Les troubles du neurodéveloppement tels que le syndrome de Rett et les troubles du spectre de l'autisme (TSA), touchent environ 2% des enfants âgés entre 1 à 17 ans au Canada et sont caractérisés par un déséquilibre de l'homéostasie des ions chlorure (Cl-). Cette perturbation de l'homéostasie Cl est souvent associée à un trouble d'inhibition neuronale lié à la fonction de l'acide gamma-aminobutyrique (GABA), le principal neurotransmetteur inhibiteur du cerveau. Cet équilibre est fortement régulé par l'expression de deux cotransporteurs, le NKCC1 (cotransporteur Na-K-Cl, importateur de Cl) et le KCC2 (cotransporteur K-Cl, exportateur de Cl). Pour étudier les troubles neurodéveloppementaux liés au transport du Cl, nous nous sommes concentrés sur l'expression du cotransporteur KCC2, un cotransporteur spécifique aux neurones du système nerveux central (SNC). Son expression augmente au cours du neurodéveloppement, mais elle est altérée dans le contexte des troubles du neurodéveloppement. À cet égard, nous avons utilisé un modèle d'organoïdes cérébraux humains (hCOs) pour obtenir un environnement 3D fidèle à la neurogenèse humaine, fournissant des interactions biologiques complexes entre plusieurs types cellulaires. Ces hCOs ont été dérivés de cellules souches pluripotentes induites (hiPSCs) reprogrammées à partir de cellules de patientes atteintes du syndrome de Rett, portant des mutations sur le gène MECP2 et leurs lignées contrôles isogéniques. Pour aider à comprendre l'importance des cotransporteurs NKCC1 et KCC2 dans les troubles d'inhibition neuronale lors du neurodéveloppement, nous avons performé une série de RT-qPCR sur des hCOs mutés pour le gène MECP2 à différents moments dans le temps. Puisqu'une compréhension de la cause et des conséquences d'un débalancement de l'équilibre excitateur/inhibiteur (E/I) du GABA est la première étape vers la conception d'une thérapie, ce modèle pourrait éventuellement être utilisé pour investiguer la pharmacogénétique associée à de futurs traitements. / Neurodevelopmental disorders, such as Rett syndrome and autism spectrum disorder (ASD), affect approximately 2% of children aged 1 to 17 years in Canada and are characterized by an imbalance in chloride ion (Cl-) homeostasis. This disruption of Cl homeostasis is often associated with a neuronal inhibition disorder related to the function of gamma-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the brain. This balance is heavily regulated by the expression of two cotransporters, the NKCC1 (Na-K-Cl cotransporter, importer of Cl ) and the KCC2 (K-Cl cotransporter, exporter of Cl ). To investigate neurodevelopmental disorders related to Cl transport, we focused on KCC2, the cotransporter specific to neurons in the central nervous system (CNS). Its expression increases during healthy neurodevelopment but is altered in the context of neurodevelopmental disorders. In this regard, we use a model of human cerebral organoids (hCOs) to obtain a 3D environment faithful to human neurogenesis, providing complex biological interactions between multiple cell types. These hCOs were derived from induced pluripotent stem cells (hiPSCs) obtained from female patients with Rett syndrome carrying mutations in the MECP2 gene and isogenic control hiPSC lines. To help understand the importance of cotransporters NKCC1 and KCC2 in neuronal inhibition disorders during neurodevelopment, we performed a series of RT-qPCRs on hCOs carrying mutations in the MECP2 gene, at different time points. Since an understanding of the cause and consequences of an imbalance in the excitatory/inhibitory (E/I) balance of GABA is the first step towards the development of a therapy, this model could potentially be used to investigate the pharmacogenetics associated to future treatments.

A síndrome de Rett (SR) é um distúrbio neurológico progressivo de causa genética que afeta quase exclusivamente o sexo feminino. É causada por mutações, geralmente esporádicas, do gene MECP2, localizado no cromossomo X. Apresenta como características principais: estagnação no desenvolvimento neuropsicomotor, perda de comunicação, do contato visual, do interesse por pessoas e objetos e estereotipias manuais. Em conseqüência do grave comprometimento cognitivo e motor, as portadoras de SR têm muita dificuldade em realizar as tarefas do dia-a-dia. O objetivo desse trabalho foi avaliar as habilidades funcionais e averiguar as necessidades de assistência do cuidador, conforme determinadas pelo Inventário de Avaliação Pediátrica de Incapacidade (PEDI). Esse instrumento de avaliação, que possui 197 itens nas áreas de autocuidado, mobilidade e função social, foi aplicado em 64 portadoras de SR que preenchiam os critérios para a forma clássica da doença. Elas tinham idade entre 2 e 26 anos, com média de 10 anos. Entre as 73 atividades da área de autocuidado do PEDI, 52 (71,2%) não foram realizadas por qualquer criança; na área de mobilidade, entre as 59 atividades propostas, 8 (13,5%) não foram feitas pelas portadoras de SR; e finalmente na área de função social, nenhuma das 50 (76,9%) entre 65 atividades foi realizada. O desempenho médio ajustado em escala de 0 a 100 para a área de autocuidado foi de 8,9/100, variando de 0 a 26; para a de mobilidade, foi em média de 30,2/100, variando de 1,7 a 74,5; e a de função social foi de 5,2/100, com variação de 0 a 21,5. A necessidade de assistência foi, de forma complementar, maior nas áreas de autocuidado e função social do que na de mobilidade. Não encontramos, em nossa amostra, uma relação entre a idade e o grau de incapacidade, sugerindo que as portadoras de SR apresentam um nível de comprometimento que é, desde o início, bastante grave. Infelizmente, o menor comprometimento da mobilidade, comparado com as áreas de autocuidado e função social, não traz vantagens adaptativas ou maior independência às portadoras de SR. / Rett syndrome (RS) is a progressive neurological disturbance of genetic cause that affects females almost exclusively. It is caused by mutations, usually sporadic, of the MECP2 gene located in the X chromosome. Presented as main characteristics: stagnation in neuromotor development; losses of communication, visual contact, interest for people and objects; and manual stereotypes. In consequence to the serious cognitive and motor compromise, the RS patients have great difficulty in accomplishing day-to-day tasks. The objective of this work was to evaluate the functional abilities and to discover the needs of assistance by the caregiver, conforming to the established Pediatric Evaluation of Disability Inventory (PEDI). That evaluation instrument, which possesses 197 items in the areas of self-care, mobility and social function, was applied to 64 individuals with RS that matched the criteria for the classic form of the disease. Their ages ranged between 2 years and 26 years, with an average of 10 years. Among the 73 PEDI activities in the area of self-care, 52 (71.2%) were not accomplished by any child; in the area of mobility, among the 59 proposed activities, 8 (13.5%) were not done by any RS patient; and finally in the area of social function, none of the 50 (76.9%) activities among 65 were accomplished. The average performance adjusted in a scale from 0 to 100 for the area of self-care was of 8.9/100, varying from 0 to 26; for mobility, it was an average of 30.2/100, varying from 1.7 to 74.5; and of social function was 5.2/100, with variation from 0 to 21.5. The need of attendance was, in a complementary way, greater in the self-care areas and social function than in mobility. We didn\'t find, in our sample, a relationship between the age and the degree of incapacity, suggesting that RS individual present a compromising level that is from the beginning quite serious. Unfortunately, the smallest compromise of mobility, compared with the areas of self-care and social function, doesn\'t bring adaptive advantages or greater independence to the RS patients.

Made available in DSpace on 2016-03-15T19:40:30Z (GMT). No. of bitstreams: 1 Renata de Lima Velloso.pdf: 575032 bytes, checksum: 2ded8ecbcde5b280b54ac0be7c3a6a35 (MD5) Previous issue date: 2008-01-29 / Fundo Mackenzie de Pesquisa / Children with Rett Syndrome (RS) are supposed to present progressive regression of psychomotor development and speech abilities as well as spontaneous hand movement loss, resulting in severe difficulties for their communication. Several studies have been reporting that RS girls use the eyes with intentional purpose for communicating or expressing desires, and these findings make possible the use of eyes movements as a tool for assessing other RS aspects, such as the cognitive aspects. Ten girls aged 4y8m to 12y10m with RS were assessed for this investigation with a computer system for visual tracking regarding their ability of recognizing concepts of color (red, yellow and blue), shape (circle, square and triangle), size (big and small) and spatial position (over and under). Results from comparing the time of eyes fixation on required and not required concepts did not differ significantly. Correlation between age advancement and ability for recognizing the concept of the color "blue" could be observed. Children did not show to recognize the most part of the required concepts when assessed with eye tracking system. / Crianças com Síndrome de Rett (SR) apresentam regressão progressiva do desenvolvimento psicomotor e das habilidades de linguagem verbal e perda das habilidades manuais voluntárias, o que lhes dificulta a comunicação. Estudos relatam que meninas com SR utilizam o olhar com finalidade intencional, como forma de comunicação ou de expressão de desejos, o que levanta a possibilidade de avaliação de outros aspectos por meio do olhar, como os aspectos cognitivos. O objetivo deste estudo foi avaliar, em crianças com SR, o reconhecimento dos conceitos de cor (vermelho, amarelo e azul), forma (círculo, quadrado e triângulo), tamanho (grande e pequeno) e posição espacial (em cima e embaixo), com a utilização de equipamento computadorizado de rastreamento ocular. Participaram do estudo 10 crianças com diagnóstico de SR com idade entre 4 anos e 8 meses e 12 anos e 10 meses. Comparando-se o tempo de fixação do olhar das crianças para o conceito solicitado com o tempo de fixação para outros conceitos não solicitados, os resultados não indicaram muitas diferenças significativas. Houve correlação entre o conceito cor "azul" e o aumento da idade, indicando que as crianças mais velhas aprendem o conceito "azul". Concluiu-se que, com o método de avaliação utilizado, as crianças não reconheceram a maior parte dos conceitos de cor, forma, tamanho e posição.

A síndrome de Rett (SR) é um distúrbio neurológico progressivo de causa genética que afeta quase exclusivamente o sexo feminino. É causada por mutações, geralmente esporádicas, do gene MECP2, localizado no cromossomo X. Apresenta como características principais: estagnação no desenvolvimento neuropsicomotor, perda de comunicação, do contato visual, do interesse por pessoas e objetos e estereotipias manuais. Em conseqüência do grave comprometimento cognitivo e motor, as portadoras de SR têm muita dificuldade em realizar as tarefas do dia-a-dia. O objetivo desse trabalho foi avaliar as habilidades funcionais e averiguar as necessidades de assistência do cuidador, conforme determinadas pelo Inventário de Avaliação Pediátrica de Incapacidade (PEDI). Esse instrumento de avaliação, que possui 197 itens nas áreas de autocuidado, mobilidade e função social, foi aplicado em 64 portadoras de SR que preenchiam os critérios para a forma clássica da doença. Elas tinham idade entre 2 e 26 anos, com média de 10 anos. Entre as 73 atividades da área de autocuidado do PEDI, 52 (71,2%) não foram realizadas por qualquer criança; na área de mobilidade, entre as 59 atividades propostas, 8 (13,5%) não foram feitas pelas portadoras de SR; e finalmente na área de função social, nenhuma das 50 (76,9%) entre 65 atividades foi realizada. O desempenho médio ajustado em escala de 0 a 100 para a área de autocuidado foi de 8,9/100, variando de 0 a 26; para a de mobilidade, foi em média de 30,2/100, variando de 1,7 a 74,5; e a de função social foi de 5,2/100, com variação de 0 a 21,5. A necessidade de assistência foi, de forma complementar, maior nas áreas de autocuidado e função social do que na de mobilidade. Não encontramos, em nossa amostra, uma relação entre a idade e o grau de incapacidade, sugerindo que as portadoras de SR apresentam um nível de comprometimento que é, desde o início, bastante grave. Infelizmente, o menor comprometimento da mobilidade, comparado com as áreas de autocuidado e função social, não traz vantagens adaptativas ou maior independência às portadoras de SR. / Rett syndrome (RS) is a progressive neurological disturbance of genetic cause that affects females almost exclusively. It is caused by mutations, usually sporadic, of the MECP2 gene located in the X chromosome. Presented as main characteristics: stagnation in neuromotor development; losses of communication, visual contact, interest for people and objects; and manual stereotypes. In consequence to the serious cognitive and motor compromise, the RS patients have great difficulty in accomplishing day-to-day tasks. The objective of this work was to evaluate the functional abilities and to discover the needs of assistance by the caregiver, conforming to the established Pediatric Evaluation of Disability Inventory (PEDI). That evaluation instrument, which possesses 197 items in the areas of self-care, mobility and social function, was applied to 64 individuals with RS that matched the criteria for the classic form of the disease. Their ages ranged between 2 years and 26 years, with an average of 10 years. Among the 73 PEDI activities in the area of self-care, 52 (71.2%) were not accomplished by any child; in the area of mobility, among the 59 proposed activities, 8 (13.5%) were not done by any RS patient; and finally in the area of social function, none of the 50 (76.9%) activities among 65 were accomplished. The average performance adjusted in a scale from 0 to 100 for the area of self-care was of 8.9/100, varying from 0 to 26; for mobility, it was an average of 30.2/100, varying from 1.7 to 74.5; and of social function was 5.2/100, with variation from 0 to 21.5. The need of attendance was, in a complementary way, greater in the self-care areas and social function than in mobility. We didn\'t find, in our sample, a relationship between the age and the degree of incapacity, suggesting that RS individual present a compromising level that is from the beginning quite serious. Unfortunately, the smallest compromise of mobility, compared with the areas of self-care and social function, doesn\'t bring adaptive advantages or greater independence to the RS patients.

Methyl-CpG binding protein 2 (MeCP2) was discovered as a protein binding to methylated DNA more than 20 years ago. It is very abundant in the brain and was shown to be able to repress transcription. The mutations in MeCP2 cause Rett syndrome, an autism-spectrum neurological disorder affecting girls. Yet, the exact role of MeCP2 in Rett disease, its function and mechanism of action are not fully elucidated. In order to shed some light on its role in the disease the aim of this project was to identify proteins interacting with MeCP2. Affinity purification of MeCP2 from mouse brains and mass spectrometry analysis revealed new interactions between MeCP2 and protein complexes. Detailed analysis confirmed the findings and narrowed down the top interactions to distinct regions of MeCP2. One of the domains interacts with identified NCoR/SMRT co-repressor complex and is mutated in many patients with Rett syndrome. In vitro assays proved that these mutations abolish the putative transcriptional repressor function of MeCP2. We propose a model in which Rett syndrome is caused by two types of mutations: either disrupting the interaction with DNA or affecting the interaction with the identified complex, which has an effect on the global state of chromatin. The presented findings can help to develop new therapies for Rett syndrome in the future.

No description available.

<p>Bakgrund: Rett syndrom är ett syndrom som drabbar i stort sett bara flickor. Flickorna utvecklas till synes normalt fram till ca 6-8 månaders ålder. Sedan sker en tillbakagång som gör att de förlorar förmågor och färdigheter de tidigare lärt sig. De utvecklar de typiska handstereotypierna och får så småningom ett svårt flerhandikapp som gör dem mycket beroende av sin omgivning. Dessa handstereotypier ses som ett utmärkande drag för personer med Rett syndrom och dessutom är handstereotypierna ett av diagnoskriterierna för syndromet.</p><p>Syfte och frågeställning: Syftet med denna studie var att undersöka hur handstereotypierna kan te sig vid Rett syndrom. Frågor att besvara med studien var att se hur handstereotypierna vanligen yttrar sig och om det är någon viss situation eller känsla som gör att handstereotpierna framträder. En annan intressant fråga var att se om det genom arbetsterapijournalerna gick att utläsa hur flickorna/kvinnorna reagerar när handstereotypierna medvetet bryts av någon annan än de själva.</p><p>Metod: Studien är kvantitativ, där datainsamlingen var att studera 59 arbetsterapijournaler vid Rett Center, Frösön, Jämtland.</p><p>Resultat: Det mest intressanta resultatet visade att av de 59 journaler som studerats var det 16% av personerna som inte hade de karaktäristiska handstereotypierna.</p><p>Diskussion: Vi kan genom denna studie se att tillförlitligare svar på frågorna skulle gå att få med mer strukturerade rutiner vid journaldokumentation.</p>

<p>Med mitt examensarbete vill jag förklara vad FMT-metoden är. Jag berättar kort musikterapins historia och jag ger också en förklaring på metoden. Förklarar kort Rett syndrom och autism. Jag beskriver vidare mitt praktikarbete där jag valt att undersöka vad det är i metoden som gör att det känns meningsfullt för adepten. Trots att jag inte kunnat se några större förändringar efter 15 gånger har adepterna ändå tyckt det varit roligt att komma till sessionerna. Med  mitt arbete har jag fått svar på FMT-metodens styrka. Med musiken kan vi väcka en lust att reagera. Vi möter adepten där den befinner sig i sin utveckling och skapar på så sätt förutsättningar för att lyckas. Det i sin tur ger en lust som leder till utveckling.</p>

Bakgrund: Rett syndrom är ett syndrom som drabbar i stort sett bara flickor. Flickorna utvecklas till synes normalt fram till ca 6-8 månaders ålder. Sedan sker en tillbakagång som gör att de förlorar förmågor och färdigheter de tidigare lärt sig. De utvecklar de typiska handstereotypierna och får så småningom ett svårt flerhandikapp som gör dem mycket beroende av sin omgivning. Dessa handstereotypier ses som ett utmärkande drag för personer med Rett syndrom och dessutom är handstereotypierna ett av diagnoskriterierna för syndromet. Syfte och frågeställning: Syftet med denna studie var att undersöka hur handstereotypierna kan te sig vid Rett syndrom. Frågor att besvara med studien var att se hur handstereotypierna vanligen yttrar sig och om det är någon viss situation eller känsla som gör att handstereotpierna framträder. En annan intressant fråga var att se om det genom arbetsterapijournalerna gick att utläsa hur flickorna/kvinnorna reagerar när handstereotypierna medvetet bryts av någon annan än de själva. Metod: Studien är kvantitativ, där datainsamlingen var att studera 59 arbetsterapijournaler vid Rett Center, Frösön, Jämtland. Resultat: Det mest intressanta resultatet visade att av de 59 journaler som studerats var det 16% av personerna som inte hade de karaktäristiska handstereotypierna. Diskussion: Vi kan genom denna studie se att tillförlitligare svar på frågorna skulle gå att få med mer strukturerade rutiner vid journaldokumentation.

Med mitt examensarbete vill jag förklara vad FMT-metoden är. Jag berättar kort musikterapins historia och jag ger också en förklaring på metoden. Förklarar kort Rett syndrom och autism. Jag beskriver vidare mitt praktikarbete där jag valt att undersöka vad det är i metoden som gör att det känns meningsfullt för adepten. Trots att jag inte kunnat se några större förändringar efter 15 gånger har adepterna ändå tyckt det varit roligt att komma till sessionerna. Med  mitt arbete har jag fått svar på FMT-metodens styrka. Med musiken kan vi väcka en lust att reagera. Vi möter adepten där den befinner sig i sin utveckling och skapar på så sätt förutsättningar för att lyckas. Det i sin tur ger en lust som leder till utveckling.