Epilepsieverläufe bei neurokutanen Syndromen unter Berücksichtigung von Phänotyp- und Genotyp-Korrelation

Die Gruppe der neurokutanen Syndrome umfasst eine Vielzahl von klinisch sehr heterogenen Erkrankungen, deren Gemeinsamkeit im Auftreten kutaner und neurologischer Symptome liegt. Die vorliegende Dissertation beschäftigt sich mit den beiden häufigsten neurokutanen Syndromen, der Neurofibromatose Typ 1 (NF1) und dem Tuberöse Sklerose Complex (TSC). Die Prävalenz einer Epilepsie ist bei NF1 und beim TSC im Vergleich zur Normalbevölkerung deutlich erhöht. Dabei weist der Epilepsieverlauf in Hinblick auf die Schwere der epileptischen Anfälle und dem Erreichen einer anhaltenden Anfallsfreiheit ein großes Spektrum auf. Während bei TSC-Patienten eher von einem schweren Verlauf und einer Therapieresistenz der Epilepsie ausgegangen werden kann, zeigen Patienten mit einer NF1 in der Regel einen milden Epilepsieverlauf. Prognostische Faktoren zur frühzeitigen Beurteilung des Epilepsieoutcomes sind rar beziehungsweise bei der NF1 bisher nicht beschrieben. Weiterhin bleibt die Genese der Epilepsie bei NF1 bis heute nahezu ungeklärt. In einigen Fällen lassen sich strukturelle Ursachen, wie zum Beispiel ein intrazerebraler Tumor, finden, bei einem Großteil der Patienten ist der Pathomechanismus bisher jedoch nicht gelöst. In dieser Arbeit wurden ein NF1- und ein TSC-Kollektiv untersucht, um den Epilepsieverlauf phänotypisch zu beschreiben und Zusammenhänge zwischen zugrundeliegenden NF1- beziehungsweise TSC1/TSC2-Genvarianten und dem Epilepsieoutcome aufzuzeigen. Zusätzlich wurde bei NF1-Patienten mit West-Syndrom (WS) ein Trio Whole Exome Sequencing (WES) durchgeführt, um genetische Ursachen für Epilepsien außerhalb des NF1-Gens zu identifizieren. Die Ergebnisse zum TSC zeigen, dass Patienten mit familiärem TSC im Vergleich zur sporadischen Form einen milderen Epilepsieverlauf aufweisen. Zudem scheint es auch eine Korrelation zwischen Missense-Mutationen und einem günstigen Epilepsieoutcome zu geben. Der Epilepsieverlauf von NF1-Patienten war, wie in der Literatur beschrieben, auch in der vorliegenden Kohorte insgesamt milde. Eine Phänotyp-Genotyp-Korrelation in Hinblick auf das NF1-Gen ließ sich nicht bestätigen. Mittels Trio WES konnte bei der Patientin mit einem für NF1 außergewöhnlich schlechtem Epilepsieoutcome KCNC2 als neues Kandidatengen für Epilepsien identifiziert werden. Diese Hypothese wurde durch funktionelle Studien mit Nachweis eines loss-of-function Effekts der Genvariante unserer Patientin gestärkt

Literatur-Rundschau

Jan-Heiner Tück (Hg.): Risse im Fundament? Die Pfarrerinitiative und der Streit um die Kirchenreform (Heinz Niederleitner)Charles Martig/Natalie Fritz/Fabian Perline-Pfister (Hg.): Nur für reife Erwachsene. Katholische Filmarbeit in der Schweiz (Peter Hasenberg)Stefan Brunner: Redigieren (Annika Franzetti)Larissa Krainer/Peter Heintel: Prozessethik. Zur Organisation ethischer Entscheidungsprozesse (Lars Rademacher)Tobias Eberwein/Susanne Fengler/Epp Lauk/Tanja Leppik-Bork (Hg.): Mapping Media Accountability – in Europe and Beyond (Alexander Filipovic)Ramin M. Nowzad: Zeit der Medien – Medien der Zeit (Joachim Westerbarkey)

GWAS meta-analysis of over 29,000 people with epilepsy identifies 26 risk loci and subtype-specific genetic architecture

Epilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here we report a multi-ancestry genome-wide association study including 29,944 cases, stratified into three broad categories and seven subtypes of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants explain between 39.6% and 90% of genetic risk for GGE and its subtypes. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analyses of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current antiseizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment

Genome-wide identification and phenotypic characterization of seizure-associated copy number variations in 741,075 individuals

Copy number variants (CNV) are established risk factors for neurodevelopmental disorders with seizures or epilepsy. With the hypothesis that seizure disorders share genetic risk factors, we pooled CNV data from 10,590 individuals with seizure disorders, 16,109 individuals with clinically validated epilepsy, and 492,324 population controls and identified 25 genome-wide significant loci, 22 of which are novel for seizure disorders, such as deletions at 1p36.33, 1q44, 2p21-p16.3, 3q29, 8p23.3-p23.2, 9p24.3, 10q26.3, 15q11.2, 15q12-q13.1, 16p12.2, 17q21.31, duplications at 2q13, 9q34.3, 16p13.3, 17q12, 19p13.3, 20q13.33, and reciprocal CNVs at 16p11.2, and 22q11.21. Using genetic data from additional 248,751 individuals with 23 neuropsychiatric phenotypes, we explored the pleiotropy of these 25 loci. Finally, in a subset of individuals with epilepsy and detailed clinical data available, we performed phenome-wide association analyses between individual CNVs and clinical annotations categorized through the Human Phenotype Ontology (HPO). For six CNVs, we identified 19 significant associations with specific HPO terms and generated, for all CNVs, phenotype signatures across 17 clinical categories relevant for epileptologists. This is the most comprehensive investigation of CNVs in epilepsy and related seizure disorders, with potential implications for clinical practice

Conceptualizing callous-unemotional traits in preschoolers: Associations with social-emotional competencies and aggressive behavior

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

Identification et caractérisation des gènes impliqués dans l'élimination TEP1 dépendante du parasite chez Anopheles gambiae

STRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF

AP-1/Fos-TGase2 axis mediates wounding-induced Plasmodium falciparum killing in Anopheles gambiae

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

Genetic clonality of Plasmodium falciparum affects the outcome of infection in Anopheles gambiae

International audienc

Antimicrobial resistance in patients with decompensated liver cirrhosis and bacterial infections in a tertiary center in Northern Germany.

Background and aims: Bacterial infections are common in patients with decompensated liver cirrhosis and a leading cause of death. Reliable data on antibiotic resistance are required to initiate effective empiric therapy. We here aim to assess the antimicrobial resistance profile of bacteria among patients with liver cirrhosis and infection. Methods: Overall, 666 cirrhotic patients admitted to Hannover Medical School between January 2012 and April 2018 with ascites were assessed for bacterial infection. In case of infection, bacteria cultured from microbiological specimens of ascites, blood or urine were identified and analyzed for resistances against common antibiotic agents. Furthermore, analyses compared two periods of time and community-acquired vs. nosocomial infections. Results: In 281 patients with infection, microbiological sampling was performed and culture-positive results were obtained in 56.9%. Multidrug-resistant (MDR)-bacteria were found in 54 patients (19.2%). Gram-positive organisms were more common (n = 141/261, 54.0%) and detected in 116/192 culture-positive infections (60.4%). Comparing infections before and after 2015, a numerical decline for MDR-bacteria (23.8% vs. 15.6%, p = 0.08) was observed with a significant decline in meropenem resistance (34.9% vs. 19.5%, p = 0.03). MDR-bacteria were more frequent in the case of nosocomial infections. Of note, in ascites the majority of the tested bacteria were resistant against ceftriaxone (73.8%) whereas significantly less were resistant against meropenem (27.0%) and vancomycin (25.9%). Conclusions: In our tertiary center, distinct ratios of gram-positive infection with overall low ratios of MDR-bacteria were found. Adequate gram-positive coverage in the empiric therapy should be considered. Carbapenem treatment may be omitted even in nosocomial infection. In contrast, 3rd generation cephalosporins cannot be recommended even in community-acquired infection in our cirrhotic population