Dissertations / Theses on the topic 'Autism – Etiology'

Boston University. University Professors Program Senior theses.
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2031-01-02

Thesis: S.M., Massachusetts Institute of Technology, Department of Electrical Engineering and Computer Science, 2014.
Cataloged from PDF version of thesis.
Includes bibliographical references (pages 99-109).
Understanding the genetic background of complex diseases is crucial to medical research, with implications to diagnosis, treatment and drug development. As molecular approaches to this challenge are time consuming and costly, computational approaches offer an efficient alternative. Such approaches aim at predicting and prioritizing genes for a particular disease of interest. State-of-the-art gene prediction and prioritization methods rely on the observation that disease-causing genes have some sort of functional similarity based on either sequence, phenotype, protein-protein interaction (PPI) network, or functional annotation. Another increasingly accepted view is that human diseases result from perturbations of molecular networks, and genes causing the same or similar diseases tend to be close to one another in molecular networks. Such observations have built the basis for a large collection of computational approaches to find previously unknown genes associated with certain diseases. The majority of the methods are designed based on protein interactome networks, with integration of other large-scale omics data, to infer how likely it is that a gene is associated with a disease. In this thesis, we set out to address this outstanding challenge of understanding the genetic etiology of autism spectrum disorder (ASD), which refers to a group of complex neurodevelopmental disorders sharing the common feature of dysfunctional reciprocal social interaction. We introduce three novel methods for computing how likely a given gene is to be involved in ASDs based on copy number variations (CNVs), phenotype similarity, and protein interactome network topology. We also customize a random walk with restarts algorithm for ASD gene prioritization for the first time. Finally, we provide a novel integrative approach for combining CNV, phenotype similarity, and topology-related information with existing knowledge from literature. Our integrative approach outperforms the individual schemes in identifying and ranking ASD related genes. Our candidate gene set provides a number of interesting biological insights in that it is overrepresented in a number of interesting signaling, cell-adhesion and neurological pathways, molecular functions, and biological processes that are worth further investigation in connection with ASDs. We also find evidence for an interesting connection between gastrointestinal disorders, particularly inflammatory bowel diseases (IBD), and ASDs. The subnetworks we identify indicate the possibility of existence of subclasses of disorders along the autism spectrum.
by Sumaiya Nazeen.
S.M.

Autism is a complex disorder with possible genetic, epigenetic and environmental components. As the etiology remains uncertain and an increase in incidence is suspected, the involvement of possible environmental risk factors has gained increasing attention. With this thesis, I aim to provide tools for assessing such risk factors. Firstly, I aim to construct a questionnaire for the analysis of an environmental component in the etiology of autism. Secondly, I aim to assess the importance of prenatal exposure to metals in certain diseases and thirdly I aim to construct a methodology enabling the analysis of the mitochondrial epigenome, which is especially interesting in relation to autism as mitochondrial diseases occur more frequently in an autistic population than in the general population. For the creation of the questionnaire the scientific literature was reviewed. The resulting questionnaire contains general, prenatal, neonatal and paternal risk factors. The metal analysis was conducted on the cord blood of patients who later developed autism, antinuclear antibodies positive rheumatoid arthritis or diabetes, which were then compared to healthy control subjects. My findings propose a link between elevated levels of cord blood cadmium or aluminum and rheumatic arthritis. In addition, elevated aluminum levels might be associated with autism. In regards to the analysis of the mitochondrial epigenome, to my knowledge, no standard protocol exists with frozen human whole blood as a source. In this thesis, I succeeded in creating the basis for such a protocol, however still needing several small modifications for an increased overall yield.

Impairments in both theory of mind (ToM; the ability to attribute mental states to oneself and others) and executive function (EF; a group of high-level cognitive functions which help guide and control goal-directed behaviour) have been demonstrated in individuals with autism spectrum disorders (ASDs). Both deficits have been proposed by different groups of researchers as being the single primary cognitive deficit of autism, which can subsume the other deficit as secondary or artefactual. However, few studies have examined the nature of the relationship between ToM and EF in ASDs or conducted a systematic investigation of their relative primacy. This research principally sought to establish the primacy and independence of impairments in ToM and EF in ASDs and thereby evaluate the validity of single versus multiple primary deficit models of autism. These aims were addressed in two studies, both broad in scope. The first study was an investigation of the profile, primacy, and independence of ToM and EF impairments in individuals with ASDs. The sample included 46 participants with ASDs and 48 control participants matched on age and non-verbal ability. The profile of impairments was examined by measuring ToM and a range of EF components using tasks employing, wherever possible, process-pure indices of performance. Primacy was measured by focussing on i) whether or not the deficits observed were universal among individuals with ASDs; ii) whether the deficits were able to discriminate individuals with ASDs from matched controls (i.e., predict group membership); and iii) the ability of ToM and EF deficits to explain the full range of autistic symptomatology, as measured by correlating cognitive performances with behavioural indices. The relationship between ToM and EF impairments was investigated by conducting correlations between ToM and EF variables as well as analysing the incidence of dissociations between impairments in the two domains. The ASD group was found to demonstrate significant impairments in ToM and several components of EF including planning, verbal inhibition, working memory (in a context where inhibitory control was required), and both verbal and non-verbal generativity. However, neither ToM nor EF impairments were able to meet all of the criteria for a primary deficit in ASDs. EF deficits were found to be more primary, but could not account for ToM as a secondary deficit, as ToM and EF were found to be independent (i.e., uncorrelated and dissociable) deficits in the ASD group. This pattern of results suggested that a multiple deficits model involving at least two independent impairments appeared to best characterise ASDs, but the data were compatible with several variants of such a model (e.g., involving distinct subtypes versus a multidimensional spectrum). The second study was an investigation of ToM and EF impairments in siblings of individuals with ASDs, who have previously been found to demonstrate a subclinical “broad autism phenotype”. The main aims of this study were i) to identify whether ToM or EF deficits could meet criteria for an “endophenotype” or vulnerability marker for the autism genotype in unaffected relatives, which would have further implications about the primacy of ToM and EF in ASDs; and ii) to further investigate the validity of various multiple deficits models of ASDs by examining the pattern of ToM and EF performance in those showing the broad phenotype. Participants were 108 siblings of individuals with ASDs and 67 siblings of controls, tested on the same ToM and EF tasks used in the first study. Confirming the superior primacy of EF deficits found in Study One, there was no significant difference in ToM performance between ASD and control siblings, but ASD siblings showed weaknesses on two measures of EF. Furthermore, there appeared to be different subgroups of siblings demonstrating different cognitive profiles, consistent with the heterogeneity evident in the first study. This research indicated that ASDs cannot be explained by a single primary cognitive deficit. These findings hold important theoretical and empirical implications and highlight further questions about which type of multiple deficits model might best explain ASDs.

This heuristic self-search inquiry (Sela-Smith, 2001, 2002) study reviews empirical and theoretical research on Autism Spectrum Disorder (Asperger, 1938, 1944; Bleuler, 1910, 1911a, 1911b; Kanner, 1943) and Turner Syndrome (Funke, 1902; Turner, 1938; Ullrich, 1930). It conjoins with existing literature on the main principles of existential-humanistic psychology and psychotherapy to prompt a heuristic investigation of the problem of the researcher-participant’s veridical reference as it pertains to her subjective experience. The purpose of the study was to elucidate the complementarity of what the existential-humanistic literature refers to as the intelligible responses of her equiprimordial I-who-feels encounter with biopsychological trauma as an initiator of chronic existential injury as an adult diagnosed with a conglomerate of associated clinical symptoms to sketch out their possible existential etiologies.

Stimuli precipitating heuristic data collection included psychotherapy sessions, childhood medical records, medical examinations and consultations conducted during the study, and prior academic work. The heuristic data collection adhered to Moustakas’ (1990) phases and processes of research. Schneider’s (2008/2015) expansion-constriction continuum model of consciousness of six-domains (physiological, environmental, cognitive, psychosexual, interpersonal, and experiential) was used to analyze the heuristic data and decipher whether tacit knowledge of the researcher-participant’s I-who-feels experience was discovered in the inquiry. A Heuristic-Expansion-Constriction Change scale was designed to subjectively measure degree of change in each domain. Bronfenbrenner’s (1979) biosystemic model of human development was employed to conceptualize the etiology of existential injury across four systems of being: the microsystem, mesosystem, ectosystem, and macrosystem.

The heuristic research findings indicated a high degree of meta-level abstraction in the researcher-participant paralleled by the review of the literature. Populations experiencing recalcitrant complications of similar ilk might gain insight into their psychological etiologies of by, through self-examination and change, acknowledging resistance to the I-who-feels . Additionally, ongoing interdisciplinary intervention by an established care team providing medical and psychotherapeutic support might prove satisfactorily beneficial. Data was distilled into a series of recommendations that existential-humanistic psychotherapists might adopt when working with clients exhibiting chronic existential injury due to multiplex medical symptoms. Implications for these populations were subsequently discussed, with special recommendations provided for medical providers on addressing existential concerns in patients.

Perturbações do espectro autista é o termo usado para identificar um grupo de alterações invasivas do desenvolvimento caracterizadas por défices na socialização e comunicação e por comportamentos bizarros e repetitivos. Esta classificação inclui o Autismo, o Síndrome de Asperger e a Perturbação Global do Desenvolvimento Sem Outra Especificação [1]. Leo Kanner em 1943 e Hans Asperger em 1944 foram possivelmente os primeiros a descrever o tipo de distúrbios englobados nesta categoria, destacando a especificidade do défice de interação social que tem sido, desde então, considerado o sintoma principal do autismo [2]. A prevalência do autismo situa-se entre 10 e 20 casos por cada 10000 crianças e tem vindo a aumentar significativamente desde a década de 1960 sendo este aumento justificado pelo maior reconhecimento desta doença como problema de saúde pública e ainda pelas constantes mudanças na prática dos mesmos. Os sintomas clínicos estão usualmente presentes aos três anos, contudo o défice no desenvolvimento da linguagem atrasa a sua identificação [2,3]. As Perturbações do Espectro Autista são fortemente genéticas e multifatoriais, havendo interação entre muitos fatores de risco [3]. Há uma incessante procura de marcadores biológicos para o Autismo, ou seja, indicadores mensuráveis em simples amostras biológicas que podem ser utilizados como fatores de risco, indicadores diagnósticos e podem ainda ajudar na elaboração do plano de tratamento mais adequado [1]. O objetivo deste trabalho passa por fazer uma revisão e sistematização sobre o autismo e os seus biomarcadores, estudando os benefícios clínicos e diagnósticos de cada um. Através da evolução destes estudos pretende-se ainda perspetivar o futuro desta patologia. A pesquisa bibliográfica foi realizada através das bases de dados: Medline/PubMed, Medscape, E-medicine assim como vários livros de referência sobre a especialidade. Esta pesquisa foi realizada em português e inglês. Após uma pesquisa detalhada foi possível concluir que as Perturbações do Espectro Autista apresentam inúmeros fatores causais, sendo ainda uma área de investigação com muitos desafios a enfrentar. O perfil genético e metabólico, o perímetro cefálico, a estrutura e fisiologia cerebral, entre muitos outros, são exemplos de biomarcadores propostos para o autismo. Apesar da grande evolução das técnicas e metodologias de estudo do autismo e da melhoria na sua compreensão científica, pouco se tem conseguido no que toca a traduzir os biomarcadores em evidências clínicas.
Autism spectrum disorder is used for a diverse group of developmental conditions characterized by impairments in social skills and communication and repetitive or unusual behaviors. This classification includes Autism, Asperger’s syndrome and Pervasive Developmental Disorder not otherwise specified [1]. Leo Kanner (1943) and Hans Asperger (1944) were possibly the first ones to describe the type of empathy disorders encompassed in this category, highlighting the specificity of the social interaction deficit which has, ever since, been regarded as the core symptom of Autism [2]. Autistic disorder’s prevalence is between 10 and 20 per 10 000 children and apparently has greatly increased since 1960’s. This is justified by its recognition as a public health problem and also by changes made in policy and practice. Clinical signs are usually present at the age of 3 years, but impairments in language development might delay identification of these symptoms [2,3]. Autism spectrum disorders are highly genetic and multifactorial, with many risk factors acting together [3]. There is constant search for Autism’s biological markers, which are defined as measurable indicators in simple biological samples. They can be used as risk factors, diagnostic indicators and even help planning the most appropriate treatment [1]. The aim of this work is to review and systematize Autism and its biomarkers, studying both the clinical and diagnostic benefits of each one of them. Through the evolution of these studies, we also intend to look at the future of this pathology. The literature search was performed using the following databases: Medline/PubMed, Medscape, E-medicine as well as several reference books on the specialty. This research was conducted both in Portuguese and English. After a detailed research a conclusion was made that Autism Spectrum Disorders have several causal factors and it is an area of investigation with many challenges. The genetic and metabolic profile, head circumference, brain structure and many others, are possible biomarkers for autism. Despite great development and understanding of the techniques and methodologies, little has been achieved with regard to translate biomarkers on clinical evidence.

BACKGROUND: Autism Spectrum Disorder is a range of neurodevelopmental disorders that typical manifest as social deficits, delayed or impaired communication skills, and repetitive behaviors in day-to-day life. Patients with Autism Spectrum Disorder (ASD) often present with other concurrent clinical disorders. Sleep disorders (SD) and sleep issues are highly prevalent in ASD children and rank as one of the most common concurrent clinical disorders. Prevalence rates vary widely, ranging from 40 to 80 percent, as compared with that of typically developing children in which prevalence rates are approximately 30 percent. Sleep problems can have an impact on daytime health and may result in neurocognitive dysfunction and behavioral disruptions. A cyclical pattern arises: individuals with autism are observed to have sleep difficulties, which may exacerbate autistic traits, which can in turn further worsen their quality of sleep. Therefore, sleep disorders may have wide ranging effects on daytime functioning, developmental progress, and quality of life for children with ASD. OBJECTIVES: The purpose of this thesis is to provide a review of the research status of ASD, SD, the interplay between these two disorders, and therapeutic interventions that have been researched or are currently being investigated. A goal of this thesis is also to recommend areas of future investigation based on the current state of autism research. METHODS: A literature review of studies, abstracts, and clinical trial data relating to ASD, SD, and other comorbidities observed in ASD was performed. CONCLUSION: Current models and theories on the relationship between ASD and SD suggest that the underlying etiology of autism itself may contribute to sleep troubles, and might even have wide-reaching impacts on other unrelated aspects of ASD. Gastrointestinal, otolaryngologic, and psychiatric comorbidities are observed in autism and may affect sleep in these patients, but the mechanism by which this occurs is unclear. There are many treatments for sleep troubles in ASD such as melatonin and behavioral interventions, with varying success. Much work is required to understand the underlying mechanism between both autism and sleep disorders. There is also a need for more efficacious therapeutic interventions, but there are multiple clinical trials underway which may have promising results. Future studies should also incorporate robust data-collection instruments such as polysomnography to validate findings.
2021-06-14T00:00:00Z

Dissertação de Mestrado em Ciências da Educação
Para a realização deste trabalho optámos por um estudo de um caso real, utilizando o método de investigação qualitativa, usando a entrevista para a recolha de dados. Foi escolhida esta metodologia pelo facto de se considerar a mais adequada face ao assunto em estudo: “O autismo e o seu impacto na família”. No último século, surgiram métodos e filosofias de abordagem divergentes, desde que o autismo foi descrito pela primeira vez em 1943 por Kanner. Neste trabalho, procuramos, através de uma revisão bibliográfica, fazer uma abordagem à evolução histórica do autismo, destacando algumas perspectivas sobre a sua etiologia, bem como, os meios de diagnóstico, nomeadamente no que se refere aos critérios segundo o DSMIV e o seu diagnóstico diferencial, a avaliação e intervenção. Hoje, segundo a perspectiva de Gillberg (1990), poder-se-á considerar que o autismo é uma síndrome comportamental com múltiplas etiologias e com um distúrbio de desenvolvimento, caracterizado por um deficit na interacção social, com perturbações de linguagem e alterações de comportamento. Estudos epidemiológicos sugerem taxas de Transtorno Autista de 5 casos por 10.000 indivíduos, cifrando-se o seu espectro de 1 em cada 700 a 1.000. Apesar de não haver uma cura para o Autismo, pois uma criança autista é-o para toda a vida, pode diminuir-se algumas limitações que lhe estão associadas. De acordo com o grau de comprometimento, a possibilidade do autista desenvolver a comunicação verbal, a integração social, a alfabetização e outras competências dependerá da intensidade e adequação do tratamento, bem como da intervenção mais adequada às suas características, tendo em vista desenvolver as suas potencialidades. Existem vários métodos de intervenção para as crianças com autismo, no entanto, o modelo TEACCH – modelo de intervenção estruturado e o PECS, sistema de comunicação por associação de imagens, são os que têm dado melhores resultados com a criança em estudo no nosso trabalho. A família, sociologicamente, é definida como um grupo social, sendo o primeiro e o mais importante contexto para o crescimento físico e psicológico da criança. As famílias são consideradas as primeiras instituições educativas das crianças, visto que, é no seio delas que se inicia o processo de socialização. Logo, cabe à família integrar a criança na sociedade, funcionando, também, como meio cultural de crescimento e bem – estar. Brofenbrenner (1992) defende um modelo ecológico, pelo qual há uma relação dinâmica e recíproca entre o indivíduo em desenvolvimento e os contextos que se relacionam com ele (familiar, social, económico e cultural). Daí que, se houver uma falha num dos contextos, todos os indivíduos da família são influenciados por essas alterações. A definição de autismo, corrobora que ele compromete seriamente o grupo familiar quando este assume em definitivo viver com o problema. Usualmente, as relações familiares são naturalmente afectadas quando um elemento do seu grupo apresenta uma doença, neste caso, autismo. Assim, o autismo do filho coloca os pais frente a emoções de luto pela perda da criança saudável que esperavam. Por sua vez, os irmãos assumem uma maior responsabilidade para com o irmão autista, assumindo muitas vezes, atitudes de super protecção. A família em estudo no nosso trabalho, passou por diferentes fases, até à altura do diagnóstico: duvidas, incertezas, desilusão e por fim aceitação. No meio deste turbilhão de sentimentos houve a procura da cura para o seu filho. O problema do filho acabou por unir ainda mais a família, fortalecendo os laços afectivos entre todos. A dinâmica familiar desenvolve-se num sentido único, proporcionar ao seu filho o máximo de condições para que se possa desenvolver num meio o mais normalizado possível. A grande preocupação da família é o futuro do filho.
In order to obtain a better result for this work we’ve chosen to study a real case using the method of qualitative interview to obtain the data we needed. The reason for this choice was the belief that it was the best way to treat the subject we intended to study: “Autism and its impact in family.”. During the last century, different methods and ways to treat this subject have appeared since autism was described, for the first time, in 1943 by Kanner. In this work we are looking forward to, by a bibliographic review, make an approach to the historic evolution of autism, pointing out some perspectives about its etiology, as well as means of diagnostic, namely the criteria according to DSMIV and its differential diagnostic, evaluation and intervention. Nowadays, according to Gillberg’s (1990) perspective, it is possible to say that autism is a behavioral syndrome with multiple etiologies and with a developing disorder, characterized by a social interaction deficit, with language disorder and behavioral alteration. Epidemiologic studies suggest Autism Upset rates to be such as 5 cases for every 10000 individuals, being its spectre of 1 for each 700 to 1000. Although there is no cure for autism, because an autistic child will remain autistic for all of his lifetime, it is possible to reduce some of its associated limitations. According to the disease degree, the autistic’s possibility to develop verbal communication, social integration, literacy and other capabilities will depend on the intensity and adequacy of the treatment, as well as the most adequate intervention to its characteristics in order to develop its capabilities. There are several intervention methods to autistic children, however the TEACCH model (structured intervention model) and PECS model (communication by image association system) are the ones that show the best results with the child we studied. Family, sociologically, can be defined as social system, being considered as the first and the most important context to both physical and psychological growth of the child. Families are considered as children’s first educational institutions, because it’s in their environment that takes place the beginning of the socialization process. Therefore it’s up to the family to integrate their children in the society acting, also, as a cultural mean of growth and wellness. Brofenbrenner (1992) stands for an ecological model which says that there is a dynamic and reciprocal relation between the developing individual and its surrounding contexts (family, social, economical and cultural). If it occurs a failure in one of these contexts, every single member of the family is influenced by that fact. The definition of autism tells us that it is responsible by seriously compromising the whole family group when it decides to live side by side with this problem. Normally, family relationships are naturally affected when one of its members is victim of an illness, in this particular case, autism. So, the son’s autism leads the parents to face feelings of mourning and loss of their healthy son. In other way, brothers take on themselves a great responsibility for his autistic brother, being sometimes extra protective. The family in study for our work has passed by different stages to reach the time of the diagnostic: doubt, uncertainty, disappointment and at last acceptance. Besides all of these hard feelings, there has been a search for a cure to their son disease. After all, their son illness has been an additional union factor for the family, fortifying their affective bonds. All the members of the family started working to the same objective, trying to give their child the best possible conditions so that he can develop in a normal environment. The main concern of that family was from now on the future of their child.

Trabalho Final do Mestrado Integrado em Medicina apresentado à Faculdade de Medicina
INTRODUÇÃO: A perturbação do espetro do autismo (PEA) é uma condição médica heterogénea caracterizada por défices persistentes na comunicação e interação social, assim como por padrões de comportamentos, atividades e interesses repetitivos e restritivos (CAIRR). A prevalência estimada é de cerca de 1 em cada 1000 crianças, em idade escolar, em Portugal, com um predomínio significativo do sexo masculino, numa razão de 4:1. Esta distribuição por sexo tem sido motivo de controvérsia, na comunidade científica, com diversos estudos a revelar prováveis mecanismos etiológicos e fenótipos distintos entre os dois géneros. Com este estudo, visou-se efetuar uma revisão narrativa das diferenças entre géneros nos vários domínios desta perturbação. METODOLOGIA: Foi efetuada uma pesquisa na base bibliográfica informática da Elsevier, ClinicalKey, e na base de dados do National Center for Biotechnology Information, na secção PubMed. Foram ainda consultadas as normas de orientação clínica e as escalas de diagnóstico da perturbação. DISCUSSÃO: Do ponto de vista etiológico, verificaram-se diferenças significativas entre géneros nos mecanismos neuro-hormonais, genéticos, cromossómicos e neuroanatómicos subjacentes ao desenvolvimento da PEA. A resposta aos fatores de risco ambientais e imunológicos apresentou-se também de forma distinta entre géneros. De uma perspetiva fenotípica, o dimorfismo sexual destacou-se essencialmente no domínio dos CAIRR, uma vez que se constatou maior incidência destes sinais e sintomas no sexo masculino e, ainda, diferenças no tipo de CAIRR apresentado por cada género. No domínio social, as diferenças entre géneros mostraram-se maioritariamente qualitativas. Estas diferenças podem motivar o subdiagnóstico nas raparigas. Os próprios testes e escalas de rastreio e diagnóstico utilizados na prática clínica aparentam ser pouco sensíveis para o reconhecimento de autismo no sexo feminino. A reformulação da nosologia e dos métodos de diagnóstico da PEA poderá ter impacto positivo no tratamento e prognóstico das crianças com PEA, particularmente do sexo feminino. CONCLUSÃO: As diferenças etiológicas entre géneros contribuem para o aumento de prevalência de PEA no sexo masculino e as diferenças fenotípicas promovem o subdiagnóstico no sexo feminino. Este dimorfismo presente no autismo é crucial para a predominância masculina acentuada da razão de PEA entre géneros.
INTRODUCTION: Autism spectrum disorder (ASD) is a heterogeneous medical condition characterized by persistent deficits in communication and social interaction, as well as repetitive and restrictive behaviors, activities and interests (RRBAI). The estimated prevalence of ASD is about 1 in 1000 in school-age children in Portugal, with a significant male predominance, with a ratio of 4:1. This ratio has been a matter of controversy in the scientific community, with several studies highlighting distinct etiological mechanisms and phenotypes between genders. This study aimed to carry out a narrative review of the differences between genders in various domains of the disorder. METHODOLOGY: A search was carried out in the online bibliographic database of Elsevier, ClinicalKey, and in the National Center for Biotechnology Information database, in the PubMed section. Clinical guidelines and scales used for the diagnosis of the disorder were also consulted. DISCUSSION: Ethiologically, there are significant differences between genders in the neurohormonal, genetic, chromosomal and neuroanatomical mechanisms underlying the development of the disorder. The response to environmental and immunological risk factors is also different between genders. Phenotypically, sexual dimorphism stands out essentially in the RRBAI domain. There is a higher incidence of these signs and symptoms in males but also differences in the type of RRBAI presented by each gender. In the social domain, gender differences are mostly qualitative. These differences can lead to underdiagnosis in girls. The screening and diagnostic tests and scales used in clinical practice appear to be little sensitive to the recognition of autism in females. The reformulation of ASD's nosology and diagnostic criteria may have a positive impact on the treatment and prognosis of children with ASD, particularly females. CONCLUSION: Etiological gender differences contribute to the increase in the prevalence of ASD in males and phenotypic differences promote underdiagnosis in females. This dimorphism present in autism is crucial for the marked male predominance of the ratio between genders.

Trabalho Final do Mestrado Integrado em Medicina apresentado à Faculdade de Medicina
INTRODUÇÃO: A perturbação do espetro do autismo (PEA) é uma condição médica heterogénea caracterizada por défices persistentes na comunicação e interação social, assim como por padrões de comportamentos, atividades e interesses repetitivos e restritivos (CAIRR). A prevalência estimada é de cerca de 1 em cada 1000 crianças, em idade escolar, em Portugal, com um predomínio significativo do sexo masculino, numa razão de 4:1. Esta distribuição por sexo tem sido motivo de controvérsia, na comunidade científica, com diversos estudos a revelar prováveis mecanismos etiológicos e fenótipos distintos entre os dois géneros. Com este estudo, visou-se efetuar uma revisão narrativa das diferenças entre géneros nos vários domínios desta perturbação. METODOLOGIA: Foi efetuada uma pesquisa na base bibliográfica informática da Elsevier, ClinicalKey, e na base de dados do National Center for Biotechnology Information, na secção PubMed. Foram ainda consultadas as normas de orientação clínica e as escalas de diagnóstico da perturbação. DISCUSSÃO: Do ponto de vista etiológico, verificaram-se diferenças significativas entre géneros nos mecanismos neuro-hormonais, genéticos, cromossómicos e neuroanatómicos subjacentes ao desenvolvimento da PEA. A resposta aos fatores de risco ambientais e imunológicos apresentou-se também de forma distinta entre géneros. De uma perspetiva fenotípica, o dimorfismo sexual destacou-se essencialmente no domínio dos CAIRR, uma vez que se constatou maior incidência destes sinais e sintomas no sexo masculino e, ainda, diferenças no tipo de CAIRR apresentado por cada género. No domínio social, as diferenças entre géneros mostraram-se maioritariamente qualitativas. Estas diferenças podem motivar o subdiagnóstico nas raparigas. Os próprios testes e escalas de rastreio e diagnóstico utilizados na prática clínica aparentam ser pouco sensíveis para o reconhecimento de autismo no sexo feminino. A reformulação da nosologia e dos métodos de diagnóstico da PEA poderá ter impacto positivo no tratamento e prognóstico das crianças com PEA, particularmente do sexo feminino. CONCLUSÃO: As diferenças etiológicas entre géneros contribuem para o aumento de prevalência de PEA no sexo masculino e as diferenças fenotípicas promovem o subdiagnóstico no sexo feminino. Este dimorfismo presente no autismo é crucial para a predominância masculina acentuada da razão de PEA entre géneros.
INTRODUCTION: Autism spectrum disorder (ASD) is a heterogeneous medical condition characterized by persistent deficits in communication and social interaction, as well as repetitive and restrictive behaviors, activities and interests (RRBAI). The estimated prevalence of ASD is about 1 in 1000 in school-age children in Portugal, with a significant male predominance, with a ratio of 4:1. This ratio has been a matter of controversy in the scientific community, with several studies highlighting distinct etiological mechanisms and phenotypes between genders. This study aimed to carry out a narrative review of the differences between genders in various domains of the disorder. METHODOLOGY: A search was carried out in the online bibliographic database of Elsevier, ClinicalKey, and in the National Center for Biotechnology Information database, in the PubMed section. Clinical guidelines and scales used for the diagnosis of the disorder were also consulted. DISCUSSION: Ethiologically, there are significant differences between genders in the neurohormonal, genetic, chromosomal and neuroanatomical mechanisms underlying the development of the disorder. The response to environmental and immunological risk factors is also different between genders. Phenotypically, sexual dimorphism stands out essentially in the RRBAI domain. There is a higher incidence of these signs and symptoms in males but also differences in the type of RRBAI presented by each gender. In the social domain, gender differences are mostly qualitative. These differences can lead to underdiagnosis in girls. The screening and diagnostic tests and scales used in clinical practice appear to be little sensitive to the recognition of autism in females. The reformulation of ASD's nosology and diagnostic criteria may have a positive impact on the treatment and prognosis of children with ASD, particularly females. CONCLUSION: Etiological gender differences contribute to the increase in the prevalence of ASD in males and phenotypic differences promote underdiagnosis in females. This dimorphism present in autism is crucial for the marked male predominance of the ratio between genders.

Introdução: O Transtorno do Espectro do Autismo corresponde a uma síndrome que contempla um défice de comunicação e interação social, que cursa com padrões de comportamento repetitivos e restritivos característicos. Pode haver atrasos/anormalidades no desenvolvimento, estando afetada/comprometida a linguagem. Considera-se que a prevalência mundial tenha vindo a aumentar, com os estudos mais recentes a relatarem uma prevalência de 1-3%. Embora esteja bem estabelecido que existe uma forte componente genética associada a esta doença, a sua fisiopatologia ainda não é conhecida. Desta forma, o seu diagnóstico é clínico e o tratamento multidisciplinar, tendo como principal objetivo a melhoria da comunicação e interação social e das capacidades cognitivas. Objetivo: Efetuar um levantamento dos estudos mais recentes e principais resultados relativamente à investigação sobre a prevalência e etiologia dos Transtornos do Espectro do Autismo nos últimos 5 anos. Métodos: Nesta revisão de literatura foram utilizados como motores de busca a PubMED/MEDLINE, NCBI, Scielo, DARE e Elsevier para encontrar estudos publicados entre 2013 e Dezembro de 2018 relativos à prevalência e etiologia dos Transtornos do Espectro do Autismo (TEA). Foram também consultadas publicações com data de publicação prévia à janela estabelecida no âmbito dos TEA, a sua etiologia, prevalência, manifestações clínicas, diagnóstico e tratamento quando considerado necessário. No final da análise dos estudos, procedeu-se à síntese narrativa e discussão dos resultados encontrados. Discussão: Foi denotado no decorrer deste estudo uma tendência de aumento global da prevalência dos TEA, com valores estimados de prevalência nos EUA de 2.5%, na Europa entre 2-3%, com restantes estudos a nível mundial com valores bastante variáveis. O rácio de TEA entre rapazes e raparigas é de aproximadamente 4:1. É de realçar a forte componente familiar na etiologia deste transtorno, com valores de recorrência entre irmãos de 20-50%. Alguns síndromes genéticos têm sido associados aos TEA, com destaque para síndrome de Rett (61%), síndrome de Cohen (54%) e o síndrome de Cornelia de Lange (43%). Vários estudos relatam um importante papel dos neurotransmissores na etiologia dos TEA, evidenciando que desequilíbrios na sua função possam acometer processos celulares importantes, como a transmissão e plasticidade sináptica. Estudos evidenciam que várias alterações genéticas estão associadas a genes que codificam proteínas essenciais à normal função sináptica, como moléculas de adesão celular ou proteínas de scaffolding. Apesar desta forte componente genética, estudos indicam como importante agente etiológico dos TEA a interação com fatores maternos como a idade, doenças ou estado nutricional, e fatores de exposição ambiental, com períodos distintos de exposição implicados (periconcepcional, pré-natal, pós-natal). Conclusões: A prevalência dos TEA apresenta uma tendência de subida a nível mundial. Contudo, existe grande variabilidade de estimativas obtidas em várias partes do mundo, possivelmente consequência de diferentes métodos de estudo, meios de diagnóstico ou consciencialização. Está bem estabelecida a forte componente genética dos Transtornos do Espectro do Autismo, contudo crê-se que o processo etiológico da doença esteja também sujeito à influência de fatores ambientais e maternos. Considerando a provável etiologia multifatorial dos TEA, os estudos dos fatores de risco devem dar prioridade a fatores de risco modificáveis. Devido à elevada heterogeneidade de métodos utilizados na investigação dos TEA, deve-se procurar uniformizar os mesmos de modo a serem obtidos resultados reprodutíveis e mais coerentes.
Introduction: Autism Spectrum Disorder corresponds to a syndrome that includes a deficit in communication and social interaction, which is characterized by repetitive and restrictive patterns of behavior. There may be developmental delays or abnormalities, with a compromise to language. World prevalence is estimated to be increasing, with the most recent studies reporting a prevalence of 1-3%. Although it is well established that there is a strong genetic component associated with this disease, its pathophysiology is not yet known. Due to this, diagnosis is clinical and the treatment multidisciplinary, with the improvement of communication and social interaction and cognitive abilities as main therapeutic goal. Objective: To carry out a survey of the most recent studies and main results regarding research on the prevalence and etiology of Autism Spectrum Disorders in the last 5 years. Methods: In this literature review, PubMED / MEDLINE, NCBI, Scielo, DARE and Elsevier were used as search engines to find studies published between 2013 and December 2018 regarding the prevalence and etiology of Autism Spectrum Disorders (ASD). Publications with a date of publication prior to the window established in the scope of ASD, its etiology, prevalence, clinical manifestations, diagnosis and treatment were also consulted when considered necessary. At the end of the analysis of the studies, we proceeded to the narrative synthesis and discussion of the results found. Discussion: In the course of this study, a trend of rising global prevalence of ASD was observed, with estimated prevalence in the USA of 2.5%, in Europe between 2-3%, with other studies worldwide reporting very variable values. The ASD ratio for boys and girls is approximately 4:1. It is important to highlight the strong familial component in the etiology of this disorder, with recurrence values between siblings of 20-50%. Some genetic syndromes have been associated with ASD, with emphasis on Rett syndrome (61%), Cohen syndrome (54%) and Cornelia de Lange syndrome (43%). Several studies report an important role of neurotransmitters in the etiology of ASD, showing that imbalances in their function can affect important cellular processes such as synaptic plasticity and transmission. Studies show that several genetic alterations are associated with genes encoding proteins essential for normal synaptic function, such as cell adhesion molecules or scaffolding proteins. Despite the strong genetic component, studies indicate that the interaction with maternal factors and environmental exposure, with distinct periods of exposure (periconceptional, prenatal, and postnatal), may be implicated in ASD. Conclusions: The prevalence of ASD is rising worldwide. However, there is great variability of estimates obtained in various parts of the world, possibly due to different methods of study, diagnosis or awareness to the disease. The strong genetic component of Autism Spectrum Disorders is well established, but it is believed that the etiological process of the disease is also influenced by environmental and maternal factors. Considering the probable multifactorial etiology of ASD, risk factors studies should give priority to modifiable risk factors. Due to the high heterogeneity of methods used in the investigation of ASD, it should be sought to standardize them in order to obtain reproducible and more coherent results.

Dissertação de mestrado em Bioquímica, apresentada à Faculdade de Ciências e Tecnologia da Universidade de Coimbra
O autismo é um distúrbio do desenvolvimento e apresenta uma incidência cerca de 34/10000 indivíduos. Esta patologia manifesta-se na infância, persistindo ao longo da vida e pode dar origem a uma grande variedade de quadros clínicos, tais como, dificuldades de interação social e de comunicação, comportamentos repetitivos e estereotipados. Os factores genéticos representam um papel importante, apesar da sua origem por vezes incerta e numa taxa relevante de casos o diagnóstico etiológico é desconhecido. Porém, regiões cromossómicas, tais como, 15q11-q13, 16p11 e o 22q13.3 têm sido associadas ao autismo. O objectivo deste trabalho é relacionar as manifestações do espectro do autismo com alterações cromossómicas submicroscópicas, das regiões 15q11-q13, 16p11.2 e 22q13.3, através da técnica de MLPA, avaliando a sua incidência na população em estudo. Foram encontradas anomalias cromossómicas em três pacientes, duas na região 15q11.2-q13.3 e uma na região 16p11.2, comprovando a sua importância na etiologia do autismo. A técnica de MLPA revelou ser adequada na pesquisa direcionada de alterações cromossómicas e é uma mais valia num laboratório de diagnóstico.
Autism is a developmental disorder and has an incidence of about 34/10000 individuals. This pathology manifests itself in childhood and persists throughout life and can give rise to a wide variety of clinical manifestations, such as difficulties in social interaction and communication, repetitive and stereotyped behaviors. Genetic factors play an important role, despite its origins sometimes uncertain. In most of the cases its etiology is unknown. In some cases chromosomal rearrangements are the most commonly identified abnormalities. There are certain chromosomal regions that have been most associated with autism, as for exemple the regions 15q11-q13, 16p11 and 22q13. The aim of this work is to relate the manifestations of the autism spectrum with the above submicroscopic chromosomal changes through the MLPA technique, assessing its impact in the population. Chromosomal abnormalities were found two in region 15q11-q13 and one in 16p11.2 confirming its importance in the autism etiology. The MLPA technique has proved suitable for the research of chromosomal abnormalies and is an asset in a diagnostic laboratory.

Dissertação de mestrado em Biologia Celular e Molecular, apresentada ao Departamento de Zoologia da Faculdade de Ciências e Tecnologia da Universidade de Coimbra.
O autismo trata-se de uma síndrome comportamental complexa, em que o paciente apresenta dificuldades de interacção social e de comunicação, assim como comportamentos repetitivos e estereotipados, havendo uma prevalência de cerca de 34/10000 indivíduos. Nesta patologia, os factores genéticos representam um papel importante, não se sabendo ainda quais os genes associados, no entanto, existem determinadas regiões cromossómicas mais susceptíveis, como por exemplo, a região proximal do braço longo do cromossoma 15 (15q11-q13). Aproximadamente, 1% a 4% das crianças que têm autismo apresentam anomalias citogenéticas nesta região. Como a citogenética convencional apenas detecta delecções ou duplicações com tamanho entre 3-5 Mb é necessário recorrer a técnicas de citogenética molecular, como a Fluorescent in situ Hybridization (FISH), que tem sido amplamente usada na deteccção de anomalias cromossómicas em pacientes autistas. Recentemente, têm surgido novas metodologias, como a Multiplex Ligation-Dependent Probe Amplification (MLPA) que tem vindo a responder às necessidades exigidas pelos novos avanços da ciência. O objectivo deste trabalho foi relacionar o autismo com alterações cromossómicas na região 15q11.2, e assim, avaliar a sua frequência na etiologia do autismo. Dos 556 casos autistas que foram referenciados ao laboratório, 429 foram estudados pela metodologia de FISH com as sondas para os loci SNRPN e UBE3A. Desses, 134 foram ainda analisados pela técnica de Methylation-Specific Multiplex Ligation-dependent Probe Amplification (MS-MLPA) com o kit ME028. Dos 429 casos, foram encontradas um total de 7 alterações: duas duplicações intersticiais da região 15q11-q13, duas triplicações intersticiais desta mesma região, um cromossoma supranumerário derivado do cromossoma 15, um marcador do cromossoma 15 em mosaico, e uma microduplicação localizada na região entre os pontos de quebra BP1 e BP2. A frequência destas anomalias cromossómicas neste estudo (1,6%) está dentro da variabilidade reportada noutros trabalhos e são uma causa significante para a etiologia do autismo. Estas descobertas indicam que a MS-MLPA é um método eficiente para o screening deste tipo de anomalias cromossómicas, sendo um método simples, rápido,sensível e económico, permitindo a detecção simultânea de alterações no número de cópias e nos padrões de metilação.
Autism is a complex behavioral syndrome, in which the patient presents deficit in social interaction and communication and has stereotyped and repetitive behaviors. Autism has a prevalence of 34/10000 individuals. In this pathology, genetic factors play a significant role, and although the autism associated genes are not yet known, there are chromosomes regions such as the proximal region of the long arm of the chromosome 15 (15q11-q13) that share a certain susceptibilities. Approximately 1 to 4% of the children who have autism present cytogenetic abnormalities in this region. As the convencional cytogenetic methods only detect deletions or duplications of 3-5 Mb in size, researchers usually use molecular cytogenetic techniques such as the Fluorescent in situ Hybridization (FISH) to evaluate them. Recently, new methodologies have arise such as the Multiplex Ligationdependent Probe Amplification (MLPA), which has several advantages in the diagnosis of such chromosomal abnormalities. The aim of this work was to find an association between autism and chromosomal alterations in the 15q11.2 region and to evaluate its prevalence in the autism etiology. 556 cases of autism have been reported to the laboratory. 429 were studied by FISH technique with probes to the SNRPN and UBE3A loci. Of these, 134 were analyzed by Methylation-Specific Multiplex ligation-dependent Probe Amplification (MS-MLPA) technique with the ME028 kit.Of the 429 cases, we found two interstitial duplications and two interstitial triplications in the region 15q11-q13, one supernumerary marker chromosome derived from chromosome 15, one supernumerary mosaic marker chromosome 15 and a microduplication of the region between breakpoint BP1 and breakpoint BP2. The frequency of these chromosomal abnormalities in this study (1,6%) is within the reported frequencies in other studies. These findings also showed that the MSMLPA is an efficient method for the screening of this type of chromosomal abnormalities, being simple, rapid, sensitive, economic and allowing the simultaneous detection of copy number alterations as well as methylation patterns.

Tese de mestrado. Biologia (Biologia Humana e Ambiente). Universidade de Lisboa, Faculdade de Ciências, 2010
O Autismo é um perturbação do desenvolvimento infantil que se caracteriza por desvios na interacção social e na comunicação verbal e não verbal, assim como, por comportamentos repetidos, estereotipados e ritualizados. Estudos baseados em gémeos e em famílias demonstraram que o autismo apresenta uma forte componente genética. Contudo, pelo facto de ser uma doença complexa, existem várias variantes envolvidas, cada uma conferindo um risco reduzido no fenótipo o que tem dificultado a identificação dos genes de susceptibilidade desta doença. O objectivo principal deste estudo foi a identificação dos genes de susceptibilidade envolvidos nas vias biológicas activadas pela neurotrofina BDNF (Brain derived neurotrophic factor) e pelo seu receptor TrkB (Neurotrphic tyrosine kinase receptor type 2). Estudos anteriores encontraram níveis significativamente elevados desta neurotrofina no soro de pacientes com autismo e uma associação entre marcadores do gene que codifica o seu receptor, NTRK2 e o autismo, colocando a hipótese de que exista uma alteração da via de sinalização BDNF/TrkB nesta patologia. No presente estudo foi explorada esta hipótese, utilizando os resultados de um rastreio genómico de associação levado a cabo pelo consórcio internacional Autism Genome Project, onde participaram 1369 famílias, compostas pelo paciente ao qual foi diagnosticado autismo e os respectivos pais, cerca de um terço das quais eram de origem portuguesa (subpopulação PT). Especificamente, investigou-se a associação genética entre o autismo e os genes que codificam factores de transcrição (genes homeobox) que se ligam ao promotor do gene NTRK2 bem como os genes das vias biológicas induzidas pela ligação do BDNF ao seu receptor TrkB (MEK-ERK, PI3K-AKT e PLC<). Pretendeu-se ainda identificar interacções genéticas entre os genes homeobox, NTRK2 e BDNF com impacto na susceptibilidade ao autismo. Em última análise, pretendeu-se analisar o enriquecimento do sinal de associação das vias biológicas supracitadas e identificar outros grupos de genes relevantes na susceptibilidade ao autismo. Em paralelo, foi realizado o rastreio por sequenciação de regiões do gene NTRK2 anteriormente associadas ao autismo na população portuguesa. Os resultados revelam novas regiões de susceptibilidade nos genes participantes nas três vias biológicas activadas por BDNF/TrkB, com especial interesse para os genes da via biológica PI3K-AKT e para o gene NTRK2. Alterações na expressão do gene NTRK2 e dos genes participantes na via biológica PI3K-AKT poderão estar envolvidos na susceptibilidade ao autismo. O presente estudo permitiu também identificar três novas vias biológicas que poderão estar envolvidas na susceptibilidade à doença: Via biológica do metabolismo dos compostos isoprenóides, Via biológica do processo de aminoacilação do tRNA (RNA de transferência) na síntese proteica e a Via de sinalização da m-Calpaína na mobilidade celular. Embora sejam necessários estudos adicionais para esclarecer o papel dos genes e vias identificadas, este estudo constituiu mais um importante passo na compreensão das vias metabólicas que poderão estar alteradas nesta doença, assim como um contributo na detecção de novos factores genéticos de susceptibilidade associados ao autismo.
Autism is a childhood neurodevelopment disorder that is characterized by impairments in social interaction, verbal and non-verbal communication, and stereotyped and ritualistic behaviors. Twin and family studies show that autism has a strong genetic component. However, since it’s a complex trait there are several genetic variants involved each one with a small risk to the phenotype, which is a challenge in the identification of the susceptibility genes. The main goal of this study is to identify susceptibility genes involved in the pathways activated by the neurotrophin BDNF (Brain derived neurotrophic factor) and its receptor TrkB (Neurotrphic tyrosine kinase receptor type 2). Previous studies found significantly high levels of the neurotrophin BDNF in the platelet-rich plasma of autistic patients and genetic markers of the gene encoding the BDNF receptor, NTRK2, were associated with autism. This leads to the hypothesis that alterations in BDNF/TrkB signaling contribute to an increased susceptibility in this disorder. In the present study we explored this hypothesis using the results of a genomewide association study performed by Autism Genome Project with 1369 families that include the autistic patient and his non-affected parents, of which are one third from Portugal. Specifically, we tested for association between autism and the genes that encode homeodomain transcription factors (homeobox genes) that bind to the promoter region of NTRK2 gene as well as the genes belonging to the pathways actived by BDNF/TrkB signaling (MEK-ERK, PI3K-AKT and PLC<). In addition we also pretended to identify genetic interactions between the homeobox, NTRK2 and BDNF genes that contribute to autism susceptibility. Finally, we used a pathway analysis approach with GWAS results to analyze gene sets (of interest) for enrichment of the association signal and to identify new pathways relevant to susceptibility of autism. In parallel, we have conducted a screening test of sequence changes in the NTRK2 gene regions previously associated with autism, in the Portuguese population. Results show new susceptibility regions in the genes of the three pathways induced by BDNF/TrkB signaling, specially the genes of the PI3K-AKT pathway and NTRK2. Modifications on the expression of the genes NTRK2 and those from the PI3K-AKT pathway can be involved in the susceptibility of autism. The present study provided also the identification of three new pathways that could be involved in the disease risk: Isoprenoid metabolic pathway, tRNA aminoacylation for protein translation pathway and mCalpain pathway in cell motility. Although future studies will be necessary to clarify the role of the identified genes and pathways, this study was an important step in the knowledge of the metabolic pathways that can be disrupt in the disease, as well as detecting new genetic factors underlying the susceptibility to autism.

Trabalho Final do Curso de Mestrado Integrado em Medicina, Faculdade de Medicina, Universidade de Lisboa, 2020
As perturbações do espetro do autismo (PEA) são um conjunto heterogéneo de condições do neurodesenvolvimento, caracterizadas por dificuldades na comunicação social, bem como comportamentos e interesses repetitivos e restritivos de instalação precoce. A etiologia desta patologia é multifatorial e culmina num desenvolvimento cerebral atípico, determinando uma elevada heterogeneidade clínica. Esta revisão da literatura tem como objetivos analisar as diversas etiologias possíveis e os mecanismos fisiopatológicos que provocam alterações do neurodesenvolvimento nos indivíduos afetados. Relativamente à metodologia, foi feita uma pesquisa de artigos nos motores PubMed e Medline (utilizando as palavras-chave “autism”, “autism spectrum disorder”, “ASD”, “etiology”, “genes”, “connectivity”, “neurobiology” e “default mode network”), assim como consulta de livros de texto e websites relevantes. Sendo a etiologia da PEA multifatorial, os fatores contribuintes são mutações genéticas (incluindo dos genes PTEN, MECP2 e CHD8, por exemplo), alterações epigenéticas, modificações do ambiente e disfunções imunológicas (diferenciadas em modificações pré- e pós-natais). Relativamente aos mecanismos fisiopatológicos, são frequentes alterações de vias de sinalização celular (RAS/ERK, PI3K/AKT, WNT e β-catenina) e de vários neurotransmissores, com impacto negativo no neurodesenvolvimento e na sintomatologia. Os diversos insultos sofridos resultam em modificações cerebrais: conetividade de longa-distância deficitária e aumento tendencial da conetividade local; alterações na matéria branca, especialmente no corpo caloso, fascículos longitudinal superior, longitudinal inferior, occipitofrontal e uncinado, e giro cingulado; alterações no córtex, cerebelo e default mode network. Além disso, as atipias cerebrais sugerem ter uma variação com a idade, havendo um crescimento cefálico anormalmente aumentado nos primeiros anos de vida, seguido de posterior regressão em idades mais avançadas. Assim, a melhor compreensão dos mecanismos etiológicos e fisiopatológicos da PEA permite um conhecimento aprofundado e individualizado dos sintomas, um diagnóstico mais preciso e, no futuro, uma abordagem terapêutica possivelmente mais eficaz e antecipada.
The autism spectrum disorders (ASD) are a heterogeneous set of neurodevelopmental conditions, characterized by impairments in social communication, as well as repetitive and restrictive behaviors and interests of early onset. The etiology of this disorder is multifactorial and culminates in atypical brain development, thus determining a high clinical heterogeneity. The present literature revision aims to analyze the diverse possible etiologies and the physiopathological mechanisms underlying the neurodevelopmental alterations in affected individuals. Referring to the methodology, an article search was done in PubMed and Medline search engines (using the keywords “autism”, “autism spectrum disorder”, “ASD”, “etiology”, “genes”, “connectivity”, “neurobiology” and “default mode network”), along with the consultation of textbooks and relevant websites. Given that the etiology of ASD is multifactorial, the contributing factors are genetic mutations (including PTEN, MECP2 and CHD8 genes, for example), epigenetic alterations, environmental modifications and immunological disfunctions (distinguished between pre and postnatal modifications). Referring to the pathophysiological mechanisms, cell signaling pathways (RAS/ERK, PI3K/AKT, WNT and β-catenin) and several neurotransmitter alterations are frequent, negatively impacting on the neurodevelopment and symptomatology. The various suffered insults result in cerebral modifications: long-range underconnectivity and tendential shortrange overconnectivity; changes in white matter, especially the corpus callosum, superior and inferior longitudinal fasciculi, occipitofrontal and uncinate fasciculi and cingulum; modifications in the cortex, cerebellum and default mode network. Moreover, the cerebral changes seem to be age-related, with an abnormally enlarged head growth in the first years, followed by regression in older ages. Therefore, a more comprehensive understanding of the etiological and physiopathological mechanisms of ASD allows for a broader and more individualized knowledge of the symptoms, a more accurate diagnosis and, in the future, possibly an earlier and more effective therapeutic approach.

As células da microglia são células imunes residentes do sistema nervoso central que desempenham funções essenciais no desenvolvimento e na homeostasia deste sistema. Nos últimos anos, um número crescente de estudos sugere que a microglia tem um papel fundamental na patogénese de distúrbios do desenvolvimento neurológico, tais como as Perturbações do Espectro do Autismo (PEA), tendo sido proposto que mutações em genes que alterem o número da microglia podem afetar profundamente o neurodesenvolvimento. Neste sentido, a microglia surge como um potencial alvo para o tratamento destes distúrbios. Contudo, os reguladores moleculares subjacentes ao desenvolvimento da microglia e à aquisição de suas propriedades funcionais são ainda pouco conhecidos. No passado, a nossa equipa identificou o gene DIA1R (Deleted in Autism 1 Related) como um novo gene implicado em PEA que se encontra altamente expresso nos progenitores hematopoiéticos das células da microglia em embriões de vertebrados. Neste projeto fomos investigar o papel do gene dia1r no desenvolvimento da microglia do peixe-zebra. Para tal, quantificamos o número de células da microglia presentes no cérebro de larvas de peixe-zebra morfantes e mutantes para dia1r utilizando técnicas de citometria de fluxo, coloração com Neutral Red e microscopia confocal. Os nossos resultados demonstraram que o número de microglia é significativamente inferior em larvas morfantes e mutantes para dia1r em relação aos respetivos controlos, sugerindo que DIA1R promove o desenvolvimento da microglia. Estas evidências apresentam o DIA1R como um novo regulador da ontogenia da microglia, papel que pode estar subjacente à sua implicação em PEA. Para além disso, esta investigação contribui para esclarecer o papel etiológico da disfunção da microglia nos distúrbios do desenvolvimento neurológico, trazendo novas perspetivas de diagnóstico e potencial tratamento de subtipos de PEA mediados pela microglia.
Microglia are resident immune cells of the central nervous system that play essential roles in the development and homeostasis of this system. In recent years, a growing body of evidence implicates microglia in the pathogenesis of neurodevelopmental disorders such as Autism Spectrum Disorders (ASD). It has been proposed that gene mutations that alter the number of microglia can profoundly affect neurodevelopment. Therefore, microglia has arisen as a novel potential target for the treatment of these disorders. However, little is known about the molecular regulators underlying the development of microglial cells and their acquisition of functional properties. In the past, our team identified DIA1R (Deleted in Autism 1 Related) as a novel gene implicated in ASD that is highly expressed in the hematopoietic progenitors of microglial cells in the vertebrate embryo. In this project, we investigated the role of dia1r in zebrafish microglia development. For this, we quantified the number of microglial cells present in the brain of dia1r morphant and mutant zebrafish larvae using flow cytometry, Neutral Red staining and confocal microscopy. Our results demonstrated that the number of microglia in the brains of dia1r morphant and mutant larvae is significantly lower in comparison to their respective controls, suggesting that DIA1R promotes microglia development. These evidences introduce DIA1R as a novel regulator of microglia ontogeny, a role that may underlie its implication in ASD. In addition, this investigation contributes to clarify the etiological role of microglia disfunction in neurodevelopmental disorders, bringing new perspectives for the diagnosis and potential treatment of microglia-mediated subtypes of ASD.