La revolució del DNA

Avenços en genètica forens

De novo Mutations (DNMs) in Autism Spectrum Disorder (ASD): Pathway and Network Analysis

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder (NDD) defined by impairments in social communication and social interactions, accompanied by repetitive behavior and restricted interests. ASD is characterized by its clinical and etiological heterogeneity, which makes it difficult to elucidate the neurobiological mechanisms underlying its pathogenesis. Recently, de novo mutations (DNMs) have been recognized as strong source of genetic causality. Here, we review different aspects of the DNMs associated with ASD, including their functional annotation and classification. In addition, we also focus on the most recent advances in this area, such as the detection of PZMs (post-zygotic mutations), and we outline the main bioinformatics tools commonly employed to study these. Some of these approaches available allow DNMs to be analyzed in the context of gene networks and pathways, helping to shed light on the biological processes underlying ASD. To end this review, a brief insight into the future perspectives for genetic studies into ASD will be provided

Deletion of the CYP2D6 gene as a likely explanation for the serious side effects of the antipsychotic drug pimozide: a case report

CYP2D6 analysis prior to the prescription of pimozide is required above a certain dose by the Food and Drug Administration in order to detect individuals with the poor metabolizer status. This precautionary measure aims to prevent the occurrence of serious adverse drug reactions. This study presents a case of a patient diagnosed with schizophrenia spectrum disorder. The patient suffered re-admission in the psychiatry ward because of severe secondary symptoms due to the antipsychotic drug pimozide, previously prescribed on a first admission. In order to assess the patient’s medication profile, real-time PCR was performed to analyze the main genes responsible for its metabolization, namely, CYP2D6 and CYP3A4. The pharmacogenetic study revealed that the patient is a poor metabolizer for CYP2D6, presenting deletion of both copies of the gene (diplotype *5/*5). Fortunately, the symptomatology disappeared after the withdrawal of the responsible drug. In conclusion, abiding by the pharmacogenetic clinical practice guidelines and the pharmacogenetic analysis of CYP2D6 when prescribing pimozide would have probably saved the patient from the consequences of severe side effects and the health system expenditure. There is an important need for more training in the pharmacogenetic field for specialists in psychiatry

Morphometric and connectivity white matter abnormalities in Obsessive Compulsive Disorder

Two psychological mechanisms seem to be associated with the obsessive-compulsive cycle: (1) an emotional mechanism characterized by intense emotional arousal associated with intrusive thoughts of impending danger; (2) a cognitive mechanism exemplified by difficulties with inhibitory control. Several studies found more extensive cognitive deficits in Obsessive Compulsive Disorder (OCD) beyond problems of inhibitory control and emotional regulation, namely: visual-spatial processing and memory. Thus, there is now extensive research showing that alterations of these psychological mechanisms in OCD (i.e., inhibitory control, emotional regulation, working memory, and visual spatial processing) are associated with morphological gray matter alterations in widespread brain regions. More recently, researchers have started looking at white matter abnormalities in OCD. In this article we review the research looking at white matter morphometric and structural connectivity alterations in OCD. Altogether, while some contradictory findings are still present, there is now evidence for widespread white matter morphometric and connectivity abnormalities affecting major white matter tracts (superior longitudinal fasciculus, inferior fronto-occipital fasciculus, inferior longitudinal fasciculus, cingulum bundle, semioval center, internal capsule, different regions of the corpus callosum, thalamic radiation, uncinate fasciculus and optic radiation) as well as white matter in regions adjacent to gray matter structures (superior frontal gyrus, dorsolateral prefrontal medial frontal cortex; inferior frontal gyrus, caudate, insulate cortex, parietal cortex, supramarginal and lingual gyri, and thalamus). These white matter alterations may help explaining the diversity of OCD psychological impairments in inhibitory control, emotional regulation, memory and visual spatial processing.The authors have no financial or personal conflicts of interest. The first author was funded by the Brazilian National Counsel for Scientific and Technological Development (CNPq) as a Special Visiting Researcher of the Science Without Borders program (grant number: 401143/2014-7). This study was partially conducted at the Neuropsychophysiology Lab from the Psychology Research Centre (UID/PSI/01662/2013), University of Minho, and supported by the Portuguese Foundation for Science and Technology and the Portuguese Ministry of Science, Technology and Higher Education through national funds and co-financed by FEDER through COMPETE2020 under the PT2020 Partnership Agreement (POCI-01-0145- FEDER-007653).info:eu-repo/semantics/publishedVersio

Gray matter morphological alteration in Obsessive Compulsive Disorder: evidence for an inhibitory control and emotional regulation disorder

The integration of obsessive compulsive disorders (OCD) in the Obsessive Compulsive and Related Disorders cluster, while emphasizing the centrality of inhibitory control and repetitive behaviors may fail to fully acknowledge the existence of significant affective and other cognitive impairments. The objective of this paper is to present examples on available gray matter imaging studies and meta-analyses that may help understanding cognitive and emotional related factors implicated in OCD. Building on these studies, OCD seems to be a disorder of both inhibitory control and emotional regulation. Volumetric and shape abnormalities in different brain territories of the prefrontal cortex, orbitofrontal cortex, thalamus, striate and cerebellum may contribute to impairments in inhibitory control. On the other side, gray matter shape and volume alterations in regions such as the anterior cingulate, insula, amygdala and supramarginal gyrus may contribute to difficulties in emotional regulation. Beyond this inhibitory control – emotional regulation dichotomy, there are other psychological impairments that may be associated with gray matter alterations. For example, difficulties in memory monitoring may be sustained by shape and volumetric alterations in the dorso-lateral prefrontal cortex and the hippocampus. Additionally, visual-spatial impairments may be explained by gray matter shape and volume alterations in the superior parietal and occipital lobes as well as the precuneus. Overall the research confirms changes in volume and shape in multiple cortical and subcortical regions that can help explaining the complexity of OCD symptomatology and the diversity of OCD endophenotypes. Additionally, the evidence from brain shape anomalies may suggest the additional possibility of neurodevelopmental changes associated with the pathogenesis of OCD.The first author was funded by the Brazilian National Counsel for Scientific and Technological Development (CNPq) as a Special Visiting Researcher of the Science Without Borders program (grant number: 401143/2014-7). This study was partially conducted at the Neuropsychophysiology Lab from the Psychology Research Centre (UID/PSI/01662/2013), University of Minho, and supported by the Portuguese Foundation for Science and Technology and the Portuguese Ministry of Science, Technology and Higher Education through national funds and co-financed by FEDER through COMPETE2020 under the PT2020 Partnership Agreement (POCI-01-0145- FEDER-007653). This work was also supported by the Portuguese Foundation for Science and Technology (FCT) and European Union (FSE-POPH) with two individual grants (SFRH/BPD/86041/2012 and SFRH/BPD/86027/2012).info:eu-repo/semantics/publishedVersio

Gray matter morphological alteration in Obsessive Compulsive Disorder: evidence for an inhibitory control and emotional regulation disorder

The integration of obsessive compulsive disorders (OCD) in the Obsessive Compulsive and Related Disorders cluster, while emphasizing the centrality of inhibitory control and repetitive behaviors may fail to fully acknowledge the existence of significant affective and other cognitive impairments. The objective of this paper is to present examples on available gray matter imaging studies and meta-analyses that may help understanding cognitive and emotional related factors implicated in OCD. Building on these studies, OCD seems to be a disorder of both inhibitory control and emotional regulation. Volumetric and shape abnormalities in different brain territories of the prefrontal cortex, orbitofrontal cortex, thalamus, striate and cerebellum may contribute to impairments in inhibitory control. On the other side, gray matter shape and volume alterations in regions such as the anterior cingulate, insula, amygdala and supramarginal gyrus may contribute to difficulties in emotional regulation. Beyond this inhibitory control – emotional regulation dichotomy, there are other psychological impairments that may be associated with gray matter alterations. For example, difficulties in memory monitoring may be sustained by shape and volumetric alterations in the dorso-lateral prefrontal cortex and the hippocampus. Additionally, visual-spatial impairments may be explained by gray matter shape and volume alterations in the superior parietal and occipital lobes as well as the precuneus. Overall the research confirms changes in volume and shape in multiple cortical and subcortical regions that can help explaining the complexity of OCD symptomatology and the diversity of OCD endophenotypes. Additionally, the evidence from brain shape anomalies may suggest the additional possibility of neurodevelopmental changes associated with the pathogenesis of OCD.The first author was funded by the Brazilian National Counsel for Scientific and Technological Development (CNPq) as a Special Visiting Researcher of the Science Without Borders program (grant number: 401143/2014-7). This study was partially conducted at the Neuropsychophysiology Lab from the Psychology Research Centre (UID/PSI/01662/2013), University of Minho, and supported by the Portuguese Foundation for Science and Technology and the Portuguese Ministry of Science, Technology and Higher Education through national funds and co-financed by FEDER through COMPETE2020 under the PT2020 Partnership Agreement (POCI-01-0145- FEDER-007653). This work was also supported by the Portuguese Foundation for Science and Technology (FCT) and European Union (FSE-POPH) with two individual grants (SFRH/BPD/86041/2012 and SFRH/BPD/86027/2012).info:eu-repo/semantics/publishedVersio

Alteraciones ejecutivas en el Trastorno Obsesivo Compulsivo: una revisión sistemática con paradigmas emocionales y no emocionales

Precedent: Impairments in executive functioning may be associated with compulsive symptoms in Obsessive Compulsive Disorder (OCD). The aim of this study was to conduct a systematic review of cognitive flexibility, inhibitory control and working memory in OCD patients. using emotional and non-emotional paradigms. Method: we reviewed research published in PubMed, Web of Science, PsychInfo, Scopus, Scielo, and ProQuest Psychology databases, from January 2008 to April 2019. The review followed a two-stage process. In the first stage, we selected only studies using neutral stimuli paradigms, while in the second we selected executive-emotional paradigms. Results: The first stage of the review provided 16 final results, while the second stage, with emotional stimuli, provided 3 results. Conclusions: There is some initial evidence for the existence of executive impairments in OCD, as expressed in the performance and/or processing of working memory inhibitory control and cognitive flexibility. There is also initial evidence that these latter two could be modulated by the presentation or mental representation of negative valence stimuli or images, as well as the presence of aversive contingencies.Antecedentes: las alteraciones en el funcionamiento ejecutivo podrían estar asociadas a los síntomas compulsivos del Trastorno Obsesivo Compulsivo (TOC). El objetivo de este estudio fue realizar una revisión sistemática en fl exibilidad cognitiva, control inhibitorio y memoria de trabajo en pacientes con TOC, empleando paradigmas emocionales y no emocionales. Método: revisamos investigaciones publicadas en PubMed, Web of Science, PsychInfo, Scopus, Scielo y ProQuest Psychology databases, desde enero de 2008 hasta abril de 2019. La revisión siguió un proceso de dos etapas: la primera centrada en estudios con paradigmas ejecutivos neutros y la segunda con paradigmas ejecutivos emocionales. Resultados: la primera etapa de búsqueda arrojó un resultado de 16 estudios, mientras que la segunda, con paradigmas emocionales, arrojó tres resultados. Conclusiones: a pesar de la escasa cantidad de investigación, existen evidencias de alteraciones ejecutivas en TOC que se expresan en la ejecución o en el procesamiento de memoria de trabajo, control inhibitorio y fl exibilidad cognitiva. También hay evidencias de que estos dos últimos componentes podrían estar modulados por la presentación o representación mental de estímulos negativos, así como por la presencia de contingencias aversivas.M.T.F. acknowledges Xunta de Galicia-GAIN for the Principia research grant. This work was supported by Fundacion Maria Jose Jove. O.F.G and S.C. were supported by the Portuguese Foundation for Science and Technology and the Portuguese Ministry of Science, through national funds and co-financed by FEDER through COMPETE2020 under the PT2020 Partnership Agreement (POCI-01-0145-FEDER-007653) and along with J.L. were also funded through the grants: P2020-PTDC/MHC; PCN/3950/2014; PTDC/PSI-ESP/30280/2017 and PTDC/PSI-ESP/29701/2017), S.C. was also funded by the individual grant IF/00091/2015

Methylenetetrahydrofolate reductase gene, homocysteine and coronary artery disease: the A1298C polymorphism does matter. Inferences from a case study (Madeira, Portugal)

Elevated levels of plasma homocysteine, an independent risk factor and a strong predictor of mortality in patients with coronary artery disease (CAD), can result from nutritional deficiencies or genetic errors, including methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C polymorphisms. The contribution of these polymorphisms in the development of CAD remains controversial. We analysed the impact of MTHFR C677T and A1298C on fasting homocysteine and CAD in 298 CAD patients proved by angiography and 510 control subjects from the Island of Madeira (Portugal). After adjustment for other risk factors, plasma homocysteine remained independently correlated with CAD. Serum homocysteine was significantly higher in individuals with 677TT and 1298AA genotypes. There was no difference in the distribution of MTHFR677 genotypes between cases and controls but a significant increase in 1298AA prevalence was found in CAD patients. In spite of the clear effect of C677T mutation on elevated homocysteine levels we only found an association between 1298AA genotype and CAD in this population. The simultaneous presence of 677CT and 1298AA genotypes provides a significant risk of developing the disease, while the 1298AC genotype, combined with 677CC, shows a significant trend towards a decrease in CAD occurrence. The data shows an independent association between elevated levels of homocysteine and CAD. Both MTHFR polymorphisms are associated with increased fasting homocysteine (677TT and 1298AA genotypes), but only the 1298AA variant shows an increased prevalence in CAD group. Odds ratio seem to indicate that individuals with the MTHFR 1298AA genotype and the 677CT/1298AA compound genotype had a 1.6-fold increased risk for developing CAD suggesting a possible association of MTHFR polymorphisms with the risk of CAD in Madeira population.info:eu-repo/semantics/publishedVersio