Serotonin - a complex, puzzling biomarker in Autism Spectrum Disorder

Introdução: Hiperserotonemia tem sido reportada em pacientes com Perturbação do Espetro do Autismo (PEA) e nos seus familiares. Dado o potencial heurístico da serotonina, esta revisão narrativa visa discutir a plausibilidade biológica da possível existência de disfunção serotoninérgica na PEA, bem como a relevância e implicações clínicas do uso da serotonina como biomarcador. Métodos: Estudos em humanos e animais relativos a disfunção serotoninérgica na PEA foram pesquisados, bem como artigos que reportam medições sanguíneas de serotonina em pacientes com PEA e familiares de primeiro-grau. Não foi aplicado limite temporal, apenas artigos em Inglês foram incluídos. Resultados: Várias linhas de prova confirmam o envolvimento do sistema serotoninérgico na PEA. Níveis maternos e placentários de serotonina anormais podem influenciar o embrião, o que suporta o modelo da hiperserotonemia do desenvolvimento do autismo. É documentada hiperserotonemia em mais de 25% da população com PEA, sendo um possível traço familiar, possivelmente relacionado com o processamento plaquetário da serotonina, estando vários genes serotoninérgicos concebivelmente implicados. Dados existentes destacam a fiabilidade da hiperserotonemia como biomarcador e denotam a serotonina como uma potencial ligação entre o eixo microbiota-intestino-cérebro e a PEA. Conclusões: O sistema serotoninérgico desempenha um papel preponderante no neurodesenvolvimento, sendo que disfunção desta rede neuromodulatória pode estar implicada na PEA. Medição da serotonina providenciaria informações sobre mecanismos patofisiológicos e fatores de risco, identificaria subgrupos homogéneos de pacientes com uma trajetória delineada de desenvolvimento, facilitaria um diagnóstico mais preciso, enquanto preveria respostas terapêuticas, reações adversas e ajudaria no desenvolvimento de novas terapias. Investigação adicional é aconselhada, tendo em vista a promoção mais célere da translação destes conhecimentos das ciências básicas para a prática clínica.Background: Hyperserotonemia has been reported in Autism Spectrum Disorder (ASD) patients and their relatives. Due to serotonin's heuristic potential, this narrative review aims to discuss the biological plausibility of the serotonergic dysfunction hypothesis in ASD, as well as relevance and clinical implications of using serotonin as a biomarker. Methods: Human and animal studies addressing serotonergic dysfunction in ASD were surveyed, as well as articles reporting blood serotonin measurements in ASD patients and first-degree relatives. No time limit was applied, exclusively articles written in English were included. Results: Several lines of evidence confirm the involvement of the serotonergic system in ASD. Altered maternal and placental serotonin levels may influence the embryo, thus supporting the developmental hyperserotonemia model of autism. Hyperserotonemia is recorded in more than 25% of the ASD population and is thought to be a familiar trait, possibly related to platelet's handling of serotonin with several serotonergic genes conceivably implicated. Existing data highlights the reliability of hyperserotonemia as a biomarker and denotes serotonin as a potential nexus between the microbiome-gut-brain axis and ASD. Conclusions: The serotonin system plays a preponderant role in neurodevelopment, thus dysfunction of this neuromodulatory network might be implicated in ASD. Serotonin measurement would provide insights about pathophysiologic mechanisms and risk factors, identify homogenous subsets of patients with a delineated developmental trajectory, facilitate a more accurate diagnosis, while predicting treatment response, adverse reactions and help developing novel therapies. Further investigation is advised, as it will promote a faster translation of these basic science findings to clinical practice

SARS-CoV-2 introductions and early dynamics of the epidemic in Portugal

Genomic surveillance of SARS-CoV-2 in Portugal was rapidly implemented by the National Institute of Health in the early stages of the COVID-19 epidemic, in collaboration with more than 50 laboratories distributed nationwide. Methods By applying recent phylodynamic models that allow integration of individual-based travel history, we reconstructed and characterized the spatio-temporal dynamics of SARSCoV-2 introductions and early dissemination in Portugal. Results We detected at least 277 independent SARS-CoV-2 introductions, mostly from European countries (namely the United Kingdom, Spain, France, Italy, and Switzerland), which were consistent with the countries with the highest connectivity with Portugal. Although most introductions were estimated to have occurred during early March 2020, it is likely that SARS-CoV-2 was silently circulating in Portugal throughout February, before the first cases were confirmed. Conclusions Here we conclude that the earlier implementation of measures could have minimized the number of introductions and subsequent virus expansion in Portugal. This study lays the foundation for genomic epidemiology of SARS-CoV-2 in Portugal, and highlights the need for systematic and geographically-representative genomic surveillance.We gratefully acknowledge to Sara Hill and Nuno Faria (University of Oxford) and Joshua Quick and Nick Loman (University of Birmingham) for kindly providing us with the initial sets of Artic Network primers for NGS; Rafael Mamede (MRamirez team, IMM, Lisbon) for developing and sharing a bioinformatics script for sequence curation (https://github.com/rfm-targa/BioinfUtils); Philippe Lemey (KU Leuven) for providing guidance on the implementation of the phylodynamic models; Joshua L. Cherry (National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health) for providing guidance with the subsampling strategies; and all authors, originating and submitting laboratories who have contributed genome data on GISAID (https://www.gisaid.org/) on which part of this research is based. The opinions expressed in this article are those of the authors and do not reflect the view of the National Institutes of Health, the Department of Health and Human Services, or the United States government. This study is co-funded by Fundação para a Ciência e Tecnologia and Agência de Investigação Clínica e Inovação Biomédica (234_596874175) on behalf of the Research 4 COVID-19 call. Some infrastructural resources used in this study come from the GenomePT project (POCI-01-0145-FEDER-022184), supported by COMPETE 2020 - Operational Programme for Competitiveness and Internationalisation (POCI), Lisboa Portugal Regional Operational Programme (Lisboa2020), Algarve Portugal Regional Operational Programme (CRESC Algarve2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF), and by Fundação para a Ciência e a Tecnologia (FCT).info:eu-repo/semantics/publishedVersio