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BACKGROUND: The VPS50 protein functions in synaptic and dense core vesicle acidification, and perturbations of VPS50 function produce behavioral changes in Caenorhabditis elegans. Patients with mutations in VPS50 show severe developmental delay and intellectual disability, characteristics that have been associated with autism spectrum disorders (ASDs). The mechanisms that link VPS50 mutations to ASD are unknown. RESULTS: To examine the role of VPS50 in mammalian brain function and behavior, we used the CRISPR/Cas9 system to generate knockouts of VPS50 in both cultured murine cortical neurons and living mice. In cultured neurons, KO of VPS50 did not affect the number of synaptic vesicles but did cause mislocalization of the V-ATPase V1 domain pump and impaired synaptic activity, likely as a consequence of defects in vesicle acidification and vesicle content. In mice, mosaic KO of VPS50 in the hippocampus altered synaptic transmission and plasticity and generated robust cognitive impairments. CONCLUSIONS: We propose that VPS50 functions as an accessory protein to aid the recruitment of the V-ATPase V1 domain to synaptic vesicles and in that way plays a crucial role in controlling synaptic vesicle acidification. Understanding the mechanisms controlling behaviors and synaptic function in ASD-associated mutations is pivotal for the development of targeted interventions, which may open new avenues for therapeutic strategies aimed at ASD and related conditions.
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Camundongos Knockout , Vesículas Sinápticas , Animais , Camundongos , Comportamento Animal/fisiologia , Encéfalo/metabolismo , Neurônios/metabolismo , Neurônios/fisiologia , Sinapses/metabolismo , Sinapses/fisiologia , Transmissão Sináptica , Vesículas Sinápticas/metabolismo , ATPases Vacuolares Próton-Translocadoras/metabolismo , ATPases Vacuolares Próton-Translocadoras/genética , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/metabolismoRESUMO
BACKGROUND: The brain cortex is responsible for many higher-level cognitive functions. Disruptions during cortical development have long-lasting consequences on brain function and are associated with the etiology of brain disorders. We previously found that the protein tyrosine phosphatase receptor delta Ptprd, which is genetically associated with several human neurodevelopmental disorders, is essential to cortical brain development. Loss of Ptprd expression induced an aberrant increase of excitatory neurons in embryonic and neonatal mice by hyper-activating the pro-neurogenic receptors TrkB and PDGFRß in neural precursor cells. However, whether these alterations have long-lasting consequences in adulthood remains unknown. RESULTS: Here, we found that in Ptprd+/- or Ptprd-/- mice, the developmental increase of excitatory neurons persists through adulthood, affecting excitatory synaptic function in the medial prefrontal cortex. Likewise, heterozygosity or homozygosity for Ptprd also induced an increase of inhibitory cortical GABAergic neurons and impaired inhibitory synaptic transmission. Lastly, Ptprd+/- or Ptprd-/- mice displayed autistic-like behaviors and no learning and memory impairments or anxiety. CONCLUSIONS: These results indicate that loss of Ptprd has long-lasting effects on cortical neuron number and synaptic function that may aberrantly impact ASD-like behaviors.
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Transtorno Autístico , Neurônios , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores , Animais , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/metabolismo , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/genética , Camundongos , Transtorno Autístico/genética , Transtorno Autístico/fisiopatologia , Modelos Animais de Doenças , Masculino , Córtex Cerebral/metabolismo , Camundongos Knockout , Transmissão Sináptica/fisiologia , Camundongos Endogâmicos C57BL , FemininoRESUMO
Resumen Los Trastornos del Espectro Autista (TEA) y los Tras tornos por Déficit de Atención Hiperactividad (TDAH) son Trastornos del Neurodesarrollo (TN) que coexisten frecuentemente y que tienen factores etiológicos, bio lógicos, clínicos en común. La comorbilidad de ambos TN se asocia a un retraso en el diagnóstico del TEA o un diagnóstico que nunca llegan a recibir y es frecuente el desarrollo de alteraciones perceptivas, emocionales, cognitivas y conductuales relacionadas con la Desregu lación Emocional (DE). Cuando ambos TN no son diag nosticados en infancia, frecuentemente reciben diag nósticos equivocados en edades más tardías, siendo el más frecuente el Trastorno Límite de Personalidad (TLP). Se analiza la presentación clínica de la asociación del TEA y el TDAH, la asociación con DE, diferenciación del TLP y evaluación e intervención. La comorbilidad TEA, TDAH, DE, es un trastorno más severo, asociado a poli farmacología y a ingresos hospi talarios.
Abstract Autism Spectrum Disorders (ASD) and Attention Defi cit Hyperactivity Disorders (ADHD) are Neurodevelop mental Disorders (ND) that frequently coexist together and have etiological, biological, and clinical factors in common. The comorbidity of both neurodevelopmental disorders is associated with a delay or lack of ASD di agnosis and the development of perceptual, emotional, cognitive and behavioral alterations related to Emotional Dysregulation (ED) is common. When both TN are not diagnosed in childhood, they frequently receive wrong diagnoses at later ages, the most frequent being Border line Personality Disorder (BPD). The clinical presentation of the association of ASD and ADHD, the association with ED, differentiation of BPD, and evaluation and intervention are here analyzed. The comorbidity ASD, ADHD, ED is a more severe disorder associated to polypharmacology and hospital admissions.
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Pitt-Hopkins syndrome (PTHS) is a neurodevelopmental disorder caused by haploinsufficiency of transcription factor 4 (TCF4). In this work, we focused on the cerebral cortex and investigated in detail the progenitor cell dynamics and the outcome of neurogenesis in a PTHS mouse model. Labeling and quantification of progenitors and newly generated neurons at various time points during embryonic development revealed alterations affecting the dynamic of cortical progenitors since the earliest stages of cortex formation in PTHS mice. Consequently, establishment of neuronal populations and layering of the cortex were found to be altered in heterozygotes subjects at birth. Interestingly, defective layering process of pyramidal neurons was partially rescued by reintroducing TCF4 expression using focal in utero electroporation in the cerebral cortex. Coincidentally with a defective dorsal neurogenesis, we found that ventral generation of interneurons was also defective in this model, which may lead to an excitation/inhibition imbalance in PTHS. Overall, sex-dependent differences were detected with more marked effects evidenced in males compared with females. All of this contributes to expand our understanding of PTHS, paralleling the advances of research in autism spectrum disorder and further validating the PTHS mouse model as an important tool to advance preclinical studies.
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Córtex Cerebral , Modelos Animais de Doenças , Hiperventilação , Deficiência Intelectual , Neurogênese , Fator de Transcrição 4 , Animais , Fator de Transcrição 4/metabolismo , Fator de Transcrição 4/genética , Feminino , Masculino , Camundongos , Hiperventilação/metabolismo , Hiperventilação/genética , Hiperventilação/patologia , Deficiência Intelectual/genética , Deficiência Intelectual/patologia , Deficiência Intelectual/metabolismo , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Fácies , Caracteres Sexuais , Interneurônios/metabolismo , Interneurônios/patologia , Células Piramidais/metabolismo , Células Piramidais/patologia , HaploinsuficiênciaRESUMO
Autism Spectrum Disorder (ASD) belongs to the group of neurodevelopmental disorders, and has a high prevalence, affecting 1 in 100 children according to data from the World Health Organization (WHO). To be diagnosed with ASD, the child must have persistent deficits in communication and social interactions, and restricted and repetitive patterns of behavior, interests, or activities. Despite its prevalence, the etiology of ASD is still uncertain, with multifactorial characteristics, including those associated with the gestational period, where maternal exposure to biological, chemical, or physical hazards occurs, some of which have already been proposed as causes of ASD outcomes. Since pregnancy requires a balance between the maternal-fetal binomial, the breakdown of this balance caused by such environmental hazards can lead to altered fetal neurodevelopment, including ASD. With this firmly in mind, this review aims to compile the most recent data on the gestational causes that may be associated with the development of ASD to help health professionals identify risk factors and act for the prevention and management of ASD.
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Transtorno do Espectro Autista , Transtornos do Neurodesenvolvimento , Criança , Gravidez , Feminino , Humanos , Transtorno do Espectro Autista/epidemiologia , Transtorno do Espectro Autista/etiologia , Transtorno do Espectro Autista/diagnóstico , Fatores de Risco , Exposição Materna , CausalidadeRESUMO
Zika virus (ZIKV) infection was first associated with Central Nervous System (CNS) infections in Brazil in 2015, correlated with an increased number of newborns with microcephaly, which ended up characterizing the Congenital Zika Syndrome (CZS). Here, we investigated the impact of ZIKV infection on the functionality of iPSC-derived astrocytes. Besides, we extrapolated our findings to a Brazilian cohort of 136 CZS children and validated our results using a mouse model. Interestingly, ZIKV infection in neuroprogenitor cells compromises cell migration and causes apoptosis but does not interfere in astrocyte generation. Moreover, infected astrocytes lost their ability to uptake glutamate while expressing more glutamate transporters and secreted higher levels of IL-6. Besides, infected astrocytes secreted factors that impaired neuronal synaptogenesis. Since these biological endophenotypes were already related to Autism Spectrum Disorder (ASD), we extrapolated these results to a cohort of children, now 6-7 years old, and found seven children with ASD diagnosis (5.14 %). Additionally, mice infected by ZIKV revealed autistic-like behaviors, with a significant increase of IL-6 mRNA levels in the brain. Considering these evidence, we inferred that ZIKV infection during pregnancy might lead to synaptogenesis impairment and neuroinflammation, which could increase the risk for ASD.
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Astrócitos , Transtorno do Espectro Autista , Doenças Neuroinflamatórias , Sinapses , Infecção por Zika virus , Zika virus , Infecção por Zika virus/patologia , Infecção por Zika virus/metabolismo , Infecção por Zika virus/virologia , Infecção por Zika virus/complicações , Transtorno do Espectro Autista/virologia , Transtorno do Espectro Autista/metabolismo , Transtorno do Espectro Autista/etiologia , Transtorno do Espectro Autista/patologia , Humanos , Animais , Camundongos , Zika virus/fisiologia , Feminino , Criança , Sinapses/metabolismo , Sinapses/patologia , Doenças Neuroinflamatórias/virologia , Doenças Neuroinflamatórias/metabolismo , Doenças Neuroinflamatórias/patologia , Doenças Neuroinflamatórias/etiologia , Astrócitos/virologia , Astrócitos/metabolismo , Astrócitos/patologia , Masculino , Interleucina-6/metabolismo , Interleucina-6/genética , Gravidez , Fatores de Risco , Células-Tronco Pluripotentes Induzidas/virologia , Células-Tronco Pluripotentes Induzidas/metabolismo , Brasil/epidemiologia , Modelos Animais de Doenças , NeurogêneseRESUMO
Autism Spectrum Disorders (ASD) and Attention Deficit Hyperactivity Disorders (ADHD) are Neurodevelopmental Disorders (ND) that frequently coexist together and have etiological, biological, and clinical factors in common. The comorbidity of both neurodevelopmental disorders is associated with a delay or lack of ASD diagnosis and the development of perceptual, emotional, cognitive and behavioral alterations related to Emotional Dysregulation (ED) is common. When both TN are not diagnosed in childhood, they frequently receive wrong diagnoses at later ages, the most frequent being Borderline Personality Disorder (BPD). The clinical presentation of the association of ASD and ADHD, the association with ED, differentiation of BPD, and evaluation and intervention are here analyzed. The comorbidity ASD, ADHD, ED is a more severe disorder associated to polypharmacology and hospital admissions.
Los Trastornos del Espectro Autista (TEA) y los Trastornos por Déficit de Atención Hiperactividad (TDAH) son Trastornos del Neurodesarrollo (TN) que coexisten frecuentemente y que tienen factores etiológicos, biológicos, clínicos en común. La comorbilidad de ambos TN se asocia a un retraso en el diagnóstico del TEA o un diagnóstico que nunca llegan a recibir y es frecuente el desarrollo de alteraciones perceptivas, emocionales, cognitivas y conductuales relacionadas con la Desregulación Emocional (DE). Cuando ambos TN no son diagnosticados en infancia, frecuentemente reciben diagnósticos equivocados en edades más tardías, siendo el más frecuente el Trastorno Límite de Personalidad (TLP). Se analiza la presentación clínica de la asociación del TEA y el TDAH, la asociación con DE, diferenciación del TLP y evaluación e intervención. La comorbilidad TEA, TDAH, DE, es un trastorno más severo, asociado a poli farmacología y a ingresos hospitalarios.
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Transtorno do Deficit de Atenção com Hiperatividade , Transtorno do Espectro Autista , Transtorno Autístico , Humanos , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/psicologia , Transtorno do Espectro Autista/complicações , ComorbidadeRESUMO
O Transtorno do Espectro Autista (TEA) tem seus critérios diagnósticos atuais baseados no Manual de Diagnóstico e Estatístico de Transtornos Mentais (DSM 5). Sendo um transtorno global do neurodesenvolvimento, da reciprocidade social e da comunicação, com comportamentos repetitivos, interesses restritos e inflexibilidade comportamental. O diagnóstico do TEA vem aumentando em todo o mundo trazendo uma nova realidade para a família, modificando a sua dinâmica emocional, social e financeira. Esse estudo teve por objetivo delinear um perfil e demonstrar as principais dificuldades e repercussões do cuidado da pessoa com diagnóstico de Transtorno do Espectro Autista (TEA) e suas famílias. Tratou-se de um estudo realizado através da coleta de dados nos meses de setembro e outubro de 2023 em quatro clínicas multidisciplinares de tratamento do TEA da saúde suplementar. Foram coletados dados quantitativos e qualitativos de 208 famílias, sendo os quantitativos apresentados percentuais em tabelas contendo: idade atual do paciente, idade no início das terapias e idade dos cuidadores; raça dos pacientes, sexo do paciente e dos cuidadores, idade dos pais na concepção, escolaridade dos cuidadores, tipo de parto, renda familiar, formação escolar do cuidador, presença ou não de fé declarada e estado civil do cuidador (os últimos dois considerados enquanto fatores de resiliência familiar). Os dados qualitativos foram trabalhados através da análise de conteúdo de Bardin, ilustrando e auxiliando no melhor entendimento das demandas familiares e suas dinâmicas. Os resultados encontrados concordam, em parte, com o perfil da população TEA relatada em literatura, mas com particularidades como, por exemplo, em referência a idade dos pais na concepção da criança TEA e a quantidade de diagnósticos no sexo feminino. Conseguiu-se, também, identificar fatores de resiliência familiar, como uma estrutura da dinâmica familiar e a presença de uma religião / fé. A partir da hipótese que a presença de um membro com TEA traz impacto em toda família, a autora espera, assim, contribuir na construção de políticas públicas e instituições de apoio ao TEA, norteando condutas mais assertivas frente ao atendimento às necessidades desta população; minimizando os impactos da violência sofrida através da exclusão, suas dificuldades econômicas e sociais.
The current diagnostic criteria of Autism Spectrum Disorder (ASD) is based on the Diagnostic and Statistical Manual of Mental Disorders (DSM 5). Being a global disorder of neurodevelopment, social reciprocity and communication, with repetitive behaviors, restricted interests and behavioral inflexibility. The diagnosis of ASD has been increasing throughout the world, bringing a new reality to families, changing their emotional, social and financial dynamics. This study aimed to outline a profile and demonstrate the main difficulties and repercussions of caring for people diagnosed with Autism Spectrum Disorder (ASD) and their families. This was a study carried out through data collection in the months of September and October 2023 in four multidisciplinary ASD treatment clinics in supplementary health. Quantitative and qualitative data were collected from 208 families, with the quantitative data presented in percentages in tables containing: current age of the patient, age at the beginning of therapies and age of caregivers; race of patients, sex of patient and caregivers, age of parents at conception, education of caregivers, type of birth, family income, educational background of the caregiver, presence or absence of declared faith and marital status of the caregiver (the last two considered as family resilience factors). The qualitative data were worked through Bardin's content analysis, illustrating and helping to better understand family demands and their dynamics. The results found agree, in part, with the profile of the ASD population reported in the literature, but with particularities such as, for example, in reference to the age of the parents at the conception of the ASD child and the number of diagnoses in females. It was also possible to identify factors of family resilience, such as the structure of family dynamics and the presence of a religion/faith. Based on the hypothesis that the presence of a member with ASD has an impact on the entire family, the author hopes to contribute to the construction of public policies and institutions to support ASD, guiding more assertive behaviors in meeting the needs of this population; minimizing the impacts of violence suffered through exclusion, economic and social difficulties.
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Promoção da Saúde , Mudança Social , Dissertação Acadêmica , Resiliência de Sistemas de SaúdeRESUMO
En los últimos años aumentaron las investigaciones sobre co-ocurrencia de trastorno del espectro autista (TEA) y disforia de género (DG) secundario a la necesidad de una mayor comprensión de este fenómeno clínico emergente. Objetivos: Caracterizar los estudios en torno a la co-ocurrencia entre TEA y DG en adolescentes. Metodología: Se realizó una revisión sistemática bibliográfica. Se seleccionaron los estudios que mencionaron esta correlación e incluyeron población adolescente. Resultados: La búsqueda inicial arrojó un total de 97 publicaciones. Finalmente, de acuerdo a los criterios de elegibilidad, se incluyeron 35 artículos. Existen escasos estudios enfocados sólo en adolescentes, amplios rangos de prevalencia de esta relación y heterogeneidad en los instrumentos utilizados. Conclusiones: Al evaluar individuos con DG se debiese llevar a cabo un screening de TEA, y viceversa, para no pasar por alto esta co-ocurrencia. Cabe destacar que quienes presentan TEA tienen particularidades relacionadas con el pensamiento y planificación a futuro que hay que considerar al momento de realizar cualquier tipo de tratamiento afirmativo irreversible, enmarcado dentro de un proceso terapéutico multidimensional. Palabras claves: Adolescentes, Disforia de género, Trastorno de Espectro Autista (TEA), Condición de Espectro Autista (CEA), Autismo.
Research on co-occurrence of autism spectrum disorder (ASD) and gender dysphoria (GD) increased in recent years driven by the need for greater understanding of this emerging clinical phenomenon. Objective. To characterize studies on the co-occurrence of ASD and GD in adolescents. Methodology. A systematic literature review was conducted. Studies mentioning this correlation and including adolescent population were selected. Results. The initial search showed a total of 97 publications. 35 articles were included in the review that met the eligibility criteria. There are few studies focused only on adolescents, there is a wide range of prevalence of this relationship and heterogeneity in the instruments used. Conclusions. When evaluating individuals with GD, an ASD screening should be conducted,and vice versa, to avoid overlooking this cooccurrence. It is important to note that those with ASD have particularities related to cognitive development that need to be considered when undergoing any type of irreversible affirmative treatment, within a multidimensional therapeutic process. Keywords. Adolescents, Gender dysphoria, Autism Spectrum Disorder (ASD), Autism.
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Humanos , Criança , Adolescente , Adulto , Transtorno do Espectro Autista/psicologia , Transtorno do Espectro Autista/epidemiologia , Disforia de Gênero/psicologia , Disforia de Gênero/epidemiologia , Comorbidade , PrevalênciaRESUMO
BACKGROUND: Children and adolescents with autism spectrum disorder (ASD) have difficulties that limit their opportunities to interact with peers and family members. These behaviors can lead to social exclusion, and consequently social isolation. The aim was to compare social isolation of children and adolescents with ASD according to age, marital status, and number of siblings. MATERIALS AND METHODS: Cross-sectional descriptive study in 37 subjects with ASD. Social isolation was assessed using a 6-item scale (with five alternatives). The sociodemographic variables were age, sex, marital status of parents, and number of siblings. Two groups were formed according to age (children from 4 to 10 years old and adolescents from 11 to 20 years old). RESULTS: For the total score of the social isolation scale, children showed a higher score (21.1 ± 4.7) than adolescents (17.7 ± 5.7). Children living with divorced parents had lower scores (16.2 ± 3.6), compared to married (22.2 ± 4.5) and cohabiting (22.8) children. For the number of siblings, with no siblings 17.2 ± 3.1 points, one sibling 22.2 ± 3.5 points, two siblings 22.1 ± 3.1 points, and three siblings 22.4 ± 3.2 points (P < 0.05). Age was related to social isolation (r = -0.30, P < 0.05). CONCLUSION: Children who live with divorced parents and have no siblings presented a higher degree of isolation in relation to their counterparts who live with both parents and have at least one sibling. Age plays a relevant role, with children aged 4-10 years presenting a lower degree of isolation than the adolescent group. It is suggested that the preservation of a functional family and the presence of siblings could contribute to improving social isolation.
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The etiology of Autism Spectrum Disorders (ASD) is a result of the interaction between genes and the environment. The study of epigenetic factors that affect gene expression, such as DNA methylation, has become an important area of research in ASD. In recent years, there has been an increasing body of evidence pointing to epigenetic mechanisms that influence brain development, as in the case of ASD, when gene methylation dysregulation is present. Our analysis revealed 853 differentially methylated CpG in ASD patients, affecting 509 genes across the genome. Enrichment analysis showed five related diseases, including autistic disorder and mental disorders, which are particularly significant. In this work, we identified 64 genes that were previously reported in the SFARI gene database, classified according to their impact index. Additionally, we identified new genes that have not been previously reported as candidates with differences in the methylation patterns of Mexican children with ASD.
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The application of machine learning (ML) techniques stands as a reliable method for aiding in the diagnosis of complex diseases. Recent studies have related the composition of the gut microbiota to the presence of autism spectrum disorder (ASD), but until now, the results have been mostly contradictory. This work proposes using machine learning to study the gut microbiome composition and its role in the early diagnosis of ASD. We applied support vector machines (SVMs), artificial neural networks (ANNs), and random forest (RF) algorithms to classify subjects as neurotypical (NT) or having ASD, using published data on gut microbiome composition. Naive Bayes, k-nearest neighbors, ensemble learning, logistic regression, linear regression, and decision trees were also trained and validated; however, the ones presented showed the best performance and interpretability. All the ML methods were developed using the SAS Viya software platform. The microbiome's composition was determined using 16S rRNA sequencing technology. The application of ML yielded a classification accuracy as high as 90%, with a sensitivity of 96.97% and specificity reaching 85.29%. In the case of the ANN model, no errors occurred when classifying NT subjects from the first dataset, indicating a significant classification outcome compared to traditional tests and data-based approaches. This approach was repeated with two datasets, one from the USA and the other from China, resulting in similar findings. The main predictors in the obtained models differ between the analyzed datasets. The most important predictors identified from the analyzed datasets are Bacteroides, Lachnospira, Anaerobutyricum, and Ruminococcus torques. Notably, among the predictors in each model, there is the presence of bacteria that are usually considered insignificant in the microbiome's composition due to their low relative abundance. This outcome reinforces the conventional understanding of the microbiome's influence on ASD development, where an imbalance in the composition of the microbiota can lead to disrupted host-microbiota homeostasis. Considering that several previous studies focused on the most abundant genera and neglected smaller (and frequently not statistically significant) microbial communities, the impact of such communities has been poorly analyzed. The ML-based models suggest that more research should focus on these less abundant microbes. A novel hypothesis explains the contradictory results in this field and advocates for more in-depth research to be conducted on variables that may not exhibit statistical significance. The obtained results seem to contribute to an explanation of the contradictory findings regarding ASD and its relation with gut microbiota composition. While some research correlates higher ratios of Bacillota/Bacteroidota, others find the opposite. These discrepancies are closely linked to the minority organisms in the microbiome's composition, which may differ between populations but share similar metabolic functions. Therefore, the ratios of Bacillota/Bacteroidota regarding ASD may not be determinants in the manifestation of ASD.
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Altered immune response during pregnancy has been associated with ASD susceptibility. HLA-G is expressed by the trophoblast at the maternal/fetal interface and induces allogenic tolerance toward the fetus. A 14-bp insertion in the HLA-G 3'UTR (rs371194629) was associated with reduced levels of HLA-G. We aimed to assess the influence of the HLA-G*14 bp indel variant in ASD susceptibility and symptomatology in a Brazilian admixed sample. The insertion genotype (14 bp+/14 bp+) was firstly associated with hetero aggression, but statistical significance was lost after correction (p = 0.035, pcorrected = 0.35). No association between the HLA-G variant and susceptibility to ASD or differential clinical manifestations were observed.
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Neurodevelopmental disorders have been associated with genetic mutations that affect cellular function, including chromatin regulation and epigenetic modifications. Recent studies in humans have identified mutations in KMT2C, an enzyme responsible for modifying histone tails and depositing H3K4me1 and H3K4me3, as being associated with Kleefstra syndrome 2 and autism spectrum disorder (ASD). However, the precise role of KMT2C mutations in brain disorders remains poorly understood. Here we employed CRISPR/Cas9 gene editing to analyze the effects of KMT2C brain specific knockout on animal behavior. Knocking out KMT2C expression in cortical neurons and the mouse brain resulted in decreased KMT2C levels. Importantly, KMT2C brain specific knockout animals exhibited repetitive behaviors, social deficits, and intellectual disability resembling ASD. Our findings shed light on the involvement of KMT2C in neurodevelopmental processes and establish a valuable model for elucidating the cellular and molecular mechanisms underlying KMT2C mutations and their relationship to Kleefstra syndrome 2 and ASD.
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Many neurological disorders have a distinctive colonic microbiome (CM) signature. Particularly, children with autism spectrum disorders (ASD) exhibit a very dissimilar CM when compared to neurotypical (NT) ones, mostly at the species level. Thus far, knowledge on this matter comes from high-throughput (yet very expensive and time-consuming) analytical platforms, such as massive high-throughput sequencing of bacterial 16S rRNA. Here, pure (260/280 nm, ~1.85) stool DNA samples (200 ng.µL-1) from 48 participants [39 ASD, 9 NT; 3-13 y] were used to amplify four candidate differential CM markers [Bacteroides fragilis (BF), Faecalibacterium prausnitzii (FP), Desulfovibrio vulgaris (DV), Akkermansia muciniphila (AM)], using micro-organism-specific oligonucleotide primers [265 bp (BF), 198 bp (FP), 196 bp (DV), 327 bp (AM)] and a standardized two-step [low (step 1: °Tm-5 °C) to high (stage 2: °Tm-0 °C) astringent annealing] PCR protocol (2S-PCR). The method was sensitive enough to differentiate all CM biomarkers in the studied stool donors [↑ abundance: NT (BF, FP, AM), ASD (DV)], and phylogenetic analysis confirmed the primers' specificity.
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Covered stent correction of a superior sinus venosus atrial septal defect is increasingly performed as an alternative to surgical repair. While sinus node dysfunction requiring pacemaker implantation may be required after surgical repair, this has not been previously reported after covered stent implantation. We reviewed the experience in two interventional centers. Balloon inflation in the superior vena cava was used to confirm the anomalous pulmonary vein drainage would be unobstructed after stent implantation. During balloon testing in 62 consecutive patients, we assessed gradients across the pulmonary vein to left atrium while monitoring the rhythm. We observed the outcomes after covered stent correction in 51 patients. In a single patient, significant bradycardia and pauses developed on repeat balloon testing and the procedure was abandoned without stent implantation. In another patient, there was no sign of sinus node dysfunction during balloon testing but several hours after stent implantation, the patient became symptomatic from sinus bradycardia and pauses and had a pacemaker implanted 3 days later. Over a year later there are some signs of improvement in sinus node function. While sinus node dysfunction has not been described previously during balloon testing or after stent implantation, this report demonstrates for the first time that it may occur. Larger registries are therefore required to monitor for this uncommon complication.
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Autism Spectrum Disorder (ASD) is a set of neurodevelopmental disorders mainly characterized by repetitive, restrictive and stereotypical behaviors, and impaired communication skills. Several lines of evidence indicate that alterations of the immune system account for ASD development, including the presence of brain-reactive antibodies, abnormal T cell activation, altered cytokine levels in brain, cerebrospinal fluid and peripheral blood circulation, increased levels of circulating monocytes, and dysregulation in Natural Killer (NK) cells activity. Regarding NK cells, a lower cytotoxic activity, a higher level of activation and an increased number of these cells in individuals with ASD have been described. In 2019, a study showed that NK cells derived from patients with ASD show a characteristic pattern of NKG2C overexpression, highlighting the importance of the NK cell pathway in ASD. In fact, the study of genes related to NK cell activity has proven to be an excellent research target, both in terms of susceptibility as well as a marker for the different clinical manifestations observed in ASD individuals. Here, we evaluated the influence of KLRC2 gene deletion as well as KLRK1 rs1049174 and rs2255336 variants in a cohort of 185 children diagnosed with ASD and their respective biological parents in southern Brazil. Of note, this is the first study concerning genetic variants of the KLRC2 and KLRK1 genes in an ASD sample. The KLRC2 gene deletion (p = 0.001; pc = 0.009), KLRK1 rs1049174 (p = 0.005; pc = 0.045) and KLRK1 rs2255336 (p = 0.001; pc = 0.009) were associated with epilepsy in ASD patients. The results indicate that KLRC2 deletion, KLRK1 rs2255336, and KLRK1 rs1049174 could be involved in epilepsy manifestation in ASD patients, possibly impacting the NK dysregulation already described in ASD and epileptic patients.
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Transtorno do Espectro Autista , Epilepsia , Criança , Humanos , Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/metabolismo , Células Matadoras Naturais , Encéfalo/metabolismo , Epilepsia/genética , Brasil , Subfamília C de Receptores Semelhantes a Lectina de Células NK/metabolismoRESUMO
OBJECTIVE: To examine the classification rates and screening properties, including sensitivity and specificity, of the web-based Modified Checklist for Autism in Toddler, Revised with Follow-Up (M-CHAT-R/F) compared with paper-phone administration, and to determine the extent to which electronic M-CHAT-R/F streamlines screening, increases screening fidelity, increases diagnostic evaluation participation, and decreases waiting time from screening to evaluation compared with paper-phone modality. STUDY DESIGN: Primary-care practices in urban and suburban settings administered either the web-based or paper-phone M-CHAT-R/F using a prospective nonrandomized control design. Toddlers (n = 17â900) were screened between 2009 and 2016 at routine well-child check-ups. Toddlers who screened at risk on the M-CHAT-R/F were invited to complete diagnostic evaluations; 176 children were diagnosed with autism. The χ2, Fisher exact, and t-tests, as well as regression and screening properties, were used to compare outcome distributions, screening properties, and implementation by modality. RESULTS: Classification rates of the initial M-CHAT-R into low, medium, and high risk were significantly different across modalities with very small effect sizes. Sensitivity and specificity were high across both modalities. For children in the medium-risk range, the web-based modality had a greater rate of predicting risk for autism after Follow-Up compared with the paper-phone modality, and the web eliminated delay between initial screen and Follow-Up. The web-based modality showed increased screening fidelity, no data loss, and similar rates of evaluation attendance and time to evaluation from Follow-Up administration. CONCLUSIONS: The web-based M-CHAT-R/F is a valid tool for universal autism screening. Systems-level decisions should balance the increased feasibility of the electronic administration with the increase in Follow-Up accuracy provided by skilled clinician interview.
Assuntos
Transtorno do Espectro Autista , Transtorno Autístico , Humanos , Pré-Escolar , Lactente , Transtorno Autístico/diagnóstico , Programas de Rastreamento , Lista de Checagem , Estudos Prospectivos , Sensibilidade e Especificidade , Transtorno do Espectro Autista/diagnósticoRESUMO
To understand the ASD diagnosis and treatment pathways for US families, N = 38 Mexican-heritage mothers were interviewed about how and when they obtained an ASD diagnosis for their children. Most children (84%) were diagnosed between two and three years old. One-third of mothers reported receiving four to seven referrals before diagnosis. Mothers identified multiple diagnosis circumstances including two diagnoses and services offered before diagnosis. A multiple case study design documented the diagnosis and treatment experiences of four representative participants. As compared to previous studies that utilized a deficit lens to rationalize barriers to diagnosis and treatment (e.g., parents not knowledgeable about ASD), these findings revealed a complex understanding of how structural barriers (e.g., immigration status), initial diagnosis rejection among caregivers, and abrupt service cancellation complicated the diagnosis and treatment process. Implications identified suggestions to optimize and streamline ASD diagnosis and treatment pathways for Mexican heritage families.
Assuntos
Transtorno do Espectro Autista , Criança , Feminino , Humanos , Pré-Escolar , Transtorno do Espectro Autista/diagnóstico , Pais , Mães , Cuidadores , Projetos de PesquisaRESUMO
Some important atypical antipsychotic drugs target the serotonergic receptor 2A (5-HT2AR). Currently, new therapeutic strategies are needed to offer faster onset of action with fewer side effects and, therefore, greater efficacy in a substantial proportion of patients with neuropsychological disorders such as Autism and Parkinson. The main objective of this work was to use SBDD methods to identify new hit compounds potentially useful as precursors of novel and selective 5-HT2AR antagonists. A structure-based pharmacophore screening study based on a selective antagonist was carried out in ten databases. The set obtained was refined using molecular docking, and the five most promising compounds were subjected to molecular dynamics simulations. The most stable and promising hit occupied a side pocket present in the 5-HT2AR, a site that can be explored to obtain selective ligands. Simulations against 5-HT2CR and D2R showed that the best hit could not form stable complexes with these targets, strengthening the hypothesis that the hit presents selective binding by the receptor of interest. The selected hits showed some predicted toxicity risk or violated some drug-likeness property. However, it can be concluded that the identified hits are the most promising for performing in vitro assays. Once the presence of activity is confirmed, they could become precursors of optimized and selective antagonists of 5-HT2AR. An SBDD study was carried out to identify new selective 5-HT2AR ligands potentially useful for designing selective atypical antipsychotics.