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BACKGROUND: It is the aim of this study to analyze the longitudinal relationship between premature birth and low birth weight and the reciprocal influence between hyperactive/inattentive behavior and aggressive/delinquent behavior problems in children from early to late childhood. METHODS: This study contains data from the German Erlangen-Nuremberg Development and Prevention Study. It applies prospective longitudinal path analyses on data obtained from postnatal pediatric assessments as well as later psychosocial behavior assessments by teachers and parents on N = 667 children, out of which n = 83 children (12.44%) were born preterm/small for gestational age. RESULTS: The results show direct effects of birth complications at the beginning of preschool on hyperactivity/inattentiveness (teacher rating: ß = 0.28; p = 0.017; parent rating: ß = 0.32; p = 0.005), but not on aggression/delinquency (teacher rating: ß = 0.002; p = 0.427; parent rating: ß = 0.12; p = 0.324). Reciprocal effects between aggression/delinquency and hyperactivity/inattentiveness were stable at the end of elementary school, but not at the end of preschool across informants. CONCLUSION: Our results support a differentiated view on the potential development of behavior problems after birth complications and the demand for early prevention measures. IMPACT STATEMENT: Our results extend to the existing body of research by providing insight into the longitudinal effects of prematurity and fetal growth restrictions on hyperactive and aggressive/delinquent behavioral problems throughout a rather long period of development in childhood. The results show direct effects of birth complications on the development of hyperactivity for boys, but not for girls across informants. No direct effects of birth complications on aggression/delinquency are found. Our findings speak against too simple views on behavioral consequences of birth complications and thus can relieve too anxious parents, however close monitoring of the behavioral development of respective children is indicated.
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More than 100 genetic etiologies have been identified in developmental and epileptic encephalopathies (DEEs), but correlating genetic findings with clinical features at scale has remained a hurdle because of a lack of frameworks for analyzing heterogenous clinical data. Here, we analyzed 31,742 Human Phenotype Ontology (HPO) terms in 846 individuals with existing whole-exome trio data and assessed associated clinical features and phenotypic relatedness by using HPO-based semantic similarity analysis for individuals with de novo variants in the same gene. Gene-specific phenotypic signatures included associations of SCN1A with "complex febrile seizures" (HP: 0011172; p = 2.1 × 10-5) and "focal clonic seizures" (HP: 0002266; p = 8.9 × 10-6), STXBP1 with "absent speech" (HP: 0001344; p = 1.3 × 10-11), and SLC6A1 with "EEG with generalized slow activity" (HP: 0010845; p = 0.018). Of 41 genes with de novo variants in two or more individuals, 11 genes showed significant phenotypic similarity, including SCN1A (n = 16, p < 0.0001), STXBP1 (n = 14, p = 0.0021), and KCNB1 (n = 6, p = 0.011). Including genetic and phenotypic data of control subjects increased phenotypic similarity for all genetic etiologies, whereas the probability of observing de novo variants decreased, emphasizing the conceptual differences between semantic similarity analysis and approaches based on the expected number of de novo events. We demonstrate that HPO-based phenotype analysis captures unique profiles for distinct genetic etiologies, reflecting the breadth of the phenotypic spectrum in genetic epilepsies. Semantic similarity can be used to generate statistical evidence for disease causation analogous to the traditional approach of primarily defining disease entities through similar clinical features.
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Proteínas Transportadoras de GABA en la Membrana Plasmática/genética , Proteínas Munc18/genética , Canal de Sodio Activado por Voltaje NAV1.1/genética , Convulsiones/genética , Espasmos Infantiles/genética , Trastornos del Habla/genética , Preescolar , Estudios de Cohortes , Femenino , Expresión Génica , Ontología de Genes , Humanos , Masculino , Mutación , Fenotipo , Convulsiones/clasificación , Convulsiones/diagnóstico , Convulsiones/fisiopatología , Semántica , Canales de Potasio Shab/genética , Espasmos Infantiles/clasificación , Espasmos Infantiles/diagnóstico , Espasmos Infantiles/fisiopatología , Trastornos del Habla/clasificación , Trastornos del Habla/diagnóstico , Trastornos del Habla/fisiopatología , Terminología como Asunto , Secuenciación del ExomaRESUMEN
The developmental and epileptic encephalopathies (DEEs) are heterogeneous disorders with a strong genetic contribution, but the underlying genetic etiology remains unknown in a significant proportion of individuals. To explore whether statistical support for genetic etiologies can be generated on the basis of phenotypic features, we analyzed whole-exome sequencing data and phenotypic similarities by using Human Phenotype Ontology (HPO) in 314 individuals with DEEs. We identified a de novo c.508C>T (p.Arg170Trp) variant in AP2M1 in two individuals with a phenotypic similarity that was higher than expected by chance (p = 0.003) and a phenotype related to epilepsy with myoclonic-atonic seizures. We subsequently found the same de novo variant in two individuals with neurodevelopmental disorders and generalized epilepsy in a cohort of 2,310 individuals who underwent diagnostic whole-exome sequencing. AP2M1 encodes the µ-subunit of the adaptor protein complex 2 (AP-2), which is involved in clathrin-mediated endocytosis (CME) and synaptic vesicle recycling. Modeling of protein dynamics indicated that the p.Arg170Trp variant impairs the conformational activation and thermodynamic entropy of the AP-2 complex. Functional complementation of both the µ-subunit carrying the p.Arg170Trp variant in human cells and astrocytes derived from AP-2µ conditional knockout mice revealed a significant impairment of CME of transferrin. In contrast, stability, expression levels, membrane recruitment, and localization were not impaired, suggesting a functional alteration of the AP-2 complex as the underlying disease mechanism. We establish a recurrent pathogenic variant in AP2M1 as a cause of DEEs with distinct phenotypic features, and we implicate dysfunction of the early steps of endocytosis as a disease mechanism in epilepsy.
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Complejo 2 de Proteína Adaptadora/genética , Subunidades mu de Complejo de Proteína Adaptadora/genética , Encefalopatías/etiología , Clatrina/metabolismo , Endocitosis , Epilepsia/etiología , Mutación Missense , Trastornos del Neurodesarrollo/etiología , Adolescente , Animales , Encefalopatías/patología , Niño , Preescolar , Clatrina/genética , Epilepsia/patología , Femenino , Humanos , Lactante , Ratones , Ratones Noqueados , Trastornos del Neurodesarrollo/patología , Secuenciación del ExomaRESUMEN
Patients with neurofibromatosis type 1 (NF1) have an increased risk for West syndrome (WS), but the underlying mechanisms linking NF1 and WS are unknown. In contrast to other neurocutaneous syndromes, intracerebral abnormalities explaining the course of infantile spasms (IS) are often absent and the seizure outcome is usually favorable. Several studies have investigated a potential genotype-phenotype correlation between NF1 and seizure susceptibility, but an association was not identified. Therefore, we identified three patients with NF1-related WS (NF1-WS) in a cohort of 51 NF1 patients and performed whole-exome sequencing (WES) to identify genetic modifiers. In two NF1 patients with WS and good seizure outcome, we did not identify variants in epilepsy-related genes. However, in a single patient with NF1-WS and transition to drug-resistant epilepsy, we identified a de novo variant in KCNC2 (c.G499T, p.D167Y) coding for Kv3.2 as a previously undescribed potassium channel to be correlated to epilepsy. Electrophysiological studies of the identified KCNC2 variant demonstrated both a strong loss-of-function effect for the current amplitude and a gain-of-function effect for the channel activation recommending a complex network effect. These results suggest that systematic genetic analysis for potentially secondary genetic etiologies in NF1 patients and severe epilepsy presentations should be done.
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Neurofibromatosis 1/genética , Canales de Potasio Shaw/genética , Espasmos Infantiles/genética , Comorbilidad , Humanos , Lactante , Secuenciación del ExomaRESUMEN
Anopheline mosquitoes are the only vectors of human malaria worldwide. It is now widely accepted that mosquito immune responses play a crucial role in restricting Plasmodium development within the vector; therefore, further dissection of the molecular mechanisms underlying these processes should inform new vector control strategies urgently needed to roll back the disease. Here, using genome-wide transcriptional profiling, bioinformatics, and functional gene analysis, we identify a new axis of mosquito resistance to monoclonal Plasmodium falciparum infections that includes the AP-1 transcription factor Fos and the transglutaminase 2 (TGase2), a cross-linking enzyme with known roles in wound responses. We demonstrate that Fos regulates induction of TGase2 expression after wounding but does not affect expression of the components of the well characterized complement-like system. Silencing of Fos or of TGase2 aborts the wounding-induced mosquito killing of P. falciparum. These results reveal multiple signaling pathways that are required for efficient Plasmodium killing in Anopheles gambiae.
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Anopheles/metabolismo , Anopheles/parasitología , Proteínas de Unión al GTP/metabolismo , Proteínas de Insectos/metabolismo , Plasmodium falciparum/metabolismo , Proteínas Proto-Oncogénicas c-fos/metabolismo , Factor de Transcripción AP-1/metabolismo , Transglutaminasas/metabolismo , Animales , Anopheles/genética , Proteínas de Unión al GTP/genética , Estudio de Asociación del Genoma Completo , Humanos , Proteínas de Insectos/genética , Proteína Glutamina Gamma Glutamiltransferasa 2 , Proteínas Proto-Oncogénicas c-fos/genética , Factor de Transcripción AP-1/genética , Transglutaminasas/genéticaRESUMEN
BACKGROUND: Callous-unemotional traits are associated with the development of severe behavior problems, delinquency, and psychopathy. Previous studies have repeatedly shown that CU traits may be present as early as preschool age, and they have consistently used the Inventory of Callous-Unemotional Traits (ICU) to assess CU traits in children and adolescents. A three-factor structure for the ICU has been widely endorsed. METHOD: The aim of our study is to compare the three-factor structure of the ICU in different age groups (preschool, middle childhood, early, and late adolescence) and to test for measurement invariance in a German sample of N = 2368 children and adolescents (M = 11.76 years; SD = 3.72). RESULTS: The results of our study indicate configural measurement invariance, suggesting that the ICU has the same structure in all age groups but with different meanings, parameters, and mean values in the groups. CONCLUSION: Accordingly, the ICU cannot be applied in the same way to children and adolescents of different age groups, which emphasizes the need for a more differentiated assessment.
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Inventario de Personalidad , Humanos , Alemania , Masculino , Femenino , Niño , Adolescente , Preescolar , Inventario de Personalidad/estadística & datos numéricos , Psicometría/instrumentación , Factores de Edad , Trastorno de Personalidad Antisocial/psicología , Trastorno de Personalidad Antisocial/diagnóstico , Empatía , Emociones , Trastorno de la Conducta/psicologíaRESUMEN
BACKGROUND AND OBJECTIVES: KCNC2 encodes Kv3.2, a member of the Shaw-related (Kv3) voltage-gated potassium channel subfamily, which is important for sustained high-frequency firing and optimized energy efficiency of action potentials in the brain. The objective of this study was to analyze the clinical phenotype, genetic background, and biophysical function of disease-associated Kv3.2 variants. METHODS: Individuals with KCNC2 variants detected by exome sequencing were selected for clinical, further genetic, and functional analysis. Cases were referred through clinical and research collaborations. Selected de novo variants were examined electrophysiologically in Xenopus laevis oocytes. RESULTS: We identified novel KCNC2 variants in 18 patients with various forms of epilepsy, including genetic generalized epilepsy (GGE), developmental and epileptic encephalopathy (DEE) including early-onset absence epilepsy, focal epilepsy, and myoclonic-atonic epilepsy. Of the 18 variants, 10 were de novo and 8 were classified as modifying variants. Eight drug-responsive patients became seizure-free using valproic acid as monotherapy or in combination, including severe DEE cases. Functional analysis of 4 variants demonstrated gain of function in 3 severely affected DEE cases and loss of function in 1 case with a milder phenotype (GGE) as the underlying pathomechanisms. DISCUSSION: These findings implicate KCNC2 as a novel causative gene for epilepsy and emphasize the critical role of KV3.2 in the regulation of brain excitability.
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Epilepsia Generalizada , Epilepsia , Epilepsia/genética , Epilepsia Generalizada/genética , Humanos , Fenotipo , Convulsiones/genética , Canales de Potasio Shaw/genética , Secuenciación del ExomaRESUMEN
BACKGROUND: Extensive empirical evidence suggests that high Callous-Unemotional (CU) traits in childhood and adolescence can reliably identify individuals at risk for antisocial outcomes. The present study addresses research gaps by investigating the factor structure of CU traits in children at preschool age. METHODS: The sample includes 371 children (49.6% female, M age = 4.7, SD = 0.69). Using the Inventory of Callous-Unemotional-Traits (ICU), six alternative confirmatory factor analyses were conducted to find the best fitting model for our preschool sample. Children's level of emotional competence and aggressive behavior was assed using a German questionnaire, the Behavior Rating Scales for Preschoolers (Verhaltensskalen für das Kindergartenalter, VSK) in a preschool teachers' rating. Post hoc cluster analytic strategies and ANOVA were applied to identify groups of children with regard to their combination of social-emotional competences and CU traits, and to examine associations with aggressive behavior. RESULTS: Results indicate that a two-factor model revealed the best fit to our data, including a callous and an uncaring factor using 12 of the original 24 ICU items. Cluster analytic strategies reveal a risk group of children demonstrating high rates of callousness and uncaring combined with weak emotion knowledge/empathy and social competence. ANOVA shows that children in the risk group demonstrate the highest levels of aggressive behavior. CONCLUSIONS: Group characteristics indicate that the construct of CU traits in early childhood may be nothing other than a social-emotional developmental deficit.
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Leucemia-Linfoma Linfoblástico de Células Precursoras B/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células Precursoras B/genética , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas/antagonistas & inhibidores , Proteínas/genética , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Animales , Terapia Combinada , Modelos Animales de Enfermedad , Trasplante de Células Madre Hematopoyéticas , Humanos , Ratones , Terapia Molecular Dirigida , Proteínas de Fusión Oncogénica/antagonistas & inhibidores , Proteínas de Fusión Oncogénica/genética , Leucemia-Linfoma Linfoblástico de Células Precursoras B/patología , Inhibidores de Proteínas Quinasas/farmacología , Pirazoles/farmacología , Pirimidinas/farmacología , Recurrencia , Retratamiento , Resultado del Tratamiento , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Malaria is a life-threatening human infectious disease transmitted by mosquitoes. Levels of the salivary gland sporozoites (sgs), the only mosquito stage infectious to a mammalian host, represent an important cumulative index of Plasmodium development within a mosquito. However, current techniques of sgs quantification are laborious and imprecise. Here, transgenic P. berghei reporter lines that produce the green fluorescent protein fused to luciferase (GFP-LUC) specifically in sgs were generated, verified and characterised. Fluorescence microscopy confirmed the sgs stage specificity of expression of the reporter gene. The luciferase activity of the reporter lines was then exploited to establish a simple and fast biochemical assay to evaluate sgs loads in whole mosquitoes. Using this assay we successfully identified differences in sgs loads in mosquitoes silenced for genes that display opposing effects on P. berghei ookinete/oocyst development. It offers a new powerful tool to study infectivity of P. berghei to the mosquito, including analysis of vector-parasite interactions and evaluation of transmission-blocking vaccines.
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Culicidae/parasitología , Genes Reporteros/genética , Carga de Parásitos/métodos , Plasmodium berghei/genética , Plasmodium berghei/fisiología , Glándulas Salivales/parasitología , Esporozoítos/fisiología , Animales , Animales Modificados Genéticamente , Regulación hacia Abajo , Humanos , Insectos Vectores/parasitología , Especificidad de Órganos , Proteínas y Péptidos Salivales/deficiencia , Factores de TiempoRESUMEN
Mosquito infections with natural isolates of Plasmodium falciparum are notoriously variable and pose a problem for reliable evaluation of efficiency of transmission-blocking agents for malaria control interventions. Here, we show that monoclonal P. falciparum isolates produce higher parasite loads than mixed ones. Induction of the mosquito immune responses by wounding efficiently decreases Plasmodium numbers in monoclonal infections but fails to do so in infections with two or more parasite genotypes. Our results point to the parasites genetic complexity as a potentially crucial component of mosquito-parasite interactions.