Dissertations / Theses on the topic 'Syndrome de Rubinstein-Taybi'

Examination of Autism Spectrum Disorder (ASD) phenomenology in genetic syndromes can aid our understanding of the aetiological pathways underpinning ASD. The current thesis directed attention to the specific study of Theory of Mind (ToM) development in syndrome groups with a high prevalence of ASD but fractionated social profiles. In an initial group comparison study, Rubinstein-Taybi syndrome (RTS) was highlighted as a syndrome group of interest. When compared to Down syndrome (DS), Fragile X syndrome (FXS) and idiopathic ASD, RTS showed a comparatively high prevalence of ASD but a fractionated ‘sociable’ social profile. As traditional ToM tasks load heavily on cognitive processes they are unsuitable for some individuals with intellectual disability. Consequently, a scaled battery of ToM ‘precursor’ tasks was constructed and validated using a normative sample. This scale was then applied, alongside Wellman and Liu’s (2004) ToM scale, to examine the development of ToM in RTS. An analysis of overall ability indicated that RTS may evidence relatively ‘spared’ early social cognitive skills. However, later ToM skills may be delayed due to memory difficulties. Developmental trajectory analysis indicated that RTS followed a different developmental sequence to the normative sample. Gaze understanding was found to be significantly harder than expected. These findings are discussed in relation to their theoretical implications for models of ToM and ASD, clinical implications for individuals with RTS, and potential areas for future study.

In a series of studies, repetitive behaviour, executive function development and the links between these constructs were explored in Rubinstein-Taybi syndrome (RTS). An overview of these constructs provided evidence that executive dysfunction might underpin repetitive behaviour and justified the use of a developmental trajectory approach. Repetitive behaviour was explored in RTS in relation to Autism Spectrum Disorder (ASD), Down and Fragile-X syndromes. Body stereotypy and repetitive questioning occurred at a similar frequency in RTS and ASD, but repetitive phrases occurred less frequently in RTS. A test battery was compiled and administered to profile the developmental trajectories of executive functions in RTS relative to typically developing children. Executive function development was delayed in RTS relative to mental age. Finally, the relationships between executive function development and repetitive behaviour were explored in RTS using correlational analyses. Repetitive questioning was related to poorer scores on verbal working memory and inhibition measures. Adherence to routines was related to poorer scores on a measure of shifting and emotional regulation, and completing behaviour was related to poorer scores on shifting measures. These findings highlight the merit of studying executive function development in disorder groups and that pathways can be mapped between cognition and behaviour. The implications of these findings for research and practice are discussed.

Rubinstein–Taybi syndrome (RSTS) is a rare malformation disorder caused by mutations in the closely related CREBBP and EP300 genes, accounting respectively for up to 60 and 3% of cases. About 10% of CREBBP mutations are whole gene deletions often extending into flanking regions. Using FISH and microsatellite analyses as a first step in the CREBBP mutation screening of 63 Italian RSTS patients (pts), 6 deletions were identified, 3 of which were in a mosaic condition that has not been previously reported in RSTS. The clinical presentation was typical in all cases, but more severe in the three pts carrying constitutional deletions, raising a question about the possible underdiagnosis of a few cases of mild RSTS. The use of region-specific BAC clones and small CREBBP probes allowed to assess the extent of all of the deletions by mapping their endpoints to genomic intervals of 5–10 kb. Four of five intragenic breakpoints cluster at the 5' end of CREBBP, where there is a peak of breakpoints underlying rearrangements in RSTS pts and tumours. The search for genomic motifs did not reveal any low-copy repeats (LCRs) or any greater density of repetitive sequences. The FISH analysis extended to the EP300 genomic region did not reveal any deletions. Searching for mutations of CREBBP gene in 56 patients revealed 23 different mutations. In addition, one deletion and two amplifications were identified by a-CGH in 20 RSTS pts.

A síndrome de Rubinstein-Taybi (RTS, OMIM 180849) é uma doença autossômica dominante caracterizada por dismorfismos craniofaciais típicos, polegares e háluces alargados, infecções respiratórias recidivantes, retardo mental e de crescimento. RTS está associada com mutação no gene CREBBP. Na avaliação da imunocompetência de 17 portadores de RTS, observaram-se algumas alterações na resposta imune inata e adaptativa: leucocitose persistente, neutrófilos com desgranulopoiese, elevada concentração sérica de IgM e IgG1, produção normal de anticorpos contra antígenos protéicos e anti-polissacarídeos, elevados valores absolutos de células B totais, B \"naive\", B de memória, subpopulação B1 e de linfócitos B com IgM de membrana, e elevado percentual de apoptose de linfócitos B. DTH negativo para três antígenos e baixa resposta linfoproliferativa para antígenos protéicos. Diante do exposto, concluímos que os pacientes RTS apresentam alterações em vários mecanismos da resposta imune e principalmente, na imunidade humoral. Portanto, com este trabalho foi possível identificar as principais alterações imunológicas destes pacientes, e com isso, caracterizar quais os defeitos da resposta imune que pode estar associada com gene CREBBP.
Rubinstein-Taybi syndrome (RTS, OMIM 180849) is a dominant Mendelian disorder characterized by craniofacial dysmorphisms, broad thumbs and toes, mental retardation and growth and recurrent respiratory infections. RTS is classically associated with CREBBP gene mutations, but recently, p300 gene mutations were reported in three individuals. In imunonocompetence investigation of a group of 17 patient of the RTS, we found that the patients really show alterations in more than one arm of the immune response. The main alterations were found in: a) innate immunity, patients have defects in the distribution of the granules citoplasmatic and partial absence of F-actin filament part of its polymorphonuclear cells. In addition, some patients had decreased phagocytic activity, b) humoral immunity: elevated serum IgM antibodies and IgG1 subclass, normal production of antibodies for protein antigens and antipolysaccharide, high absolute values of B cell total, B \"naive\", B memory, subpopulation B1 and B lymphocytes with the membrane IgM, and high percentage of apoptosis of B lymphocytes; c) cellular immunity: delayed hypersensitivity skin tests negative for three antigens and low lymphoproliferative response to protein antigens. Values reduced percentage of CD45RA+ , CD45RO+ T cells and high doublepositive CD45RA+/CD45RO +) T cell. Ahead of the severe recurrent respiratory infections that affect the patients with RTS, and of the evaluation of immunocompetence of these patients, we find that they have several alterations in mechanisms of immune response and mainly in humoral immunity. Therefore, with this study was to identify the major immunological alterations of these patients, and with this, which characterize the main defects of the immune response of the patients RTS that can is associated with gene CREBBP.

INTRODUÇÃO: A Síndrome de Rubinstein-Taybi (RTS) é uma doença genética rara, caracterizada por dismorfismos craniofaciais típicos, polegares e háluces alargados, deficiência mental e baixa estatura. A incidência estimada é de 1: 125 000 a 1: 330000 nativivos. A SRT geralmente ocorre esporadicamente, mas pode ser herdada com um padrão de herança autossômico dominante. O diagnóstico da SRT é essencialmente clínico. OBJETIVOS: Realizar o estudo genético-clínico e citogenético em 30 pacientes brasileiros com SRT, e descrever de forma sistematizada a freqüência de dismorfismos faciais e malformações múltiplas encontradas. MÉTODOS: Neste estudo observacional retrospectivo e prospectivo, os pacientes foram seguidos no período de agosto de 2005 a junho de 2009. O cariótipo com bandeamento G foi realizado em todos os pacientes. RESULTADOS: A maioria dos pacientes avaliados foi do sexo feminino (60%). As seguintes características foram observadas em todos os pacientes da nossa casuística: atraso de desenvolvimento neuropsicomotor, ponta nasal voltada para baixo, columela proeminente, sorriso característico, dificuldades alimentares na infância, persistência dos coxins fetais, falanges distais dos polegares alargadas e pés planos. A baixa estatura e a microcefalia foi observada em 80% e 76% dos casos, respectivamente. As principais características craniofaciais observadas foram: fronte proeminente (86%), ponte nasal larga (60%), hipertelorismo (70%), sobrancelhas espessas e arqueadas (96%) cílios longos em 93%, prega epicântica (76%), fissura palpebral infra vertidas (76%), abertura bucal estreita (93%), retrognatismo (76 %), sorriso característico em 100%, palato alto e estreito (93%), anomalias dentárias (83%). Outras anomalias identificadas foram: estrabismo, erros de refração, obstrução do canal lacrimal, háluces e polegares alargados, angulação de polegares, anomalias do pavilhão auricular (rotação/posição/tamanho/forma), angulação do hálux, clinodactilia, sobreposição dos pododáctilos, falanges distais alargadas de outros dedos, marcha rígida, hipotonia, sopro cardíaco, cardiopatia congênita, criptoquidia, hemangioma plano e hipertricose. Uma paciente apresentou translocação recíproca de novo 46, XX, t (2; 16)(q36.3; p13.3). CONCLUSÕES: A raridade da SRT e o amplo espectro das manifestações clínicas pode atrasar o diagnóstico clínico. A média da idade ao diagnóstico dos nossos pacientes com SRT foi de três anos e oito meses. Todas as crianças devem receber avaliação por geneticista pediátrico, cardiologista, oftalmologista, neuropediatra, e odontopediatra
INTRODUCTION: Rubinstein-Taybi syndrome (RTS) is a rare genetic disorder characterized by distinctive craniofacial dysmorphisms, broad thumbs and toes and mental and statural deficiency. The prevalence of RTS has been estimated to be 1 in 125000 to 1: 330000 live births. RTS usually occurs sporadically although it can be inherited as an autosomal dominant disorder. The diagnosis of RTS is primarily based on clinical features. OBJECTIVES: We performed a clinical and cytogenetic assay in a group of 30 Brazilian RTS patients. We also decribed the frequencies of facial dysmorphisms and multiple malformations. METHODS: In this observational retrospective and prospective study, the patients were followed from August 2005 to June 2009. Chromosomal analysis was performed by G-banding karyotype. RESULTS: Most of the patients were female (60%).The following abnormalities were present in all of the patients: delayed psychomotor development, beaked nose, proeminent collumel, typical facies, broad thumbs and toes, flat feet, joint laxity, feeding problems during the childhood, and finger pads. Short stature was present in 80%, and microcephalia in 76% of the cases, respectively. Main craniofacial characteristics are frontal bossing (86%), wide nasal bridge (60%), ocular hyperthelorism (70%), high arched eyebrows (96%), long eyelashes (93%), epicathal folds (76%), downslanting palpebral fissures (76%), small opening of the mouth (93%), retrognathism (76%), grimacing smile (100%), high arched palate (93%), and dental anomalies (83%). Other findings were: strabism, refractive error, lacrimal obstruction, wide thumb and halux, angulated thumbs, external ears anomalies (rotation, implantation and morfology), angulated halux, clinodactyly, crowded toes, broad distal falanges of other fingers, stiff gait, hipotonia, cardiac murmur, congenital heart defect, undescendent testis, hypertrichosis, and hemangioma. One female patient has found to have a reciprocal de novo translocation t(2;16)(q36.3;p13.3) on G-banding karyotype CONCLUSIONS: The rarity of RTS and the wide spectrum of clinical manifestations, may delay the clinical diagnosis of RTS. The average age at the diagnosis of our patients was 3 years and 8 months. All children of RTS should receive an evaluation by a pediatric geneticist, cardiologist, ophthalmologist, pediatric neurologist, and pediatric dentist

A Síndrome de Rubinstein-Taybi foi primeiramente descrita em 1963 pelos médicos Jack Rubinstein & Hooshang Taybi e está relacionada à microdeleção cromossômica na região 16p13. Suas principais características são retardo mental baixa estatura, nariz pontudo, polegares largos e angulados e problemas cardíacos. As características bucais têm sido relatadas na literatura através de casos esporádicos e incluem retrognatia, palato fendido, má-formação e apinhamento dentário. Foram estudadas as características clínicas de relevância para a odontologia, de 13 pacientes portadores da SRT que procuraram o CAPE para tratamento odontológico do período de 1998 a 2004. O manejo clínico do paciente em ambulatório foi possível na maioria dos casos apesar do comprometimento intelectual. As manifestações bucais mais frequentemente encontradas foram: gengivite e periodontite, ptose do palato mole e presença de palato ogival, malformação dos dentes incisivos laterais superiores, e alterações oclusais como retrusão mandibular e mordida cruzada posterior. Foi salientada a importância do cirurgião dentista conhecer as implicações da síndrome para que possa previní-las através de orientação aos cuidadores e intervenções precoces, especialmente no que se refere à ortodontia e periodontia.
The Rubinstein-Taybi syndrome was first report in 1963 by Jack Rubinstein and Hooshang Taybi and it’s related with the chromossomal microdelection in the region 16p13. The main characteristics are mental retardation, low stature, pointed nose, broad thumbs and toes and cardiac alterations. The buccal characteristics are reported in the literature by sporadic cases and includes retrognathia, fissured palate and dental malformation. It was studied the clinical characteristics with significance for the dentistry in 13 patients with RTS that seek treatment at the Special Care Dentristy Center during the period from 1998 to 2004. The ambulatorial clinical attendance was possible in the majority cases although the intelectual compromissing. The buccal manifestations frequently found were gingivitis and periodontitis, soft palate ptosis and ogival palate, talon cusps and oclusal alterations, like mandibular retrusion and posterior crossbite. It was accentuated the importance for the dentristry to know the implications from the syndrome to prevent them through directions for the relatives and previous interventions, especially orthodontics and periodontics.

Submitted by Aelson Maciera (aelsoncm@terra.com.br) on 2017-05-03T16:31:46Z No. of bitstreams: 1 DissTMV.pdf: 4278287 bytes, checksum: b70cfbca372b8826d977f08aa903b11c (MD5)
Approved for entry into archive by Ronildo Prado (ronisp@ufscar.br) on 2017-05-03T17:48:40Z (GMT) No. of bitstreams: 1 DissTMV.pdf: 4278287 bytes, checksum: b70cfbca372b8826d977f08aa903b11c (MD5)
Approved for entry into archive by Ronildo Prado (ronisp@ufscar.br) on 2017-05-03T17:48:49Z (GMT) No. of bitstreams: 1 DissTMV.pdf: 4278287 bytes, checksum: b70cfbca372b8826d977f08aa903b11c (MD5)
Made available in DSpace on 2017-05-03T17:58:14Z (GMT). No. of bitstreams: 1 DissTMV.pdf: 4278287 bytes, checksum: b70cfbca372b8826d977f08aa903b11c (MD5) Previous issue date: 2015-03-13
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
The society has been concerned to provide quality of life for people with disabilities. When it comes to people in disability situation, the role of physical education is especially relevant, since it can contribute significantly to the improvement of motor skills and physical condition, in turn, responsible for too typical behavior of human beings. In the case of Rubinstein Taybi Syndrome (SRT), the literature shows that there are numerous difficulties of a physical and motor that affect people, SRT is characterized by: - short stature; - Face feature; - Small head; - Slightly deformed ears; - Mental retardation; - Pulmonary stenosis; - Keloid formation in surgical scars; - Foramen magnum extended; - Vertebral and sternal abnormalities; - Thick or curved eyebrows; - Hyperextensible joints; - Pelvis small and inclined; - Stereotyped behavior: clap and sway the body when nervous or anxious. A person with SRT do not need all the features of the syndrome, but a combination of them. Baby stimulation and early intervention are highly recommended for the child with SRT. Appropriate stimuli engines through intervention programs may favor the acquisition of new functions, thus providing the best adaptation of environmental factors and aging to contribute to the education movement, body awareness and her own interaction with the environment. Motor development isintrinsically linked to cognitive and affective areas of human behavior. Thus, each individual is unique in its development and progress to the level that was determined by its environmental and biological conditions together with the special needs of the motor task. The study will contribute to the development of an overview of child motor development with Rubstein Taybi syndrome, and generate ideas and perspectives to other areas. Consist in a case study research exploratory, descriptive and qualitative type, with the aim of analyzing the effects of a motor stimulation program for a child with SRT; propose activities that promote motor development of the child; improve motor skills allowing higher levels of functioning in activities of daily life. A ten years old carrier of the syndrome is a participant in this study. Data collection was performed using the Motor Evaluation Kit Rosa Neto, video camera and computer. Data were organized and analyzed qualitatively and quantitatively. It appears in this study that WFP provided a decrease in risk factors imposed by motor condition Yasmin, giving it autonomy in activities of daily living and consequently improved quality of life.
A sociedade vem se preocupando em proporcionar qualidade de vida para as pessoas com deficiências. Em se tratando de pessoas em situação de deficiência, a atuação da educação física tem especial relevância, uma vez que pode contribuir sensivelmente para a melhoria das habilidades motoras e condições físicas, por sua vez, responsáveis pelas demais condutas típicas do ser humano. No caso da Síndrome de Rubinstein Taybi (SRT), a literatura mostra que são inúmeras as dificuldades de ordem física e motora que acometem as pessoas, A SRT é caracterizada por: - baixa estatura; - face característica; - cabeça pequena; - orelhas ligeiramente deformadas; - retardo mental; - estenose pulmonar; - formação de quelóide em cicatrizes cirúrgicas; - forame magno alargado; - anormalidades vertebral e esternal; - Sobrancelhas grossas ou curvadas; - Articulações hiperextensíveis; - Pelve pequena e inclinada; - Comportamento estereotipado: batem palmas ou balançam o corpo quando nervosas ou ansiosas. Uma pessoa com SRT não precisa ter todas as características da síndrome, mas uma combinação entre elas. Estimulação infantil e intervenção precoce são altamente recomendadas para a criança com SRT. Estímulos motores adequados por meio de programas de intervenção poderão favorecer a aquisição de novas funções, proporcionando assim a melhor adaptação dos fatores ambientais e de maturação para contribuir com a educação do movimento, consciência corporal e a própria interação dela com o ambiente. O desenvolvimento motor está intrinsecamente relacionado às áreas cognitivas e afetivas do comportamento humano. Assim, cada indivíduo é único em seu desenvolvimento e progredirá até o nível que foi determinado por suas condições ambientais e biológicas em conjunto com as necessidades especiais da tarefa motora. O estudo irá contribuir na elaboração de um panorama do desenvolvimento motor de crianças com Síndrome de Rubstein Taybi, além de gerar idéias e perspectivas para outras áreas. Consisti em uma pesquisa de estudo de caso do tipo exploratório, descritivo e qualitativa, com o objetivo de analisar os efeitos de um programa de estimulação motora em uma criança com SRT; propor atividades que promovam o desenvolvimento motor da criança; melhorar as habilidades motoras permitindo maiores níveis de funcionamento nas atividades da vida diária. Uma criança de 10 anos portadora da Síndrome é participante desse estudo. A coleta de dados foi feita através do Kit de Avaliação Motora de Rosa Neto, filmadora, e computador. Os dados foram organizados e analisados de forma qualitativa e quantitativa. Verifica-se nesse estudo que o PAM proporcionou um decréscimo nos fatores de riscos impostos pela condição motora de Yasmin, proporcionando a ela autonomia em atividades de vida diária e consequentemente melhora na qualidade de vida.

A Síndrome de Rubinstein-Taybi (RTSs) é uma doença rara de herança autossômica dominante, caracterizada por dismorfismos craniofaciais, polegares e háluces alargados, deficiência intelectual e de crescimento. RTSs tem sido associada com mutações no gene CREBBP (CBP) e mutações menos frequentes no gene EP300 que foram descritas em oito indivíduos. CBP e p300 possuem alta homologia e são extremamente importantes em várias vias de sinalização, principalmente como coativadores de transcrição e na acetilação das histonas. Nosso estudo baseou-se na análise de alterações moleculares por sequenciamento direto do CBP, FISH e array-CGH em 20 pacientes com RTSs. Dos 20 pacientes avaliados por sequenciamento direto foram identificadas oito alterações moleculares, dentre estas, seis são alterações moleculares novas as quais não foram descritas na literatura, são elas: i) duas deleções (p.M747fs STOP830 e p.G1011fs STOP1021) ii) duas alterações do tipo nonsense (p.Arg1341X, p.Arg1498X) iii) três do tipo missense (p.Arg1907Trp, p.Leu604Pro e p.His1291Arg). Também identificamos um polimorfismo de único nucleotídeo (SNP) (rs115594471/ c.5874CT). Dois pacientes apresentaram deleção do gene CBP em um dos alelos, identificado pelo método array-CGH. Outro, apresentou uma translocação aparentemente equilibrada t(2;16), cuja análise subsequente com FISH revelou uma quebra na região do CBP. Neste trabalho, a taxa de detecção de alteração molecular no CBP por sequenciamento direto foi de 40% (08/20). Porém, a taxa de detecção das alterações moleculares no CBP foi de 55% (11/20), considerando a combinação das diferentes técnicas utilizadas (FISH, sequenciamento direto e array-CGH). Não houve correlação genótipo-fenótipo, exceto por uma maior frequência da presença de epicanto nos pacientes com alteração no CBP. Os resultados obtidos neste trabalho servem como o diagnóstico molecular para os pacientes com RTSs atendidos no Ambulatório do Laboratório de investigação Médica 001 (ALIM 001) do Instituto da Criança - FMUSP, contribuindo para uma melhor orientação médica, como também para realização do aconselhamento genético às famílias
Rubinstein-Taybi syndrome (RTSs) is a rare autosomal dominant disease characterized by craniofacial dysmorphisms, broad thumbs and toes, mental and growth deficiency. RTS has been associated with CREBBP (CBP) gene mutations and less frequently with mutations in EP300 gene, which have been reported in eight individuals. CBP and p300 have high homology and are extremely important in many signaling pathways especially as transcriptional coactivators and histone acetylation. Our study was based on the alteration analysis by direct sequencing of the CBP, by FISH and array-CGH in 20 RTSs patients. We identified eight molecular alterations in 20 RTSs patients evaluated by direct sequencing: i) two deletions (p.M747fs STOP830 and p.G1011fs STOP1021) ii) two nonsense alterations (p.Arg1341X and p.Arg1498X) iii) Three missense alteration (p.Arg1907Trp, p.Leu604Pro and p.His1291Arg). Single-nucleotide polymorphism were also identified (rs115594471 / c.5874CT), and six of these are new molecular alterations, not described in literature. Two RTSs patients studied had CBP gene deletion in one allele, identified by array-CGH method. Other patient, presented with apparent balanced translocation t(2;16) in which the subsequent analysis using FISH, showed a break in region of CBP. In this work, the rate of detection of molecular alteration in CBP by direct sequencing in RTSs patient was 40.0% (08/20). However, the rate of detection of molecular alteration in CBP was 55.0% (11/20), considering the combination of different techniques (FISH, direct sequencing and array-CGH. No significant correlation could be established in this study between the different types of mutations and genotype-phenotype of RTSs patients, except a higher frequency of the presence of epicanthus in the RTS patients with alteration in the CBP. The results of this study serve as a molecular diagnosis for RTSs patients treated at the Ambulatory of the Medical Investigation Laboratory 001 (ALIM 001) of the Instituto da Criança - FMUSP, and this contributes to better clinical management, such as making an appropriate genetic counseling for families

Rubinstein-Taybi Syndrome (RTS) is a rare congenital neurodevelopmental disorder that often presents with corresponding speech and language delays. However, the available literature on communicative development in RTS is currently very limited. The purpose of this retrospective single-case research study was to evaluate the effectiveness of the Picture Exchange Communication System (PECS), an aided augmentative and alternative communication (AAC) system developed to teach functional communication to children with limited communication, on communicative abilities in RTS by providing a detailed profile of the intervention procedures utilized for a 6-year-old child with RTS. The aim of this investigation was both to contribute to the existing literature on the syndrome, as well as to document the success of the PECS system in children with RTS. Specifically, the current study explored the participant’s communicative progression and development in the areas of (a) communication initiation, (b) vocalization, and (c) eye contact after Phases 1-4 of the PECS protocol were implemented. Data records from 26 evaluation and intervention sessions completed during the participant’s Spring 2014 attendance at the CSULB Department of Speech-Language Pathology’s Speech and Language Clinic were analyzed in order to evaluate the effects of the PECS protocol on the participant’s communicative abilities. Results indicated that the PECS treatment significantly improved the participant’s communicative abilities, namely, by increasing her initiation of communicative exchanges, increasing use of vocalizations and word/phrase approximations, and increasing eye contact with communication partners. The current study supports the use of the PECS protocol in children with RTS as a functional communication system.

Les troubles neurodéveloppementaux (TND) touchent environ 10 % des enfants et constituent une source majeure d'invalidité tout au long de la vie. Caractérisés par un développement défectueux du cerveau et une grande variabilité du tableau clinique des patients, qui compromet le diagnostic et l'émergence de solutions thérapeutiques, ils représentent un coût humain, sociétal et économique important. L'objectif de ce projet est de mieux comprendre une caractéristique commune des TND - la dérégulation des voies de réponse au stress - qui constituerait une clef de lecture pour comprendre ces pathologies. L'intégration des processus déclenchés par le stress est régie par les facteurs de transcription du choc thermique (HSF), qui sont fortement dérégulés dans plusieurs TND. Cela a deux conséquences : une altération de la réponse au stress des cellules neurales qui entraîne des défauts dans le développement du cerveau. Nous avons participé a montré que ces HSF sont essentiels au bon développement du cerveau. Plus précisément, l'équipe a démontré que HSF2 joue un rôle clef dans la régulation de la prolifération des cellules progénitrices et la migration neuronale dans le cortex en modulant l'expression de gène impliqués dans l'adhésion cellulaire. La modulation pharmacologique de cette voie pourrait donc offrir de nouvelles possibilités thérapeutiques. Dans une première étude, les mécanismes sous-jacents à la dérégulation des HSF ont été étudiés dans les cellules de patients atteints du syndrome de Rubinstein-Taybi (RSTS), un TND rare d'origine génétique causé par des mutations dans les gènes CREBBP ou EP300. Notre étude a montré une diminution des niveaux protéiques de HSF2 dans les fibroblastes et dans les modèles neuraux (2D et 3D) dérivés à partir de cellules souches pluripotentes induites (iPSC) provenant de patients RSTS. Cette diminution des niveaux protéiques de HSF2 résultait d'un défaut d'acétylation par CBP ou EP300, conduisant à l'ubiquitination et à la dégradation par le protéasome. En conséquence, les cellules RSTS présentaient une altération de la réponse au stress et une réduction de l'expression de gènes essentiels au développement neural, en particulier la N-cadhérine. La restauration des niveaux de HSF2, soit par l'inhibition du protéasome, soit par des mutations imitant l'acétylation, a permis de rétablir à la fois la réponse au stress et l'expression des gènes du neurodéveloppement. Nous avons constaté que la perturbation de la voie CBP/EP300-HSF2-N-cadhérine est récapitulée dans les modèles neuraux RSTS, qui présentent des anomalies de prolifération liées à une altération de l'adhésion cellule-cellule, en particulier dans la voie de la N-cadhérine. Sur la base de ces résultats et en collaboration avec Ksilink, mon projet de thèse CIFRE vise à développer un modèle cellulaire de TND basé sur les patients RSTS. Ce modèle permettra d'explorer comment les perturbations de la voie HSF pourraient contribuer à divers TND. Pour atteindre cet objectif, j'ai d'abord généré un mutant HSF2 qui mime la forme acétylée de la protéine dans les iPSC dérivés de fibroblastes de patients RSTS. En utilisant ce modèle isogénique comme référence, j'ai développé et validé un modèle de culture neural bidimensionnel et identifié de nouvelles cibles et phénotypes dépendants de HSF2 via une approche multiparamétrique allant de la transcriptomique à haut débit à des analyses morphologiques des cellules. Cette approche a permis d'identifier le facteur pro neuronal, ASCL1, et un phénotype morphologique, la formation de rosettes, comme clefs de lecture pour l'analyse par imagerie à haut contenu. Sur la base de ces deux phénotypes, j'ai utilisé le modèle neural pour cribler une sélection de molécules à potentiel thérapeutique par imagerie à haut contenu. Ces travaux ouvriront la voie à de nouvelles approches thérapeutiques visant à moduler les voies de réponse au stress, offrant ainsi de nouvelles possibilités de traitement des TND
Neurodevelopmental disorders (NDD) affect around 10% of children and are a major source of lifelong disability. Characterised by defective brain development and great variability in the clinical picture of patients, which compromises diagnosis and the emergence of therapeutic solutions, they represent a significant human, societal and economic cost. The aim of this project is to gain a better understanding of a common feature of NDDs - the deregulation of stress response pathways - which could provide a readout to understanding these pathologies. The integration of processes triggered by stress is governed by heat shock transcription factors (HSFs), which are strongly deregulated in several NDDs. This has two consequences: an altered stress response in neural cells leading to defects in brain development. We have helped to show that these HSFs are essential for proper brain development. More specifically, the team demonstrated that HSF2 plays a key role in regulating the proliferation of progenitor cells and neuronal migration in the cortex by modulating the expression of genes involved in cell adhesion. Pharmacological modulation of this pathway could therefore offer new therapeutic possibilities. In a first study, the mechanisms underlying HSF deregulation were investigated in cells from patients with Rubinstein-Taybi syndrome (RSTS), a rare genetic NDD caused by mutations in the CREBBP or EP300 genes. Our study showed a decrease in HSF2 protein levels in fibroblasts and in neural models (2D and 3D) derived from induced pluripotent stem cells (iPSCs) from RSTS patients. This decrease in HSF2 protein levels resulted from a defect in acetylation by CBP or EP300, leading to ubiquitination and degradation by the proteasome. As a result, RSTS cells showed an altered stress response and reduced expression of genes essential for neural development, in particular N-cadherin. Restoration of HSF2 levels, either by proteasome inhibition or by acetylation-mimicking mutations, restored both the stress response and the expression of neurodevelopmental genes. We found that disruption of the CBP/EP300-HSF2-N-cadherin pathway is recapitulated in RSTS neural models, which display proliferation abnormalities linked to altered cell-cell adhesion, particularly in the N-cadherin pathway. On the basis of these results and in collaboration with Ksilink, my CIFRE thesis project aims to develop a cellular model of NDD based on RSTS patients. This model will enable us to explore how perturbations in the HSF pathway could contribute to various NDDs. To achieve this objective, I first generated an HSF2 mutant that mimics the acetylated form of the protein in iPSCs derived from RSTS patient fibroblasts. Using this isogenic model as a reference, I developed and validated a two-dimensional neural culture model and identified new HSF2-dependent targets and phenotypes using a multiparametric approach ranging from high-throughput transcriptomics to cell morphological analyses. This approach made it possible to identify the pro-neuronal factor, ASCL1, and a morphological phenotype, rosette formation, as key readouts for analysis by high-content imaging. On the basis of these two phenotypes, I used the neural model to screen a selection of molecules with therapeutic potential using high-content imaging. This work will pave the way for new therapeutic approaches aimed at modulating stress response pathways, thereby opening up new possibilities for the treatment of NDD

Notre travail s'inscrit dans l'étude des maladies polymalformatives d'origine génétique. Nous avons dans ce cadre développé deux axes de recherche : - dans le syndrome de Rubinstein-Taybi, nous avons mis en place, pour l'analyse du gène CREBBP, une technique de recherche des réarrangements, la QMF-PCR : nous avons identifié 17 délétions et 1 duplication sur un total de 83 patients, soit un taux de 20 % d'anomalies de dosage génique. Cette technique, hautement résolutive, est aujourd'hui transférée pour le diagnostic hospitalier de cette maladie. Grâce au séquençage des points de cassure, nous avons montré la prédominance du mécanisme NHEJ dans l'apparition des délétions. - nous avons également travaillé sur une famille avec une chondrodysplasie liée à l'X, afin d'identifier le gène impliqué. Le séquençage du gène HDAC6 a mis en évidence une variation dans sa région 3' non traduite. Une approche in silico a établi que cette mutation affecte le site de reconnaissance du miR-433, qui intervient dans la régulation post-transcriptionnelle. Des tests fonctionnels ont montré que la mutation suffit à abroger totalement l'action régulatrice du miRNA, entraînant la surexpression de la protéine HDAC6. Nous avons montré qe le miR-433 déstabilise l'ARNm et provoque sa dégradation. L'analyse par Western Blot a confirmé la surexpression d'HDAC6 dans le thymus d'un foetus mâle atteint, s'accompagnant de la diminution de la quantité de tubuline acétylée, qui est une des cibles d'HDAC6. Notre étude montre que cette mutation d'HDAC6 est très vraisemblablement la cause de cette nouvelle forme de chondrodysplasie
Our work concerns the study of polymalformative diseases of genetic origin. We have developped two research themes : - in patients with the Rubinstein-Taybi patients, we have searched for genetic rearrangements of the CREBBP gene by QMF-PCR. We have identified 17 deletions and 1 duplication in a total of 83 patients analysed, representing 20 % of the cases. This high resolution technique is now under current use in the hospital for diagnostic purposes. Sequencing of the deletion and duplication breakpoints showed that the NHEJ repair mechanism was responsible for the occurence of the rearrangements in the vast majority of cases. - in the second part of our work, we searched for the gene involved in a new form of dominant X-linked chondrodysplasia observed in a large family. We identified a nucleotide variant in the 3'UTR of the HDAC6 gene. An in silico analysis established that this variant affects the recognition site for miR-433, that regulates HDAC6 expression at the post-transcriptional level. Functional tests showed that the variant totally abrogates the regulatory action of miR-433, thus leading to the over expression of the HDAC6 protein. We showed that miR-433 destabilizes the mRNA and provokes its degradation. Western blot analysis confirmed the over expression of HDAC6 in the thymus of an affected male foetus, which is accompanied by a decrease in acetylated alpha tubulin, which is a target of HDAC6. Our study demonstrates that this variant of HDAC6 highly likely causes this new form of chondrodysplasia

Background: Chromatinopathies are defined as a group of disorders displaying mutations in genes of the epigenetic apparatus and sharing clinical features such as intellectual disability and abnormal growth. Among them, Rubinstein-Taybi syndrome (RSTS) is characterized by CBP/p300 lysin-acetyltransferases deficit, while classic form of Rett syndrome (RTT) is caused by mutations in the reader MECP2. Both disorders show neurodevelopmental defects and 10 to 30% of patients remains without a molecular diagnosis. Methods: In this work, we aim at deepening molecular aspects involving RSTS and RTT etiology and RSTS possible epigenetic treatments. Indeed, we tested exogenous histone deacetylase inhibitors (HDACi) in in vitro cellular models (lymphoblastoid cell lines derived from patients and healthy donors) and on a Drosophila melanogaster model of RSTS (nej) and wild type flies (yw), performing acetylation and viability assays and flies embryos immunostaining respectively. In parallel, we investigated endogenous HDACi in RSTS patients and in fruit flies models, assessing their microbiota. In addition, we applied whole exome sequencing (WES) analysis to RSTS and RTT-like probands negative for mutations in known associated genes and we then characterized two identified variants by genome editing techniques and functional analysis. Results: In RSTS studies, we observed that patients gut microbiota is significantly depleted in butyrate-producing bacteria and we demonstrate that the effects of the HDACi butyrate, as well as the differences in microbiota composition, are conserved in nej flies. From WES study, we found in one RSTS and three RTT-like patients unreported variants in HDAC2, and NBEA, DYNC1H1 and SLC35F1 genes respectively, whose role is currently under investigation through in vitro models. Conclusions: The study on microbiota composition could pave the way for novel therapeutic interventions for RSTS, while the identification of new RSTS and RTT genes could expand the genotype-phenotype correlation for these chromatinopathies, and characterization of new candidate genes could give insights into pathogenesis of these disorders.

Social behaviour is critical to successful functioning in life. Across a series of studies, aspects of social behaviour and social cognition were explored in Fragile X (FXS), Cornelia de Lange (CdLS), and Rubinstein-Taybi syndromes (RTS). Experimentally manipulated social situations revealed that heightened social anxiety, which was not mediated by changes in the social environment, was evident in FXS and RTS, whilst social anxiety in CdLS was governed by the social demands of a situation. These differences were evident despite social motivation being comparable across all groups. A further study documents the use of a novel eye-tracking paradigm, which successfully differentiates between FXS, CdLS and RTS in attentional priority for social information, mirroring the profile of similarities and differences in social behaviour highlighted in the behavioural study. A FXS-related aversion for looking to the eye region of faces was also revealed using eye-tracking technology. These findings highlight the merit of experimental manipulation when utilising both implicit and observational measures to investigate social behaviour and cognition in genetic disorder. Furthermore, the empirical work reported here furthers understanding of the behavioural and cognitive aspects of the social phenotypes of FXS, CdLS and RTS and highlights theoretical implications for the dissociation of social anxiety and social motivation.

Este relatório de estágio pretende dar a conhecer toda a atividade desenvolvida pelo estagiário no âmbito do Mestrado de Reabilitação Psicomotora, durante o ano letivo 2017/2018 na instituição CERCICA, mais concretamente no CerMov, prestando apoio a clientes de várias idades. Neste sentido, este documento encontra-se dividido em duas grandes partes: a primeira, dedicada ao enquadramento teórico e que pretende a caracterização da instituição de acolhimento, bem como do diagnóstico principal dos clientes para uma melhor compreensão do mesmo que se pretende repercutido ao nível de boas práticas, terminando com a abordagem da intervenção psicomotora como um dos apoios às pessoas com Dificuldade Intelectual e Desenvolvimental. A segunda parte retrata toda a prática psicomotora, desde o horário, passando pela progressão da atividade do profissional, os casos e contextos onde interveio, bem como pelo processo de avaliação, entre outros. Será ainda apresentado um estudo de caso, um adulto com Síndrome Rubinstein-Taybi, como exemplo mais pormenorizado de toda a intervenção, estruturada com base nos resultados iniciais. A avaliação final permitiu a análise da evolução do caso, bem como uma reflexão sobre a atividade do estagiário. As atividades extracurriculares serão listadas mesmo antes da conclusão e da reflexão pessoal sobre esta experiência de estágio.
This report aims to present the internship student’ actvitiy, of Psychomotor therapy Master of Faculdade de Motricidade Humana, in CERCICA during the academic year 2017_2018. The intervention took place in CerMov providing psychomotor supports to clients of all ages. This document is organized in two main parts. Firstly, there is a section dedicated to theoretical framework where it will be characterized the: institution; the main and most prevalent diagnosis of clients – Intellectual and Developmental Disability, and the approach of the psychomotor therapy as a support. This literature review allowed a better understanding of the all constructs and was the basis of the practical part. Secondlym it will be presented the internship psychomotor activity, starting from the timetable, student activity’ progression, clients and contexts of intervention, assessment and procedures. A study case – an adult with Rubinstein-Taybi, will be describe as a more detailed example of all intervention, which was based in initial assessment. Final assement results allowed the discussion of data about the case progress as well as the reflection about the student activity. Extra-curricular activities will be list. Final conclusion and a personal reflection about the entire experience ends this report