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Title: Genetic factors in autism spectrum disorders (ASD) and in variability in individual response to risperidone therapy
Author: Correia, Catarina Alexandra Tavares, 1980-
Advisor: Fialho, Maria da Graça Monteiro de Azevedo, 1943-
Vicente, Astride Carolina Lentz de Moura
Keywords: Autismo
Teses de doutoramento
Defense Date: 2009
Abstract: Autism is a complex neurodevelopmental disorder resulting from a combination of genetic, environmental, and immunological factors. This work aimed at the characterization of autism-associated phenotypes and the identification of genes regulating such phenotypes and contributing to autism risk. A second objective was the identification of genetic factors underlying the variability in individual response of autistic patients to risperidone therapy. Association studies performed with genes ITGA4 and SLC25A12, mapping to the autism linkage region on 2q31-33, confirmed that the ITGA4 gene is a susceptibility gene for autism. Further, this gene may be involved in the process of neuroinflammation suggested by the observation of a widespread occurrence of autoreactivities to brain tissue in a subset of patients. On the contrary, the SLC25A12 gene was not associated with autism or with mitochondrial dysfunction markers frequently observed in our sample. Increased circulating levels of brain derived neurotrophic factor (BDNF) were observed in 25% of our patients, and this trait mapped to the chromosome 5q11.2-q13 region, likely to the RNF180 gene. Taken together with the association of NTRK2 genetic variants with autism, our results provide strong evidence for an alteration of the BDNF/TrkB signalling in autism. Association with autism of the BDNF regulatory genes CADPS2 and SLC1A2 was not fully conclusive, requiring replication in larger populations. Risperidone, administered to forty-five patients for one year, was very effective in reducing some autism symptoms and caused few serious adverse effects. Although association results should be taken as suggestive, we identified for the first time several genes implicated in risperidone efficacy and safety in autism patients. Overall, the results of this work contribute to the identification of susceptibility genes for autism. In particular, it defined a disruption of the BDNF/TrkB signalling pathway as contributing to autism. Additionally, our pharmacogenetic study constitutes a step toward individualized therapy in autism.
Description: Tese de doutoramento, Biologia (Genética), 2009, Universidade de Lisboa, Faculdade de Ciências
Appears in Collections:FC - Teses de Doutoramento

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