Loss of O-GlcNAcylation on MeCP2 at Threonine 203 Leads to Neurodevelopmental Disorders / 神经科学通报·英文版

Mutations of the X-linked methyl-CpG-binding protein 2 (MECP2) gene in humans are responsible for most cases of Rett syndrome (RTT), an X-linked progressive neurological disorder. While genome-wide screens in clinical trials have revealed several putative RTT-associated mutations in MECP2, their causal relevance regarding the functional regulation of MeCP2 at the etiologic sites at the protein level requires more evidence. In this study, we demonstrated that MeCP2 was dynamically modified by O-linked-β-N-acetylglucosamine (O-GlcNAc) at threonine 203 (T203), an etiologic site in RTT patients. Disruption of the O-GlcNAcylation of MeCP2 specifically at T203 impaired dendrite development and spine maturation in cultured hippocampal neurons, and disrupted neuronal migration, dendritic spine morphogenesis, and caused dysfunction of synaptic transmission in the developing and juvenile mouse cerebral cortex. Mechanistically, genetic disruption of O-GlcNAcylation at T203 on MeCP2 decreased the neuronal activity-induced induction of Bdnf transcription. Our study highlights the critical role of MeCP2 T203 O-GlcNAcylation in neural development and synaptic transmission potentially via brain-derived neurotrophic factor.

Clinical and genetic analysis of two rare male patients with Rett syndrome / 中华医学遗传学杂志

OBJECTIVE@#To conduct clinical and genetic analysis of two male patients with atypical Rett syndrome.@*METHODS@#Collection of clinical data in the two patients and these parents; whole exome sequencing (WES) was used to detect the potential variants, which were verified by Sanger sequencing. X chromosome inactivation (XCI) detection is performed in the Patient 1's mother to detect the allelic expression difference of the MECP2 gene.@*RESULTS@#Patient 1, a 5-year and 10-month-old boy, had mental disorders and mild intellectual disability (ID) (IQ: 54), whose mother had ID. Patient 2 was a 9-month and 18-day-old male presented with recurrent infections, respiratory insufficiency, hypotonia and global developmental delay. WES indentified a hemizygous mutation, c.499C>T (p.R167W), in the MECP2 gene in patient 1, which was inherited from his mother. The inactivation of X chromosome is skewed, and the expression ratio of wild-type and mutant MECP2 is 100%:0. Patient 2 was found a de novo splicing mutation, c.62+2_62+3del in the MECP2 gene. They were both reported pathogenic variant related to Rett syndrome. c.499C>T (p.R167W) was defined as likely pathogenic (PS1+PM2+PP3) and c.62+2_62+3del was pathogenic (PVS1+PM2+PM6) based on American College of Medical Genetics and Genomics standards and guidelines.@*CONCLUSION@#Both the two patients were diagnosed with rare male Rett syndrome, which had atypical clinical manifestations and large difference. Above foundings have revealed novel phenotypes in Chinese male patients with Rett syndrome.

Manejo e integración estomatológica del paciente pediátrico con trastorno de Asperger / Management and dental integration of the pediatric patient with Asperger disorder

Trastorno neurológico enmarcado dentro de los trastornos de espectro autista (TEA) cuyas manifestaciones se reflejan en los ámbitos de la comunicación, interacción e imaginación social. Se clasifica en el manual diagnóstico y estadístico de trastornos mentales (DSM IV), se caracteriza por un mayor o menor grado de deterioro en las habilidades de lenguaje y comunicación, así como patrones repetitivos o restrictivos de pensamiento y comportamiento. El síntoma más distintivo es el interés obsesivo en un solo objeto o tema y la exclusión de cualquier otro pero siempre conservando habilidades de lenguaje. El pronóstico es bueno, debido a la compensación cognitiva, el enfoque repetitivo y restrictivo a actividades humanas productivas o generadoras de deferencias particulares, aunque no hay tratamiento específico, sino más bien interdisciplinario e individualizado, éste consiste en manejar los síntomas conductuales y la comorbilidad de forma independiente ya sea farmacológica o intervencionista. Paciente masculino de cinco años de edad, con un peso de 26 kg, cuadro de inmunizaciones completas, previamente diagnosticado con trastorno de Asperger (2015); caries dental de diversos grados, manejo estomatológico para su rehabilitación. El objetivo de este reporte es dar a conocer los cuidados para el tratamiento dental en pacientes con este trastorno (AU)

Neurological disorder known as autism spectrum disorders (ASD) whose main manifestations are reflected in the areas of communication, interaction and social imagination. It was first classified in the Diagnostic and Statistical Manual of Mental Disorders (DSM lV), characterized by a greater or lesser degree of deterioration in language and communication skills, as well as repetitive patterns or restrictive of thought and behavior. The most distinctive symptom is obsessive interest in a single object or topic and the exclusion of any other, but always retaining language skills. The prognosis is good in most of the cases, due to the cognitive compensation, the repetitive and restrictive approach to productive or deferential human activities, although there is no specific treatment, but rather interdisciplinary and individualized, this consists of managing behavioral symptoms and comorbidity independently either pharmacologically or interventionally. Male patient with five years old and weight of 26 kg, complete immunization chart, previously diagnosed with Asperger's disorder (2015); with dental caries of various degrees implementing dental management. The objective of this report is to make aware of the care and behavior management for dental treatment in patients with this Disorder (AU)

Factores de riesgo perinatal asociados al trastorno del espectro autista y al síndrome de Rett / Perinatal risk factors associated with autistic spectrum disorder and the Rett syndrome

Resumen El propósito de este proyecto fue identificar los factores de riesgo perinatal asociados al trastorno del espectro autista (TEA) y al síndrome de Rett y compararlos entre sí, estando enmarcado dentro de un estudio de tipo descriptivo. Para esta investigación se utilizó una unidad de análisis conformada por 421 historias clínicas, de las que 377 fueron de TEA y 44 de Rett, a las cuales se les aplicó un instrumento especializado en identificar factores de riesgo perinatales llamado Cuestionario Materno de Riesgo Perinatal (CMRP), con el que se encontró una gran prevalencia de niños nacidos por cesárea y que las ocupaciones de sus padres estaban relacionadas con los cuidados requeridos por el trastorno. Esta identificación de factores servirá para la toma de precauciones a nivel clínico médico y a nivel de prevención de los riesgos asociados al trastorno del espectro autista y el síndrome de Rett.

Abstract The purpose of this project was to identify the perinatal risk factors associated with Autism Spectrum Disorder (ASD) and Rett Syndrome and compare them to each other, being framed within a descriptive study; For this research, an analysis unit consisting of 421 medical records was used, of which 377 were from ASD and 44 from Rett, to which a specialized instrument was applied to identify perinatal risk factors called the Maternal Perinatal Risk Questionnaire (MPRQ ), which found a high prevalence of children born by caesarean section and that their parents' occupations were related to the care required by the disorder. This identification of factors will serve to take precautions at the medical clinical level and at the level of prevention of the risks associated with Autism Spectrum Disorder and Rett Syndrome.

Rett syndrome: the Brazilian contribution to the gene discovery / Síndrome de Rett: a contribuição brasileira para a descoberta do gene

ABSTRACT A brief history of the syndrome discovered by Andreas Rett is reported in this paper. Although having been described in 1966, the syndrome was only recognized by the international community after a report by Hagberg et al. in 1983. Soon, its importance was evident as a relatively frequent cause of severe encephalopathy among girls. From the beginning it was difficult to explain the absence of male patients and the almost total predominance of sporadic cases (99%), with very few familial cases. For these reasons, it was particularly difficult to investigate this condition until 1997, when a particular Brazilian family greatly helped in the final discovery of the gene, and in the clarification of its genetic mechanism. Brief references are made to the importance of the MECP2 gene, 18 years later, as well as to its role in synaptogenesis and future prospects.

RESUMO Uma breve história de uma síndrome neurológica descoberta por Andreas Rett é relatada neste artigo. Embora tenha ocorrido em 1966, a síndrome só foi reconhecida pela comunidade internacional após um relato de Hagberget al, em 1983. Logo, sua importância ficou evidente como causa relativamente frequente de encefalopatia grave entre as crianças do sexo feminino. Desde o início, foi difícil explicar a ausência de envolvimento de pacientes do sexo masculino e a quase absoluta preponderância de casos esporádicos (99%), com muitos poucos casos familiares. Por essas razões, foi difícil investigar essa condição até 1997, quando uma família brasileira em particular ajudou muito na descoberta final do gene e no esclarecimento de seu mecanismo genético. São feitas referências sucintas à importância do gene MECP2, dezoito anos depois, bem como ao seu papel na sinaptogênese e nas perspectivas futuras.

Síndrome de Rett: Análisis molecular del gen MECP2 en pacientes chilenas / Rett syndrome: MECP2 gene molecular analysis in Chilean patients

INTRODUCCIÓN: El síndrome de Rett (RTT) es un trastorno neurológico progresivo caracterizado por producir una regresión del desarrollo psicomotor en niñas previamente sanas. La mayoría de los casos son causados por variantes patogénicas en el gen MECP2, que codifica para la proteína methyl CpG- binding protein 2. OBJETIVO: Describir la frecuencia y el tipo de variantes patogénicas en MECP2 en mujeres chilenas con diagnóstico clínico de RTT. PACIENTES Y MÉTODO: Se invitó a participar en este estudio a mujeres chilenas con sospecha clínica de RTT. Se reunió información clínica mediante un cuestionario. Se analizaron variantes patogénicas en MECP2 mediante el método de secuenciación de Sanger y se utilizó Multiple Ligation-dependant Probe Amplification (MLPA) para la detección de duplicaciones y deleciones. RESULTADO: El estudio incluyó 14 pacientes con sospecha de RTT, de las cuales 8 (57%) pacientes tuvieron variantes patogénicas. Las restantes permanecen sin diagnóstico molecular. CONCLUSIÓN: Variantes patogénicas en MECP2 están presentes en pacientes chilenas con RTT. Es probable que haya otros genes o diagnósticos involucrados en las pacientes sin hallazgos en MECP2. A partir de este trabajo, el diagnóstico molecular está disponible en Chile.

INTRODUCTION: Rett syndrome (RTT) is a progressive neurological disorder characterized by regres sion of psychomotor development in previously healthy girls. Most cases are due to pathogenic va riants in the MECP2 gene which encodes for the methyl CpG-binding protein 2. OBJECTIVE: To des cribe the frequency and type of pathogenic variants in the MECP2 gene in Chilean female patients with clinical diagnosis of RTT. PATIENTS AND METHOD: Chilean women with clinical suspicion of RTT were invited to participate in the study. Clinical data were collected through a questionnaire. MECP2 pathogenic variants were analyzed by Sanger sequencing method and Multiplex Ligation-dependent Probe Amplification (MLPA) was used to detect duplications or deletions. RESULTS: The study in cluded 14 patients with suspected RTT, of which eight (57%) patients had pathogenic variants. The other patients remain without molecular diagnosis. CONCLUSIONS: Pathogenic variants in MECP2 are present in Chilean patients with RTT. It is likely that there are other genes or diagnoses involved in patients without MECP2 findings. As of this study, molecular diagnosis is available in Chile.

Diagnóstico de Rett. Presentación de un caso / Diagnosis of Rett. Presentation of a case

El síndrome de Rett es un trastorno neurológico que afecta casi únicamente a las niñas y mujeres, cuya incidencia en la población general es de un caso por cada 10 000 mujeres, su diagnóstico se basa en la observación y evaluación clínica(AU)

Transtornos autísticos e estratégias promotoras de cuidados: revisão integrativa / Trastornos autísticos y estratégias promotoras de cuidados: revisión integradora / Autistic disorders and care promotion strategies: integrative review

Objetivo analisar a produção científica brasileira recente sobre Transtornos do Espectro Autista, identificando as estratégias de cuidados investigadas. Método revisão integrativa de literatura na base de dados LILACS e na biblioteca virtual SciELO. Foram selecionados artigos publicados entre 2011 e 2017, utilizando os descritores Transtorno Autístico, Síndrome de Asperger e Síndrome de Rett. Resultados vinte e quatro artigos foram caracterizados e analisados descritivamente, com exposição dos seus níveis de evidência. Doze estudos (50%) representavam pesquisas descritivas, nível de evidência VI. Onze estudos (45,8%) equivaliam a delineamento não experimental, nível de evidência IV. A estratégia mais estudada foi de diagnóstico e avaliação para a prática clínica, com aplicação de instrumentos já validados, seguida de avaliação de resultados terapêuticos. Conclusão a produção científica brasileira atual sobre Transtorno do Espectro Autista mostrou-se direcionada para o enfoque diagnóstico nas áreas de fonoaudiologia e psicologia.

Objetivo analizar la producción científica brasileña reciente sobre Trastornos del Espectro Autista, identificando las estrategias de cuidados investigadas. Método revisión integradora de literatura en la base de datos LILACS y en la biblioteca virtual SciELO. Fueron seleccionados artículos publicados entre 2011 y 2017, utilizando los descriptores Trastorno Autístico, Síndrome de Asperger y Síndrome de Rett. Resultados veinte y cuatro artículos fueron caracterizados y analizados descriptivamente, con exposición de sus niveles de evidencia. Doce estudios (50%) representaban investigaciones descriptivas, nivel de evidencia VI. Once estudios (45,8%) correspondían a diseño no experimental, nivel de evidencia IV. La estrategia más estudiada fue de diagnóstico y evaluación para la práctica clínica, con aplicación de instrumentos ya validados, seguida de evaluación de resultados terapéuticos. Conclusión la producción científica brasileña actual sobre Trastorno del Espectro Autista se mostró orientada al enfoque diagnóstico en las áreas de fonoaudiología y psicología.

Objective to analyze the recent Brazilian scientific production about Autism Spectrum Disorders, identifying the investigated care strategies. Method integrative literature review in the database LILACS and in the virtual library SciELO. Articles published between 2011 and 2017 were selected, using the descriptors Autistic Disorder, Asperger Syndrome and Rett Syndrome. Results twenty four articles were characterized and analyzed descriptively, and their levels of evidence were presented. Twelve studies (50%) represented descriptive research, level of evidence VI. Eleven studies (45.8%) had non-experimental designs, level of evidence IV. The most studied strategy was the diagnosis and evaluation for clinical practice, by applying validated tools, followed by the assessment of therapeutic outcomes. Conclusion current Brazilian scientific production about Autism Spectrum Disorder was focused on diagnosis in speech therapy and psychology.

Use of sugammadex in Rett syndrome: A case report

Rett syndrome (RS) is a neurodevelopmental disorder characterized by loss of cognitive, motor, and social skills, epilepsy, autistic behavior, abnormal airway patterns, gastroesophageal reflux, nutritional problems, and severe scoliosis. Although girls with RS show normal or near-normal growth until 6–8 months, they lose their skills after that. The anesthetic management of these patients requires care because of all these clinical features. Especially in the postoperative period, prolonged apnea is common and extubation is delayed. In this case report, the effect of using sugammadex was presented in a 16-year-old girl with RS. The patient's all bimaxillary teeth and 4 wisdom teeth were extracted under general anesthesia in one session with minimal surgical trauma and moderate bleeding. Sugammadex can be a rapid and reliable agent for the reversal of the neuromuscular block in neurodegenerative patients.

Síndrome de Rett: revisión de la literatura con primeros casos reportados en Colombia con caracterización clínica y molecular / Rett syndrome: review of the literature and first cases reported in Colombia with clinical characterization and molecular diagnosis

RESUMEN INTRODUCCIÓN: El síndrome de Rett es una condición neurológica severa y la segunda causa genética de retraso mental profundo en mujeres. Se genera por mutaciones en el gen MECP2 y es caracterizada por una pérdida de las ganancias psicomotoras, con una prevalencia general estimada de 1:10.000 niñas, según la extrapolación de algunos estudios europeos. OBJETIVOS: Realizar una revisión de la literatura sobre el síndrome de Rett y presentar una serie de casos diagnosticados en Colombia por clínica y prueba molecular. METODOLOGÍA: Se efectuó una búsqueda bibliográfica y de reportes de casos en 21 bases de datos internacionales, más de 14 revistas del área de la salud y dos motores de búsqueda generales entre 2014 y 2016. Los casos presentados fueron seleccionados de la consulta de genética médica realizada por los autores. HALLAZGOS: No se encontró ningún caso colombiano de síndrome de Rett, ni confirmado con prueba molecular en Latinoamérica. Se reporta así la primera serie de casos nacional y la mayor latinoamericana, conformada por siete pacientes con tipo clásico y tres atípicos, todas con diagnóstico molecular. CONCLUSIONES: Pese a tener una evolución clínica caracterizada, su baja prevalencia y amplio espectro clínico convierten al síndrome de Rett en un reto diagnóstico y terapéutico. La mutación c.749_750insT se reporta por primera vez, la c.473C>G por segunda en la literatura y la c.763C>T se presenta en dos pacientes con fenotipos totalmente distintos, lo que confirma la no correlación genotipo-fenotipo de la enfermedad.

SUMMARY INTRODUCTION: Rett Syndrome is a severe neurological condition and the second genetic cause of profound mental retardation in women. It is generated by mutations in the MECP2 gene and it is characterized by a loss of psychomotor gains, with an estimated overall prevalence of 1:10,000 girls, according to the extrapolation of some European studies. Objectives. To make a review of Rett Syndrome and to present a series of cases diagnosed in Colombia by clinical criteria and molecular tests. METHODOLOGY: We made a bibliographic research in 21 international databases, more than 14 health journals and two general search engines between 2014 and 2016. The cases presented were selected from the Medical Genetics consultation carried out by the authors. FINDINGS: No Colombian case of Rett Syndrome was found nor confirmed with molecular testing in Latin America. We report the first cases in Colombia and the largest in Latin America, consisting of seven patients with classic type and three with atypical type, all with molecular diagnosis. CONCLUSIONS: In spite of having a characterized clinical evolution, its low prevalence and broad clinical spectrum, make Rett Syndrome a diagnostic and therapeutic challenge. We report for the first time the mutation c.749_750insT, the c.473C> G for second time in the literature and the c.763C> T is presented in two patients with totally different phenotypes, confirming the non-correlation genotype-phenotype of the disease.

Anesthetic management of a pediatric patient with Rett syndrome: A case report

Rett syndrome is a neurodevelopmental disease that almost always affects female patients. It is caused by mutations in MeCP2 in the majority of cases. Patients diagnosed with Rett syndrome may experience serious adverse events even with smaller amounts of medication for sedation and anesthesia. The major anesthetic concerns associated with Rett syndrome are lack of cooperation, abnormal continuous limb movements, abnormal respiratory control, difficult positioning secondary to scoliosis, and altered sensitivity to painful stimuli. Because of the risks caused by these problems, anesthesiologists should be aware of the specific anesthetic concerns of patients with Rett syndrome in order to safely administer anesthesia. Here, we describe the management of a pediatric patient diagnosed with Rett syndrome.

General and oral characteristics of Rett syndrome: case report / Características gerais e orais da Síndrome de Rett: um relato de caso

Introdução: a Síndrome de Rett é uma doença neurodegenerativa que ocorre em indivíduos do sexo feminino. É a segunda causa mais frequente de deficiência mental em meninas e pode atingir diversos grupos raciais em todo o mundo. Objetivo: descrever as características gerais e orais de um indivíduo que está no terceiro estágio da doença. Relato de caso: paciente do sexo feminino portador da síndrome, com 7 anos e sete meses de idade, leucoderma, procedente de Vallo della Lucania, Salerno, Itália. O indivíduo encontra-se no terceiro estágio da síndrome, no qual são observadas características como a redução do comportamento autista, melhoras no contato visual, no sorriso e melhoras nas habilidades comunicativas. Durante o primeiro estágio da síndrome, dos seis aos dezoito meses de vida, o indivíduo se alimentava sozinho, porém ainda não andava. Já no segundo estágio a partir dos 18 meses de vida, começou a andar com a base alargada e com dois anos parou de falar. O exame genético molecular para síndrome de Rett acusou que houve uma mutação genética chamada "ad novo", ou seja, a mutação não foi de caráter hereditário. Conclusão: não há tratamento específico para a síndrome de Rett, apenas de suporte por meio da fisioterapia, hidroterapia, terapia ocupacional, musicoterapia, equoterapia, além de terapêuticas que tratam apenas alguns sintomas apresentados pela síndrome. O tratamento deve ser realizado de maneira multidisciplinar. O prognóstico consiste em acompanhar o paciente por toda a vida, tratando os sintomas por ele apresentados.(AU)

Introduction: Rett syndrome is a neurodegenerative disease that affects females of all races worldwide. It is the second most frequent cause of mental disability in girls. Objective: To describe the general and oral characteristics at stage three. Case report: A girl aged seven years and seven months, leukoderma, coming from Vallo della Lucania, Salerno, Italy was at the stage three of Rett syndrome. At the first stage, from six to eighteen months of life, the girl ate by herself, but she did not walk. At the second stage, from eighteen months of life, she started the ataxic gait and stopped talking. At the third stage, she had the reduction of the autist behavior, improved the eye contact, smile and communicative abilities. The genetic examination revealed de novo mutation, that is, without inheritance. Conclusion: Rett syndrome lacks specific treatment. Adjuvant therapies include physiotherapy, hydrotherapy, occupational therapy, music therapy, equine therapy, as well as therapies to treat some symptoms. A multidisciplinary treatment is required. The prognosis consists of following-up the individual throughout life, treating the symptoms.(AU)

Application of array comparative genomic hybridization in Korean children under 6 years old with global developmental delay / 소아과

PURPOSE: Recent advancements in molecular techniques have greatly contributed to the discovery of genetic causes of unexplained developmental delay. Here, we describe the results of array comparative genomic hybridization (CGH) and the clinical features of 27 patients with global developmental delay. METHODS: We included 27 children who fulfilled the following criteria: Korean children under 6 years with global developmental delay; children who had at least one or more physical or neurological problem other than global developmental delay; and patients in whom both array CGH and G-banded karyotyping tests were performed. RESULTS: Fifteen male and 12 female patients with a mean age of 29.3±17.6 months were included. The most common physical and neurological abnormalities were facial dysmorphism (n=16), epilepsy (n=7), and hypotonia (n=7). Pathogenic copy number variation results were observed in 4 patients (14.8%): 18.73 Mb dup(2)(p24.2p25.3) and 1.62 Mb del(20p13) (patient 1); 22.31 Mb dup(2) (p22.3p25.1) and 4.01 Mb dup(2)(p21p22.1) (patient 2); 12.08 Mb del(4)(q22.1q24) (patient 3); and 1.19 Mb del(1)(q21.1) (patient 4). One patient (3.7%) displayed a variant of uncertain significance. Four patients (14.8%) displayed discordance between G-banded karyotyping and array CGH results. Among patients with normal array CGH results, 4 (16%) revealed brain anomalies such as schizencephaly and hydranencephaly. One patient was diagnosed with Rett syndrome and one with Möbius syndrome. CONCLUSION: As chromosomal microarray can elucidate the cause of previously unexplained developmental delay, it should be considered as a first-tier cytogenetic diagnostic test for children with unexplained developmental delay.

Síndrome de Rett: uma revisão da literatura / Rett Syndrome: a review of the literature

Síndrome de Rett (SR) é uma desordem neurológica severa do desenvovimento, e a sua incidência é de 1:10.000 nascimentos do sexo feminino, uma das causas genéticas mais comuns de atraso mental severo em mulheres. O desenvolvimento é aparentemente normal nos primeiros seis a 18 meses de vida até que ocorre a regressão das habilidades cognitivas, sociais e motoras. A progressão e severidade da desordem são avaliadas de forma clássica e divididas em estágio I, de estagnação precoce, estágio II, rapidamente destrutivo, estágio III, pseudo estacionária, e estágio IV, de deterioração motora tardia. As mutações no gene ligado ao X metil-CpG de ligação a proteína 2 (MECP2) está presente na maioria das pacientes com a SR. O tratamento fisioterapêutico é bastante eficaz, visto que melhora ou mantém as capacidades funcionais, funções sensoriais e motoras na SR. Benefícios estes que causam grande impacto na qualidade de vida desses indivíduos com deficiências severas.

Rett syndrome (RS) is a severe neurological developmental disorder, and its incidence is 1: 10,000 female births, one of the most common genetic causes of severe mental retardation in females. The development is apparently normal in the first six to 18 months of life until regression occurs cognitive, social and motor skills. The progression and severity of the disorder are assessed and classically divided into stage I, early stagnation, stage II, rapidly destructive, stage III, stationary pseudo, and stage IV, the late motor deterioration. Mutations in the X-linked gene 2 protein binding of methyl-CpG (MECP2) is present in most patients with MR. The physical therapy is quite effective, as it improves or maintains the funcional, sensory and motor functions in SR. These benefits that greatly impact quality of life of individuals with severe disabilities.

Functional Profiling of Human MeCP2 by Automated Data Comparison Analysis and Computerized Expression Pathway Modeling / 대한의료정보학회지

OBJECTIVES: Methyl-CpG binding protein 2 (MeCP2) is a ubiquitous epigenetic factor that represses gene expression by modifying chromatin. Mutations in the MeCP2 gene cause Rett syndrome, a progressive neurodevelopmental disorder. Recent studies also have shown that MeCP2 plays a role in carcinogenesis. Specifically, functional ablation of MeCP2 suppresses cell growth and leads to the proliferation of cancer cells. However, MeCP2's function in adult tissues remains poorly understood. We utilized a weight matrix-based comparison software to identify transcription factor binding site (TFBS) of MeCP2-regulated genes, which were recognized by cDNA microarray analysis. METHODS: MeCP2 expression was silenced using annealed siRNA in HEK293 cells, and then a cDNA microarray analysis was performed. Functional analysis was carried out, and transcriptional levels in target genes regulated by MeCP2 were investigated. TFBS analysis was done within genes selected by the cDNA microarray analysis, using a weight matrix-based program and the TRANSFAC 6.0 database. RESULTS: Among the differentially expressed genes with a change in expression greater than two-fold, 189 genes were up-regulated and 91 genes were down-regulated. Genes related to apoptosis and cell proliferation (JUN, FOSL2, CYR61, SKIL, ATF3, BMABI, BMPR2, RERE, and FALZ) were highly up-regulated. Genes with anti-apoptotic and anti-proliferative functions (HNRPA0, HIS1, and FOXC1) were down-regulated. Using TFBS analysis within putative promoters of novel candidate target genes of MeCP2, disease-related transcription factors were identified. CONCLUSIONS: The present results provide insights into the new target genes regulated by MeCP2 under epigenetic control. This information will be valuable for further studies aimed at clarifying the pathogenesis of Rett syndrome and neoplastic diseases.

Functional Profiling of Human MeCP2 by Automated Data Comparison Analysis and Computerized Expression Pathway Modeling / 대한의료정보학회지

OBJECTIVES: Methyl-CpG binding protein 2 (MeCP2) is a ubiquitous epigenetic factor that represses gene expression by modifying chromatin. Mutations in the MeCP2 gene cause Rett syndrome, a progressive neurodevelopmental disorder. Recent studies also have shown that MeCP2 plays a role in carcinogenesis. Specifically, functional ablation of MeCP2 suppresses cell growth and leads to the proliferation of cancer cells. However, MeCP2's function in adult tissues remains poorly understood. We utilized a weight matrix-based comparison software to identify transcription factor binding site (TFBS) of MeCP2-regulated genes, which were recognized by cDNA microarray analysis. METHODS: MeCP2 expression was silenced using annealed siRNA in HEK293 cells, and then a cDNA microarray analysis was performed. Functional analysis was carried out, and transcriptional levels in target genes regulated by MeCP2 were investigated. TFBS analysis was done within genes selected by the cDNA microarray analysis, using a weight matrix-based program and the TRANSFAC 6.0 database. RESULTS: Among the differentially expressed genes with a change in expression greater than two-fold, 189 genes were up-regulated and 91 genes were down-regulated. Genes related to apoptosis and cell proliferation (JUN, FOSL2, CYR61, SKIL, ATF3, BMABI, BMPR2, RERE, and FALZ) were highly up-regulated. Genes with anti-apoptotic and anti-proliferative functions (HNRPA0, HIS1, and FOXC1) were down-regulated. Using TFBS analysis within putative promoters of novel candidate target genes of MeCP2, disease-related transcription factors were identified. CONCLUSIONS: The present results provide insights into the new target genes regulated by MeCP2 under epigenetic control. This information will be valuable for further studies aimed at clarifying the pathogenesis of Rett syndrome and neoplastic diseases.

Induced Pluripotent Stem Cells as a Novel Tool in Psychiatric Research

Reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) provides a valuable opportunity to study neurodevelopmental and neurodegenerative psychiatric diseases by offering an unlimited source for patient-specific neuronal and glial cells. The present review focuses on the recent advancements in modeling psychiatric disorders such as Phelan-McDermid syndrome, Timothy syndrome, Rett syndrome, schizophrenia, bipolar disorder, and dementia. The treatment effects identified in studies on iPSCs using known therapeutic compounds are also summarized in this review. Here we discuss validation of cellular models and explore iPSCs as a novel drug screening tool. Although there are several limitations associated with the current methods used to study mental disorders, using iPSCs as a model system provides the advantage of rewinding and reviewing the development and degeneration of human neural cells.

Etiología del autismo: el continuo idiopático-sindrómico como tentativa explicativa / Etiology of autism: the idiopathic-syndromic continuum as explanatory attempt

Although already none doubt that the autism spectrum disorders (ASD) constitute a myriad of clinical syndromes, linked to neurodevelopment, there are still many questions that need be answered. Thus, researchers focus their efforts in genetic disorders that are in the origin of secondary autism, for to know more aboutprimary autism (or idiopathic), whose concrete cause is ignored. Delving into this, we review here recent findings in the research of such disorders, convinced that there is a primary-secondary autism continuum that rigorous studies in molecular genetics must show. However, there is much pathology with autistic behaviors whose etiology remains still unknown. In this line, aside from books, were selected indexed articles in MEDLINE, published from 2008 to 2015, related to advances in genetic research and diagnosis from autistic spectrum disorder. Like key words were used "autism", and the paired-words combinations of "autism and etiology", "autism and neurodevelopment" and "autism and genetics".

Aunque ya nadie duda que los trastornos del espectro autista (TEA) conformen una miríada de síndromes clínicos, vinculados al neurodesarrollo, aún existen muchos interrogantes por responder. Por ello, distintos investigadores centran sus esfuerzos en los trastornos genéticos causantes del autismo secundario, para así saber más del autismo primario (o idiopático), cuya causa concreta se ignora. Ahondando en esto, se revisan aquí hallazgos recientes obtenidos en la investigación de tales trastornos, al creer que existe un continuo entre el autismo primario y su homólogo secundario, que estudios rigurosos en genética molecular deberán evidenciar. No obstante, hay diversidad de patologías con conductas autistas cuya etiología aún se ignora. En tal línea, además de libros, se seleccionaron artículos indexados en MEDLINE, publicados entre 2008 y 2015, relacionados con avances en la investigación genética y diagnóstico del espectro autista. Como palabras claves se utilizaron "autismo", y las combinaciones "autismo y etiología", "autismo y neurodesarrollo" y "autismo y genética".

Sindrome de Rett. Reporte de dos casos / Rett syndrome. Two Cases Report

El Síndrome de Rett es un trastorno severo del neurodesarrollo, caracterizado por un desarro- llo psicomotor aparentemente normal hasta los primeros 6 meses de vida seguido por el estancamiento y regresión del crecimiento, sistema motor, lenguaje y habilidades sociales posteriores, no asociado a una injuria cerebral por trauma, desordenes metabólicos o infec- ciones severas. A menudo se observa un com- portamiento autista en etapas tempranas: otros síntomas que acompañan este trastorno incluyen convulsiones, alteraciones respirato- rias como la hiperventilación, apnea y aerofa- gia, ataxia y estereotipas con las manos. Repre- senta la segunda causa de discapacidad inte- lectual en las mujeres. Es causado por una mutación ligada a X que codifica a la proteína ligadora de metil CpG-2 (MECP2). A continua- ción se presentan dos casos de pacientes con síndrome de Rett una de ellas con estudio molecular positivo...(AU)

Bases moleculares del síndrome de Rett, una mirada actual / Molecular basis of Rett syndrome: A current look

El síndrome de Rett (SR) es un trastorno del neurodesarrollo que afecta casi exclusivamente a niñas y cursa secundariamente con autismo. Es poco frecuente y consta de 5 formas clínicas, una clásica y el resto atípicas que comprometen de manera general la habilidad manual, el lenguaje y la motricidad amplia unida a la aparición de estereotipias y epilepsia precoz. Con el objetivo de actualizar la información sobre SR, se aplicaron los descriptores de búsqueda Síndrome de Rett, genes y «Síndrome de Rett¼, «Rett Syndrome gene¼, «Rett Syndrome¼, «Rett Syndrome gene therapy¼ y «Rett Syndrome review¼. Se investigó en los archivos digitales PubMed, Hinari, SCIELO y Medline, y se consultaron los sitios web OMIM, ORPHANET, GeneMap, Genetests, Proteins y Gene, entre otros. Entre 1.348 artículos se seleccionaron 42, los cuales reportan 3 genes causantes del síndrome: MECP2, CDKL5 y FOXG. El gen MECP2 está mutado en el 80% de los pacientes con SR clásico así como en el 40% de los afectados con alguna de sus formas atípicas. El SR con epilepsia precoz y la variante congénita se deben fundamentalmente a variaciones en los genes CDKL5 y FOXG1 respectivamente. Conclusiones: El diagnóstico del SR se basa en criterios clínicos, sin embargo, los avances en la biología molecular y en la genética en particular han abierto el abanico de posibilidades diagnósticas a las diferentes formas clínicas que antes quedaban sin clasificar, a la vez que el análisis molecular permite confirmar el criterio clínico y aportar información en cuanto al pronóstico del paciente.

Rett syndrome (RS) is a neurodevelopmental disorder that exclusively affects girls, and occurs along with autism. It is very uncommon, and has five distinct forms, one classic and the others atypical, which generally compromise manual skills, language, and mobility, and widely associated with the appearance of stereotypy and early epilepsy. With the aim of updating the information about RS, a search was performed in the computer data bases of PubMed, Hinari, SCIELO and Medline, as well as consulting other web sites including OMIM, ORPHANET, GeneMap, Genetests, Proteins and Gene, using the descriptors "Síndrome de Rett", "genes y Síndrome de Rett", "Rett Syndrome gene", "Rett Syndrome", "Rett Syndrome gene therapy", and "Rett Syndrome review". Of the 1,348 articles found, 42 articles were selected, which reported 3 genes causing the syndrome: MECP2, CDKL5 and FOXG. The MECP2 gene is mutated in 80% of patients with classic RS, as well as in 40% of those affected by any of its atypical forms. RS with early epilepsy and the congenital variant are mainly due to variations in the CDKL5 and FOXG1 genes, respectively. Conclusions: The diagnosis of RS is based on clinical criteria. However, the advances in molecular biology and genetics have opened a wide range of possibilities for diagnosing the different clinical forms that could not be classified before. Molecular analysis can help confirm the clinical criteria and provided information as regards the prognosis of the patient.