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)

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.

Genetic studies in children with intellectual disability and autistic spectrum of disorders.

Autism is one of the five disorders that falls under the umbrella of Pervasive Developmental Disorders (PDD) or Autism Spectrum Disorder (ASD), a category of neurological disorders characterized by “severe and pervasive impairment in several areas of development.” ASD is characterized by varying degrees of impairment in communication skills, social interaction and restricted, repetitive stereotyped patterns of behavior. The five disorders under PDD are autistic disorder, Asperger's disorder, childhood disintegrative disorder, Rett's disorder and PDD-not otherwise specified. ASD can often be reliably detected by the age of 3 years and, in some cases, as early as 18 months. The appearance of any warning signs of ASD is reason to have the child evaluated by a professional specializing in these disorders.

Concepts of color, shape, size and position in ten children with Rett syndrome / Conceitos de cor, forma, tamanho e posição em dez crianças com síndrome de Rett

Individuals with Rett syndrome (RS) present severe motor, language and cognitive deficits, as well as spontaneous hand movement loss. On the other hand, there are strong evidence that these individuals use the eyes with intentional purpose. Ten girls aged 4y8m to 12y10m with RS were assessed with a computer system for visual tracking regarding their ability of indicating with eyes the recognition of concepts of color (red, yellow and blue), shape (circle, square and triangle), size (big and small) and spatial position (over and under) to which they were first exposed to. Results from comparing the time of eyes fixation on required and not required concepts did not differ significantly. Children did not show with eyes the recognition of the required concepts when assessed with eye tracking system.

Pessoas com síndrome de Rett (SR) apresentam severos prejuízos psicomotores, verbais, cognitivos e perda das habilidades manuais proposicionais que impedem o conhecimento de suas reais aquisições intelectuais. Entretanto, estudos relatam que essas pessoas utilizam o olhar com finalidade intencional. O objetivo deste estudo foi avaliar se crianças com SR, após terem sido expostas aos conceitos de cor (vermelho, amarelo e azul), forma (círculo, quadrado e triângulo), tamanho (grande e pequeno) e posição espacial (em cima e em baixo), manifestam o reconhecimento desses conceitos com o olhar, avaliado com equipamento computadorizado de rastreamento ocular. Foram avaliadas dez crianças com diagnóstico de SR, com idades entre 4 anos e 8 meses e 12 anos e 10 meses. Os resultados não indicaram diferenças significativas no tempo de fixação do olhar das crianças quando comparados os conceitos solicitados e os não solicitados. Concluiu-se que, com o método utilizado, as crianças não reconheceram os conceitos avaliados.

Rett syndrome: clinical and molecular characterization of two Brazilian patients

BACKGROUND: Rett syndrome (RS) is recognized as a pan-ethnic condition. Since the identification of mutations in the MECP2 gene, more patients have been diagnosed, and a broad spectrum of phenotypes has been reported. There is a lack of phenotype-genotype studies. OBJECTIVE: To describe two cases of Brazilian patients with identified MECP2 mutations. METHOD: We present two female Brazilian patients with RS. RESULTS: Both patients presented with regression at 2-3 years of age, when stereotypic hand movements, social withdrawal and postnatal deceleration of head growth rate were observed. Both patients presented verbal communication impairment. Case 1 had loss of purposeful hand movements, and severe seizure episodes. Case 2 had milder impairment of purposeful hand movements, and no seizures. They had different mutations, D97Y and R294X, found in exons 3 and 4 of MECP2 gene, respectively. CONCLUSION: Testing for MECP2 mutations is important to confirm diagnosis and to establish genotype/phenotype correlations, and improve genetic counseling.

CONTEXTO: Síndrome de Rett (RS) é doença pan-étnica de fenótipo bastante variado desde que foram identificadas mutações no gene MECP2 e um número maior de pacientes tem sido diagnosticadas. Existe uma demanda por estudos que investiguem a relação genótipo-fenotipo. OBJETIVO: Descrever dois casos brasileiros de RS com mutações identificadas. MÉTODO: Duas pacientes brasileiras com diagnóstico clínico-molecular de RS foram descritas buscando-se correlacionar genótipo-fenótipo. RESULTADOS: Ambas pacientes apresentaram regressão aos 2-3 anos de idade, movimentos esteriotipados de mãos, retraimento social e desaceleração do crescimento encefálico. Ambas apresentaram déficit de comunicação verbal. Caso 1 também apresentou perda dos movimentos manuais intencionados e crises convulsivas graves. Caso 2 apresentou-se com comprometimento parcial dos movimentos manuais e sem história de crise convulsiva. As mutações distintas, D97Y e R294X, foram encontradas respectivamente em exons 3 e 4 do gene MECP2. CONCLUSÃO: A investigacao de mutações no gene MECP2 é importante na confirmação diagnóstica, investigação genótipo-fenótipo, e aconselhamento genético em síndrome de Rett.

Transtornos invasivos do desenvolvimento não-autísticos: síndrome de Rett, transtorno desintegrativo da infância e transtornos invasivos do desenvolvimento sem outra especificação / Non-autistic pervasive developmental disorders: Rett syndrome, disintegrative disorder and pervasive developmental disorder not otherwise specified

A categoria "transtorno invasivos do desenvolvimento" inclui o autismo, a síndrome de Asperger, a síndrome de Rett, o transtorno desintegrativo da infância e uma categoria residual denominada transtornos invasivos do desenvolvimento sem outra especificação. Nesta revisão, a síndrome de Rett e o transtorno desintegrativo da infância, que são categorias bem definidas, serão discutidas, assim como as categorias não tão bem definidas que foram incluídas no grupo transtornos invasivos do desenvolvimento sem outra especificação. Diferentes propostas de categorização têm sido feitas, algumas baseadas em abordagem fenomenológica descritiva, outras baseadas em outras perspectivas teóricas, tais como a neuropsicologia. As propostas atuais são apresentadas e discutidas, seguidas por avaliações críticas sobre as vantagens e desvantagens desses conceitos.

Diagnostic mutational analysis of MECP2 in Korean patients with Rett syndrome

Rett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder affecting 1 per 10,000- 15,000 female births worldwide. The disease-causing gene has been identified as MECP2 (methyl- CpG-binding protein 2). In this study, we performed diagnostic mutational analysis of the MECP2 gene in RTT patients. Four exons and a putative promoter of the MECP2 gene were analyzed from the peripheral blood of 43 Korean patients with Rett syndrome by PCR-RFLP and direct sequencing. Mutations were detected in the MECP2 gene in approximately 60.5% of patients (26 cases/43 cases). The mutations consisted of 14 different types, including 9 missense mutations, 4 nonsense mutations and 1 frameshift mutation. Of these, three mutations (G161E, T311M, p385fsX409) were newly identified and were determined to be disease-causing mutations by PCR- RFLP and direct sequencing analysis. Most of the mutations were located within MBD (42.3%) and TRD (50%). T158M, R270X, and R306C mutations were identified at a high frequency. Additionally, an intronic SNP (IVS3+23C>G) was newly identified in three of the patients. IVS3+23C>G may be a disease-related and Korea-specific SNP for RTT. L100V and A201V are apparently disease-causing mutations in Korean RTT, contrary to previous studies. Disease-causing mutations and polymorphisms are important tools for diagnosing RTT in Koreans. The experimental procedures used in this study should be considered for clinical molecular biologic diagnosis.

Rett syndrome: a case report and overview.

A 3-year-old girl with Rett syndrome is reported in this case report. The aim of this report is to highlight the clinical features of this rare neurodegenerative disorder that mainly affects young girls. A brief review of literature of this disorder is included.

Recent experience with Rett syndrome at a tertiary care center.

Rett syndrome (RS), a neurological developmental disorder, is one of the commonest causes of cognitive impairment in girls and women. These patients are often initially misdiagnosed as idiopathic mental retardation, cerebral palsy, or autism. Despite several reports from the West, there are very few reports from the Indian population. We present four female children with RS and emphasize the importance of early diagnosis.

Rett syndrome: clinical and epidemiological aspects in a Brazilian institution

Rett syndrome (RS) is a neurodevelopmental disorder, preferentially found in females and specifically involving the functions on which intelligence and its expression depend - learning, hand use and speech - leaving many others intact. Mutations have been identified at Xq28 on the MECP2 gene (methyl-CpG 2), which selectively silences the expression of other genes whose location is still unknown. This is a study on clinical, diagnostic and epidemiological aspects of RS in a Brazilian sample. It included 33 female patients with chronic encephalopathy without known etiology. RS was diagnosed in 24 patients (72.7 percent): 17 (70.8 percent) had classical RS; 5 (20.8 percent), atypical RS and 2 (8.4 percent), potential RS. In 9 girls clinical data and/or laboratory studies excluded diagnosis of RS. Among the atypical RS patients, 4 were form fruste and one, congenital form. Among the girls with other encephalopathies, cerebral malformation was the most frequent finding

Un caso de síndrome de Rett / A case of Rett syndrome

Se reporta un caso de Síndrome de Rett clásico en una niña de 5 años de edad, quién el diagnóstico fue díficil en su fase inicial, debido a la variación de la clínica en los diferentes estadios de la enfermedad. Es así como de los 6 meses a los 18 meses se planteó el diagnóstico de síndrome hipotónico, parálisis cerebral infantil. Luego de los 2 a los 3 1/2 años de edad se planteó el diagnóstico de autismo, encefalopatía progresiva, retardo mixto del desarrollo cognitivo y psicomotor. A los 4 años de edad la enfermedad se estabilizó clínicamente, los rasgos autistas disminuyeron y fue cuando se hizo el diagnóstico clínico de Síndrome de Rett, cumpliendo con los criterios de diagnóstico para el Síndrome de Rett clásico, según Baden-Baden. Este caso es de gran intéres, tanto por la baja frecuencia de los casos y lo poco conocido para los profesionales de la salud, como por la gran diversidad de manifestaciones clínicas que se presentan en los diferentes estadios de la evolución de la enfermedad, lo cual hay que tener en cuenta para poder realizar el diagnóstico del mismo; así poder instaurar el tratamiento adecuado

Síndrome de Rett / Rett syndrome

A partir do que já se conhece sobre a síndrome de Rett, este artigo focaliza as informações mais recentes da literatura internacional sobre os aspectos genéticos e etiológicos desta condição, bem como sobre a sua identificação clínica e laboratorial, neuropatologia, eletrofisiologia, e evolução clínica (epilepsia, distúrbios respiratórios, distúrbios autonômicos e aspectos nutricionais), enfatizando, ainda, que, embora até recentemente tida como condição que afetava apenas o sexo feminino, também pode estar presente no sexo masculino, ainda que com fenótipo diverso

Rett's syndrome - a neurodevelopmental disorder: report of two cases.

Rett's syndrome (RS), a pervasive neurodevelopmental disorder, is being increasingly recognized all over the world, but there is paucity of reports from India. Due to its manifestations at any stage of development, it is important to arrive at a correct diagnosis. Two cases are presented, highlighting the need to recognize this relatively uncommon disorder and to differentiate it from various other neurodegenerative disorders.