multiplex ligation-dependent probe amplification. Adaptive functioning was assessed in all patients using the Vietnamese version of the Vineland Adaptive Behavior Scales, and the results were analyzed relative to the SCN1A variants and epilepsy severity. RESULTS: We identified 13 pathogenic or likely pathogenic variants, including 6 that have not been reported previously. We found no correlations between the presence or type of SCN1A variants and the level of adaptive functioning impairment or severity of epilepsy. Only two of nine patients aged at least 5 years had an adaptive functioning score higher than 50. Both of these patients had a low frequency of convulsive seizures and no history of status epilepticus or prolonged seizures. The remaining seven had very low adaptive functioning scores (39 or less) despite the variability in the severity of their epilepsy confirming the involvement of factors other than the severity of epilepsy in determining the developmental outcome. CONCLUSIONS: Our study expands the spectrum of known SCN1A variants and confirms the current understanding of the role of the genetic background and epilepsy severity in determining the developmental outcome of Dravet syndrome patients.

SCN1A Variants in Patients with Dravet Syndrome

PURPOSE: The aim of this study is to examine the SCN1A variants in Korean patients with Dravet syndrome. METHODS: We conducted a retrospective study of clinically confirmed thirty-nine patients with Dravet syndrome who visit our hospital from January 2007 to May 2015. We analyzed the SCN1A variants by direct sequencing. We analyzed and classified SCN1A variants according to ACMG/AMP (American College of Medical Genetics and Genomics and the Association for Molecular Pathology) guideline. RESULTS: A total thirty-nine patients (female 22, male 17) were included. Among them, twenty patients (51.2%) with Dravet syndrome had pathogenic or likely pathogenic SCN1A mutations including fifteen truncating mutations (12 nonsense and 3 splice region mutations), 5 missense mutations. The remained variants in nineteen patients with Dravet syndrome classified into ten variants of unknown significances, and 9 benign variants. In our study, truncation mutations are located whole span of SCN1A protein, while half of missense mutations are located at higher density on pore loop (S5-S6) regions. CONCLUSION: Unlike previous known study, lower positive rate of SCN1A mutation of Dravet syndrome was revealed in our study. The importance of parental test (trio test) and other additional tests have been emphasized.

SCN1A Variants in Patients with Dravet Syndrome

PURPOSE: The aim of this study is to examine the SCN1A variants in Korean patients with Dravet syndrome. METHODS: We conducted a retrospective study of clinically confirmed thirty-nine patients with Dravet syndrome who visit our hospital from January 2007 to May 2015. We analyzed the SCN1A variants by direct sequencing. We analyzed and classified SCN1A variants according to ACMG/AMP (American College of Medical Genetics and Genomics and the Association for Molecular Pathology) guideline. RESULTS: A total thirty-nine patients (female 22, male 17) were included. Among them, twenty patients (51.2%) with Dravet syndrome had pathogenic or likely pathogenic SCN1A mutations including fifteen truncating mutations (12 nonsense and 3 splice region mutations), 5 missense mutations. The remained variants in nineteen patients with Dravet syndrome classified into ten variants of unknown significances, and 9 benign variants. In our study, truncation mutations are located whole span of SCN1A protein, while half of missense mutations are located at higher density on pore loop (S5-S6) regions. CONCLUSION: Unlike previous known study, lower positive rate of SCN1A mutation of Dravet syndrome was revealed in our study. The importance of parental test (trio test) and other additional tests have been emphasized.

Role of Genetics in the Etiopathogenesis of Genetic Generalized Epilepsy: A Review of Current Literature

"Until recently; genetic generalized epilepsy (GGE) was believed to be of presumed genetic etiology with no identifiable genetic mutation or demonstrable epigenetic abnormality. A wide range of epileptic disorders has clue for an inherited susceptibility. Monogenic disorders associated with epilepsy mental retardation and structural brain lesion typified by heterotopias; tuberous sclerosis; and progressive myoclonus epilepsies account for about 1 of epilepsies. This review focuses on the role of genetic mutations and epigenetic rearrangements in the pathophysiologic mechanism of GGE. To achieve this; PubMed; EMBASE; and Google Scholar were systematically and comprehensively searched using keywords (""epilepsy"" ""juvenile myoclonic epilepsy (JME);"" ""typical absences;"" ""idiopathic generalized epilepsy;"" ""JME;"" ""juvenile absence epilepsy;"" ""childhood absence epilepsy"" ""generalized tonic-clonic seizure"" ""GTCS""). Most GGE has evidence of underlying genetic inheritance. Recent animal studies have shown that early detection and treatment of genetic generalized epilepsies can alter the phenotypic presentation in rodents. These findings suggest a critical period in epileptogenesis; during which spike-and-wave seizures can be suppressed; leading to chronic changes in the brain (epileptogenesis) and the preceding dysfunctions may; therefore; be targeted using therapeutic approaches that may either delay or inhibit the transition to active epileptic attack. The interplay between genetic mutations and epigenetic rearrangements play important roles in the development of GCE and that this process; especially at crucial developmental periods; is very susceptible to environmental modulations"

Clinical Utility of Bone Marrow Study in Gaucher Disease: A Case Report of Gaucher Disease Type 3 With Intractable Myoclonic Seizures

No abstract available.

Acute encephalopathy in Dravet syndrome: Case reports and literature review

Dravet syndrome is a rare and catastrophic type of epilepsy in infants. Acute encephalopathy has been sporadically reported in patients with Dravet syndrome; however, the risk factors for this serious complication have not been identified. We report two patients with a clinical diagnosis of Dravet syndrome who experienced acute encephalopathy initiated by refractory status epilepticus. SCN1A mutational analysis revealed a previously reported nonsense mutation in one patient and a novel missense mutation in the other. Analysis of our cases and previously published cases revealed that patients with Dravet syndrome who have a more severe phenotype have an increased likelihood of developing acute encephalopathy compared with patients with less severe phenotypes.