A síndrome de Williams Beuren (SWB), doença congênita causada pela microdeleção do cromossomo 7, incluindo o gene da elastina, pode conferir às pessoas afetadas, facies típico, retardo mental, cardiopatia congênita, hipertensão, alterações gástricas, distúrbios de desenvolvimento de dentes, dentre outras alterações. O objetivo desse estudo foi conhecer as alterações faciais e bucais, a condição de saúde bucal, características oclusais e aspectos da ATM, bem como as alterações sistêmicas e condições médicas que afetam o manejo odontológico em uma amostra significativa de indivíduos brasileiros com a SWB. Para tanto, examinamos 25 indivíduos com SWB, com média de idade de 13 anos (4 a 26 anos). Os resultados mostraram que todos os participantes exibiam algum grau de retardo mental. A hiperacusia foi encontrada em 88% (22/25), cardiopatia congênita, em 76% (19/25); especialmente estenose aórtica supravalvar), hiperatividade em 68% (17/25) e hipertensão arterial em 40% (10/25) dos participantes. Distúrbios de desenvolvimento de dente foram encontrados em todos os participantes sendo que o mais frequente foi a retenção prolongada de dentes decíduos (64% - 16/25), seguido do diastemas generalizados (60% - 15/25), anodontia parcial (42% - 9/21), hipoplasia de esmalte (28% - 7/25), incisivos em forma de chave de fenda (24% - 6/25), microdontia (8% - 2/25). Em iguais porcentagens (4% - 1/25), foram encontrados casos de geminação, taurodontismo e dente conóide. Quanto à presença de alterações oclusais, todos os pacientes examinados apresentaram maloclusão. A maioria exibiu maloclusão classe III dentária de Angle (11/19,57 %) e mordida cruzada (11/25, 44%). Setenta e dois por cento dos pacientes exibiam algum hábito parafuncional. A experiência presente e passada de cárie, entre os 25 pacientes examinados, foi classificada como muito baixa, de acordo com o índice CPO-D e ceo-d, e 76% apresentaram gengivite. Os pacientes exibiram alteração da amplitude dos movimentos excursivos de mandíbula (abertura máxima - 12/22, 54%; lateralidade - 6/9, 66%; e protrusão - 7/9; 77%), bem como alterações nas ATMs, como dor à palpação (3/22, 13%) e ruídos articulares (4/25, 16%). Concluímos que distúrbios de desenvolvimento de dentes e maloclusão são frequentes em pessoas brasileiras afetadas pela SWB, e que a maioria delas apresenta alterações sistêmicas e comportamentais que podem interferir no manejo clínico odontológico. / The Williams Beuren syndrome (WBS), congenital disease caused by micro deletion of chromosome 7, including the elastin gene, is characterized by typical facies, mental retardation, congenital heart disease, hypertension, gastric alterations, teeth development disorders, among other changes. The aim of this study was to know facial and oral abnormalities, the oral health condition, occlusal features and aspects of temporomandibular joint, as well as systemic and medical conditions that affect the dental management on a significant sample of Brazilian individuals with WBS. For this, we examined 25 patients with SWB, with a mean age of 13 years (4-26 years). The results showed that all participants had some degree of mental retardation. The hyperacusis was found in 88% (22/25), congenital heart disease in 76% (19/25; especially supravalvular aortic stenosis), hyperactivity in 68% (17/25) and hypertension in 40% (10/25) of participants. Tooth development disorders were found in all participants with the most frequent was prolonged retention of the deciduous teeth (64% - 16/25), followed by generalized diastema (60% - 15/25), hypodontia (42% - 9/21), enamel hypoplasia (28% - 7/25), incisor-shaped screwdriver (24%- 6/25), microdontia (8% - 2/25). In equal percentages (4% - 1/25) were found cases of gemination, taurodontism and conoid tooth. For the presence of occlusal changes, all the patients examined presented malocclusion. Most showed malocclusion class III dental malocclusion (11/19, 57%) and crossbite (11/25, 44%). Seventy-two percent of patients had some parafunctional habit. Present and past caries experience among the 25 patients examined was classified as very low, according to the DMFT, and 76% had gingivitis. The patients exhibited change in amplitude of excursive movements of the jaw (maximun mouth opening - 12/22, 54%; laterality - 6/9, 66%; e protrusion - 7/9; 77%), as well as changes in ATMs, such as pain on palpation (3/22,13%) and joint sounds (4/25, 16%). We conclude that teeth and malocclusion development disorders are common in Brazilian people affected by WBS, and most of them have systemic and behavioral changes that can interfere with dental clinical management.

Made available in DSpace on 2016-03-15T19:40:48Z (GMT). No. of bitstreams: 1 Yara Garzuzi.pdf: 551486 bytes, checksum: 44776cb6bcf0c1a4ffc2f15d4da4b0ab (MD5) Previous issue date: 2009-09-03 / Fundo Mackenzie de Pesquisa / There are few studies in Brazil that comprise the theme of behavioral phenotypes in people with genetic syndromes. The knowledge of behavioral patterns associated with such syndromes contributes to the planning of standardized therapeutic assessment, intervention and handling strategies, and for an improvement in assistance practices. This study presents three genetic syndromes, which have as their common behavioral phenotype the presence of mental retardation that is associated with neurobiological, clinical, behavioral, social and psychiatric patterns specific to each of them. To describe and compare the major behavior patterns of children and adolescents with Prader-Willi Syndrome (PWS), Williams-Beuren Syndrome (WBS) and Down Syndrome (DS). The sample consisted of 68 children and adolescents with diagnosis for the syndromes. From these subjects, 11 presented cytogenetic-molecular diagnosis for PWS, 10 presented clinical and/or cytogeneticmolecular diagnosis for WBS, and 47 presented clinical and/or cytogenetic-molecular diagnosis for DS. The Child Behavior Checklist for ages 1½ 5 (CBCL/1½ 5) and the Child Behavior Checklist for ages 6-18 (CBCL/6 18) were used for data collection. The major results of the comparison between groups showed that, with respect to behavior changes, the PWS group scored higher, followed by the WBS group and the DS group, respectively. The following main patterns were found: in PWS, Externalizing Problems, Social Problems, Thought Problems and Aggressive Behavior; in WBS, Social and Attention Problems; and in DS, Total Problems. Statistically significant differences were also observed between some of this response patterns when groups paired by sex and age were compared (PWS-DS and WBS-DS).The changes found mainly in groups with PWS and WBS interfere considerably with the social adjustment of these children and adolescents. If these changes are not treated, they may result in the development of risk factors for several psychiatric comorbidities tending to chronicity. Therefore, it is necessary to implement public health services for the care of behavioral changes and to help families to deal with these groups of children and adolescents. / No Brasil, são poucos os estudos que abrangem a temática dos fenótipos comportamentais em pessoas com síndromes genéticas. O conhecimento de padrões comportamentais associados a tais síndromes contribui para o planejamento de estratégias de avaliação, intervenção e manejo terapêutico padronizados, e para uma melhoria das práticas assistenciais. Este estudo apresenta três síndromes genéticas cujo fenótipo comportamental comum é a presença da deficiência mental que se associa a padrões neurobiológicos, clínicos, comportamentais, sociais e psiquiátricos específicos a cada uma delas. Descrever e comparar os principais padrões de comportamento de crianças e adolescentes com Síndrome de Prader-Willi (SPW), Síndrome de Williams-Beuren (SWB) e Síndrome de Down (SD). A amostra foi composta por 68 crianças e adolescentes com diagnóstico para as síndromes. Desses participantes, 11 apresentavam diagnóstico citogenético-molecular para a SPW, 10 apresentavam diagnóstico clínico e/ou citogenético-molecular para a SWB, e 47 apresentavam diagnóstico clínico e/ou citogenético-molecular para a SD. Para a coleta de dados, utilizaram-se o Inventário dos Comportamentos de Crianças de 1½ a 5 anos (CBCL/1½ 5) e o Inventário dos Comportamentos de Crianças e Adolescentes de 6 a 18 anos (CBCL/6 18). Os principais resultados da comparação entre os grupos mostraram que, em relação a alterações de comportamento, o grupo com SPW obteve as maiores pontuações, seguido pelo grupo com SWB e pelo grupo com SD, respectivamente. Os principais padrões encontrados foram: Na SPW, problemas externalizantes, problemas sociais, problemas de pensamento e comportamento agressivo; na SWB, problemas sociais e de atenção; e, na SD, problemas totais. Observaram-se, ainda, diferenças estatisticamente significativas entre alguns desses padrões de resposta quando se compararam os grupos pareados por sexo e idade (SPW-SD e SWB-SD). As alterações encontradas principalmente nos grupos com SPW e SWB interferem de maneira considerável na adaptação social dessas crianças e adolescentes. Se essas alterações não forem tratadas, poderão configurar o desenvolvimento de fatores de risco para diversas comorbidades psiquiátricas com tendência à cronicidade. Por isso, fazem-se necessários a implementação de serviços públicos de saúde para o cuidado das alterações comportamentais e o auxílio do manejo familiar desses grupos de crianças e adolescentes.

Les visages fournissent à l'observateur un ensemble d'informations physiques, émotionnelles et sociales qui déterminent la manière dont les gens interagissent entre eux. Grâce aux cette informations, un humain peut se faire rapidement une première impression. La capacité de former des jugements de nature sociale est au centre de ce travail de thèse ainsi qu'à la manière dont la fiabilité d'autrui peut-être détectée spontanément à partir d'un visage. J'ai employé des techniques de suivi du mouvement oculaire, d'électrophysiologie (EEG) et comportementales. Le but de l'étude 1 visait à déterminer si la capacité d'évaluer la confiance est universelle. J'ai teste si les singes peuvent montrer une préférence spontanée envers des visages humains inspirant confiance, comme il l'a été observé chez les humains. Chez les deux espèces le temps de regard étais supérieur pour les visages inspirant confiance par rapport à ceux n'inspirant pas confiance. Un autre ensemble d'études s'intéressait au syndrome de Williams-Beuren (WS). La pathologie dont une des caractéristiques est un comportement d'appétence sociale a été utilisée comme modèle neurobiologique humain afin d'étudier la capacité à détecter les informations sociales du visage. Les patients WS sont-ils capables de détecter la confiance à partir d'un visage? Comment les patients WS se représentent un visage qui inspire confiance? J'ai observé que les patients WS regardent moins longtemps les visages qui inspirent confiance, suggérant qu'ils ont une tendance à davantage faire confiance à tout le monde. Nos résultats démontrent aussi qu'en comparaison à un groupe sain, ils ne présentent pas une image stéréotypique d'un visage qui inspire confiance. Dans une dernière étude, j'ai cherché à savoir si les sources neuronales éléctrophysiologiques, en particulier dans les régions du sulcus temporal supérieur (240ms), pouvaient expliquer leur comportement. J'ai observé que l'activité de la source était modulée de manière significative par rapport à la proximité des yeux, comme dans le groupe control. Les résultats suggèrent la présence d'une voie rapide dans le cerveau qui joue le rôle fondamental de moduler les comportements d'approche et d'évitement et que cette voie peut être altérée chez des patients caractérisés par un comportement d'appétence sociale / Faces provide a complex set of physical, emotional and social information to the observer that determines how people will interact with others. From facial information, human subjects can form rapid, first impression judgments. The ability to create social judgments from faces is the core topic of this work. This thesis will focus on how social information and trust is spontaneously detected from faces. In my studies I used eye tracking procedure, electrophysiology (EEG) and behavioral measures. In a first experiment, I investigated the evolutionary origin of trustworthiness detection testing whether monkeys (Macaca Mulatta and Fascicularis) have a spontaneous preference towards trustworthy human faces, thus suggesting a capacity to detect facial cues similar to those used by humans. Using a preference visual paradigm we observed that both species spent more time looking at trustworthy faces than untrustworthy ones. I further conducted three studies with patients affected by Williams-Beuren syndrome (WS). This pathology can be considered a neurobiological human model for the overexpressed social behavior. Are Williams-syndrome patients able to detect trustworthiness from faces? How WS patients form the representation of trustable faces ? Using a preference visual paradigm I observed that WS patients looked less the trustworthy faces compared to control group. This implicit behavior supports patients’ tendency to trust everybody. In a second experiment using reverse correlation paradigm - the procedure pushes subjects to select from noise the facial features that they believe are important for a specific judgment – I found that at group level patients did not show a stereotypical image of trustworthy faces compared to healthy controls. In a final study I investigate whether electrophysiological brain sources, with particular attention to the source localized in the superior temporal sulcus, could explain patients’ behaviour. I found that the activity of a source localized in the STS at 240ms was significantly modulated by eye proximity as in the control group. Overall the results of this work suggests the presence of a fast route in the brain that plays the fundamental role of modulating approach/avoidance behavior. This route may be altered in patients characterized by an overexpressed social behavior

Les peptides élastiques (ELP, Elastin-like peptide) sont d'excellents exemples de polymères biomimétiques récemment proposés en médecine régénérative, en particulier dans le domaine de l'ingénierie tissulaire des tissus mous (peau, vaisseaux sanguins, poumons…) pour lesquels la modélisation est complexe car l'instruction correcte des cellules nécessite une élasticité fonctionnelle. L'ajustement précis de la structure primaire des ELP peut moduler voire améliorer les propriétés physico-chimiques, structurales et fonctionnelles de la protéine native. De plus, la capacité des ELP à ajuster leurs caractéristiques physico-chimiques en réponse à des stimuli externes (température, pH), les définit comme des polymères intelligents. Ces polymères bioactifs offrent ainsi une large gamme d'applications très prometteuses encore très peu explorées dans les technologies d'ingénierie tissulaire et les systèmes d'administration de médicaments. Dans ce travail de thèse, nous avons développé, caractérisé et évalué les potentiels thérapeutiques d'une protéine élastique synthétique, Elactiv', inspirée de la structure unique de la tropoélastine humaine, précurseur soluble de l'élastine. Elactiv' conserve les caractéristiques physico-chimiques (comportement thermosensible, propriétés d'autoassemblage) et les fonctions biologiques de la protéine native (prolifération, différenciation et survie des fibroblastes dermiques et kératinocytes humains, sensibilité à la dégradation enzymatique). De plus, Elactiv' possède la particularité in vitro de s'incorporer dans les fibres élastiques néo-synthétisées par des fibroblastes dermiques sains, et d'induire la synthèse de tropoélastine fibrillaire par des fibroblastes pathologiques, syndrome de Williams-Beuren, qui ne synthétisent pas ou très peu de fibres élastiques. Un hydrogel formé exclusivement d'Elactiv' a permis d'accéder aux propriétés mécaniques de l'ensemble et de vérifier sa biocompatibilité in vitro et son innocuité et sa résorption in vivo. Enfin, l'association de la protéine Elactiv' aux dendrigrafts de poly(L-lysine), polymères synthétiques hautement fonctionnalisables, a permis de faire évoluer l'architecture de l'hydrogel vers un biomatériau hybride dans le but d'augmenter ses propriétés mécaniques et biologiques. Ainsi, les potentiels biomimétiques et thérapeutiques de la protéine Elactiv' en font un candidat prometteur pour la régénération des tissus mous / Elastin-like peptides are excellent examples of biomimetic polymers recently proposed in regenerative medicine, particularly for soft tissue engineering (skin, blood vessels, lung ...) for which modeling is a complex task requiring functional elasticity to insctruct cells properelly. Fine-tuning of ELP’s primary structure can modulate or improve physicochemical, structural and functional properties of the native protein. In addition, the adjustment of ELP physicochemical characteristics through external stimuli (temperature, pH) defined them as intelligent polymers. These bioactive polymers thus provide a wide range of very promising applications in tissue engineering and drug delivery, although this has been under-explored until then. In this thesis, we have developed, characterized and evaluated therapeutic potentials of Elactiv', a synthetic elastic protein inspired by the unique structure of the human tropoelastin, the soluble precursor of elastin. Elactiv’ retains physicochemical characteristics (thermoresponsive behavior, self-assembly properties) and biological functions of the native protein (proliferation, differentiation and survival of human keratinocytes and dermal fibroblasts, susceptibility to enzymatic degradation). Besides, Elactiv’ is able to incorporate into neosynthesized elastic fibers by healthy dermal fibroblasts, and to induce fibrillar tropoelastin synthesis by pathological fibroblasts, Williams-Beuren syndrome, which do not synthesize or very few elastic fibres. A hydrogel formed exclusively of Elactiv’ allowed to access to mechanical properties of the scaffold and to verify its biocompatibility in vitro and its safety and resorption in vivo. Finally, the association of Elactiv' protein to poly(L-lysine) dendrigrafts, highly functionalizable synthetic polymers, enabled to evolve the hydrogel's architecture to a hybrid biomaterial in order to increase its mechanical and biological properties for skin tissue engineering. Taken together, biomimetic and therapeutic potentials of Elactiv' protein make it a promising candidate for soft tissue regeneration

Williams Beuren syndrome Syndrome (WBS) and 7q11.23 Duplication Syndrome (Dup7) are rare neurodevelopmental disorders associated with a range of cognitive and behavioural symptoms, caused by the deletion and duplication, respectively, of 26 genes on human chromosome 7q11.23. I have studied the effects of deletion or duplication of two candidate genes, GTF2I and GTF2IRD1, on neural stem cell growth and neurogenesis using cultured primary neuronal precursors from mouse models with gene copy number changes. I found that the number of neuronal precursors and committed neurons was directly related to the copy number of these genes in the mid-gestation embryonic cortex. I further found that in late-gestation embryos, cortical thickness was altered in a similar gene dose-dependent manner, in combination with layer-specific changes in neuronal density. I hypothesize that some of the neurological features of WS and Dup7 stem from these impairments in early cortical development.

Williams Beuren syndrome Syndrome (WBS) and 7q11.23 Duplication Syndrome (Dup7) are rare neurodevelopmental disorders associated with a range of cognitive and behavioural symptoms, caused by the deletion and duplication, respectively, of 26 genes on human chromosome 7q11.23. I have studied the effects of deletion or duplication of two candidate genes, GTF2I and GTF2IRD1, on neural stem cell growth and neurogenesis using cultured primary neuronal precursors from mouse models with gene copy number changes. I found that the number of neuronal precursors and committed neurons was directly related to the copy number of these genes in the mid-gestation embryonic cortex. I further found that in late-gestation embryos, cortical thickness was altered in a similar gene dose-dependent manner, in combination with layer-specific changes in neuronal density. I hypothesize that some of the neurological features of WS and Dup7 stem from these impairments in early cortical development.

Genomic rearrangements, particularly deletions and duplications, are known to cause many genetic disorders. The chromosome 7q11.23 region in humans is prone to recurrent chromosomal rearrangement, due to the presence of low copy repeats that promote non-allelic homologous recombination. The most well characterized rearrangement of 7q11.23 is a hemizygous 1.5 million base pair (Mb) deletion spanning more than 25 genes. This deletion causes Williams-Beuren Syndrome (WBS; OMIM 194050), a multisystem developmental disorder with distinctive physical and behavioural features. Other rearrangements of the region lead to phenotypes distinct from that of WBS. Here we describe the first individual identified with duplication of the same 1.5 Mb region, resulting in severe impairment of expressive language, in striking contrast to people with WBS who have relatively well preserved language skills. We also describe the identification of a new gene for a severe form of childhood epilepsy through the analysis of individuals with deletions on chromosome 7 that extend beyond the boundaries typical for WBS. This gene, MAGI2, is part of the large protein scaffold at the post-synaptic membrane and provides a new avenue of research into both the molecular basis of infantile spasms and the development of effective therapies. Individuals with smaller than typical deletions of 7q11.23 have delineated a minimal critical region for WBS and have implicated two members of the TFII-I transcription factor family. To better understand the contribution of these genes to WBS, I have generated animal models with these genes deleted singly and in combination. Disruption of the first gene, Gtf2ird1, resulted in phenotypes reminiscent of WBS including alterations in social behaviour, natural fear response and anxiety. An alteration in serotonin function was identified in the frontal cortex and may be linked to these behavioural phenotypes. Together with a model for the second gene, Gtf2i, and the double deletion model that was generated using Cre-loxP technology, these resources will permit the study of the individual and additive effects of hemizygosity for Gtf2i and Gtf2ird1 and will greatly expand our understanding of the role the TFII-I gene family in WBS.

Deletion (Williams-Beuren syndrome (WBS)) and duplication (Dup7q11.23) of a common interval spanning 26 genes on chromosome 7q11.23 cause disorders with a spectrum of clinical, cognitive and behavioural symptoms. Studies of individuals with atypical deletions have implicated two genes, GTF2IRD1 and GTF2I. Here I describe the behavioural characterization of mice hemizygous for Gtf2i, or Gtf2ird1 and Gtf2i together, as well as mice with additional Gtf2i copies. Dosage changes in Gtf2i were associated with working memory impairment and separation anxiety, and possibly with general anxiety and repetitive behaviours. A potential cause of these phenotypes was found in brain tissue, where subcellular localization of the calcium channel TRPC3, which is regulated by GTF2I, was found to be altered. Collectively, these results provide a better understanding of the contributions of GTF2I to the cognitive and behavioural profile of WBS and Dup7q11.23 and identify a potential biological mechanism that may underlie some of the symptoms.

Deletion (Williams-Beuren syndrome (WBS)) and duplication (Dup7q11.23) of a common interval spanning 26 genes on chromosome 7q11.23 cause disorders with a spectrum of clinical, cognitive and behavioural symptoms. Studies of individuals with atypical deletions have implicated two genes, GTF2IRD1 and GTF2I. Here I describe the behavioural characterization of mice hemizygous for Gtf2i, or Gtf2ird1 and Gtf2i together, as well as mice with additional Gtf2i copies. Dosage changes in Gtf2i were associated with working memory impairment and separation anxiety, and possibly with general anxiety and repetitive behaviours. A potential cause of these phenotypes was found in brain tissue, where subcellular localization of the calcium channel TRPC3, which is regulated by GTF2I, was found to be altered. Collectively, these results provide a better understanding of the contributions of GTF2I to the cognitive and behavioural profile of WBS and Dup7q11.23 and identify a potential biological mechanism that may underlie some of the symptoms.

Genomic rearrangements, particularly deletions and duplications, are known to cause many genetic disorders. The chromosome 7q11.23 region in humans is prone to recurrent chromosomal rearrangement, due to the presence of low copy repeats that promote non-allelic homologous recombination. The most well characterized rearrangement of 7q11.23 is a hemizygous 1.5 million base pair (Mb) deletion spanning more than 25 genes. This deletion causes Williams-Beuren Syndrome (WBS; OMIM 194050), a multisystem developmental disorder with distinctive physical and behavioural features. Other rearrangements of the region lead to phenotypes distinct from that of WBS. Here we describe the first individual identified with duplication of the same 1.5 Mb region, resulting in severe impairment of expressive language, in striking contrast to people with WBS who have relatively well preserved language skills. We also describe the identification of a new gene for a severe form of childhood epilepsy through the analysis of individuals with deletions on chromosome 7 that extend beyond the boundaries typical for WBS. This gene, MAGI2, is part of the large protein scaffold at the post-synaptic membrane and provides a new avenue of research into both the molecular basis of infantile spasms and the development of effective therapies. Individuals with smaller than typical deletions of 7q11.23 have delineated a minimal critical region for WBS and have implicated two members of the TFII-I transcription factor family. To better understand the contribution of these genes to WBS, I have generated animal models with these genes deleted singly and in combination. Disruption of the first gene, Gtf2ird1, resulted in phenotypes reminiscent of WBS including alterations in social behaviour, natural fear response and anxiety. An alteration in serotonin function was identified in the frontal cortex and may be linked to these behavioural phenotypes. Together with a model for the second gene, Gtf2i, and the double deletion model that was generated using Cre-loxP technology, these resources will permit the study of the individual and additive effects of hemizygosity for Gtf2i and Gtf2ird1 and will greatly expand our understanding of the role the TFII-I gene family in WBS.