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Item does not contain fulltext, Glutaric aciduria type 1 (GA1) is a rare neurometabolic disease caused by pathogenic variants in the gene encoding the enzyme glutaryl-CoA dehydrogenase (GCDH). We performed an extensive literature search to collect data on GA1 patients, together with unpublished cases, to provide an up-to-date genetic landscape of GCDH pathogenic variants and to investigate potential genotype-phenotype correlation, as this is still poorly understood. From this search, 421 different GCDH pathogenic variants have been identified, including four novel variants; c.179T>C (p.Leu60Pro), c.214C>T (p.Arg72Cys), c.309G>C (p.Leu103Phe), and c.665T>C (p.Phe222Ser).The variants are mostly distributed across the entire gene; although variant frequency in GA1 patients is relatively high in the regions encoding for active domains of GCDH. To investigate potential genotype-phenotype correlations, phenotypic descriptions of 532 patients have been combined and evaluated using novel combinatorial analyses. To do so, various clinical phenotypes were determined for each pathogenic variant by combining the information of all GA1 patients reported with this pathogenic variant, and subsequently mapped onto the 2D and 3D GCDH protein structure. In addition, the predicted pathogenicity of missense variants was analyzed using different in silico prediction score models. Both analyses showed an almost similar distribution of the highly pathogenic variants across the GCDH protein, although some hotspots, including the active domain, were observed. Moreover, it was demonstrated that highly pathogenic variants are significantly correlated with lower residual enzyme activity and the most accurate estimation was achieved by the REVEL score. A clear correlation of the genotype and the clinical phenotype however is still lacking.

01 juni 2023, Item does not contain fulltext, PURPOSE: This study aimed to define the genotypic and phenotypic spectrum of reversible acute liver failure (ALF) of infancy resulting from biallelic pathogenic TRMU variants and determine the role of cysteine supplementation in its treatment. METHODS: Individuals with biallelic (likely) pathogenic variants in TRMU were studied within an international retrospective collection of de-identified patient data. RESULTS: In 62 individuals, including 30 previously unreported cases, we described 47 (likely) pathogenic TRMU variants, of which 17 were novel, and 1 intragenic deletion. Of these 62 individuals, 42 were alive at a median age of 6.8 (0.6-22) years after a median follow-up of 3.6 (0.1-22) years. The most frequent finding, occurring in all but 2 individuals, was liver involvement. ALF occurred only in the first year of life and was reported in 43 of 62 individuals; 11 of whom received liver transplantation. Loss-of-function TRMU variants were associated with poor survival. Supplementation with at least 1 cysteine source, typically N-acetylcysteine, improved survival significantly. Neurodevelopmental delay was observed in 11 individuals and persisted in 4 of the survivors, but we were unable to determine whether this was a primary or a secondary consequence of TRMU deficiency. CONCLUSION: In most patients, TRMU-associated ALF was a transient, reversible disease and cysteine supplementation improved survival.

Contains fulltext : 296182.pdf (Publisher’s version ) (Open Access), BACKGROUND AND OBJECTIVES: Pathogenic variants in STXBP1 are among the major genetic causes of neurodevelopmental disorders. Despite the increasing number of individuals diagnosed without a history of epilepsy, little is known about the natural history and developmental trajectories in this subgroup and endpoints for future therapeutic studies are limited to seizure control. METHODS: We performed a cross-sectional retrospective study using standardized questionnaires for clinicians and caregivers of individuals with STXBP1-related disorders capturing medical histories, genetic findings, and developmental outcomes. Motor and language function were assessed using Gross Motor Function Classification System (GMFCS) scores and a speech impairment score and were compared within and across clinically defined subgroups. RESULTS: We collected data of 71 individuals with STXBP1-related disorders, including 44 previously unreported individuals. Median age at inclusion was 5.3 years (interquartile range 3.5-9.3) with the oldest individual aged 43.8 years. Epilepsy was absent in 18/71 (25%) of individuals. The range of developmental outcomes was broad, including 2 individuals presenting with close to age-appropriate motor development. Twenty-nine of 61 individuals (48%) were able to walk unassisted, and 24/69 (35%) were able to speak single words. Individuals without epilepsy presented with a similar onset and spectrum of phenotypic features but had lower GMFCS scores (median 3 vs 4, p < 0.01) than individuals with epilepsy. Individuals with epileptic spasms were less likely to walk unassisted than individuals with other seizure types (6% vs 58%, p < 0.01). Individuals with early epilepsy onset had higher speech impairment scores (p = 0.02) than individuals with later epilepsy onset. DISCUSSION: We expand the spectrum of STXBP1-related disorders and provide clinical features and developmental trajectories in individuals with and without a history of epilepsy. Individuals with ep

Contains fulltext : 237831.pdf (Publisher’s version ) (Open Access), SYNCRIP encodes for the Synaptotagmin-binding cytoplasmic RNA-interacting protein, involved in RNA-binding and regulation of multiple cellular pathways. It has been proposed as a candidate gene for neurodevelopmental disorders (NDDs) with autism spectrum disorder (ASD), intellectual disability (ID), and epilepsy. We ascertained genetic, clinical, and neuroradiological data of three additional individuals with novel de novo SYNCRIP variants. All individuals had ID. Autistic features were observed in two. One individual showed myoclonic-atonic epilepsy. Neuroradiological features comprised periventricular nodular heterotopia and widening of subarachnoid spaces. Two frameshift variants in the more severely affected individuals, likely result in haploinsufficiency. The third missense variant lies in the conserved RNA recognition motif (RRM) 2 domain likely affecting RNA-binding. Our findings support the importance of RRM domains for SYNCRIP functionality and suggest genotype-phenotype correlations. Our study provides further evidence for a SYNCRIP-associated NDD characterized by ID and ASD sporadically accompanied by malformations of cortical development and myoclonic-atonic epilepsy.

Item does not contain fulltext, Mevalonic aciduria (MVA) and hyperimmunoglobulinemia D syndrome (MKD/HIDS) are disorders of cholesterol biosynthesis caused by variants in the MVK gene and characterized by increased urinary excretion of mevalonic acid. So far, 30 MVA patients have been reported, suffering from recurrent febrile crises and neurologic impairment. Here, we present an in-depth analysis of the phenotypic spectrum of MVA and provide an in-silico pathogenicity model analysis of MVK missense variants. The phenotypic spectrum of 11 MVA patients (age range 0-51 years) registered in the Unified European Registry for Inherited Metabolic Disorders database was systematically analyzed using terms of the Human Phenotype Ontology. Biochemical, radiological as well as genetic characteristics were investigated. Six of eleven patients have reached adulthood and four have reached adolescence. One of the adolescent patients died at the age of 16 years and one patient died shortly after birth. Symptoms started within the first year of life, including episodic fever, developmental delay, ataxia, and ocular involvement. We also describe a case with absence of symptoms despite massive excretion of mevalonic acid. Pathogenic variants causing MVA cluster within highly conserved regions, which are involved in mevalonate and ATP binding. The phenotype of adult and adolescent MVA patients is more heterogeneous than previously assumed. Outcome varies from an asymptomatic course to early death. MVK variants cluster in functionally important and highly conserved protein domains and show high concordance regarding their expected pathogenicity.

After an introductory reflection about general problems of dating and locating early Christian texts, the present contribution focuses on a particularly interesting example which is, however, extremely difficult to contextualise: It is a fragmentarily preserved gospel text that might be a relatively early example of a gospel that in the end was not included in the New Testament canon, but instead was almost forgotten, together with its original tradents or communities. The Gospel according to the Hebrews, as it is called already in Antiquity¹, might also be one of the earliest preserved Christian texts from the ancient intellectual “hub”², the...

Contrary to the current majority view, the formation process of early Judaism(s) reflects less an innovative achievement of an elite group of Judean exiles than a complex and multilayered process of negotiation between diverse groups. The most prominent and well researched groups that come to mind here are the Judean and the Samarian group(s). This thesis leads to the corollary that the late texts of the Hebrew Bible reflect this debate, especially with regard to the two most impactful religious and cultural-historical achievements of the post-exilic epoch, namely the temple, the cult centralization and the Torah. To illustrate this argument, article deals with the Judean and Samarian involvement in the production of the Pentateuch/Hexateuch. The article focuses on two particular Pentateuchal traditions regarding cult centralization, the late Persian redactional additions Deut 11:29–30; Deut 27* and the late Priestly texts. This uncovers a crucial debate revolving around the two important post-exilic institutions of temple and Torah, which, in turn, helps to understand the redactional processes of the final redaction(s) of the Pentateuch. In sum, the article provides a necessary clarification and modification of the modern theory of the so-called Common Torah, that is the Pentateuch understood as a Judean-Samarian co-production.

In wenig normierten, dialogischen Textumgebungen bieten sich den AutorInnen der Texte Freiräume, die sie innovativ, spielerisch und strategisch nutzen. Basierend auf Phraseologismen werden Modifikationen, Variationen sowie weitere Formen der innertextlichen, deiktischen Bezüge funktional eingesetzt. Sie können kulturanalytisch als Spielarten für inter- und transmediale Muster und Bezüge innerhalb einzelner Threads wie auch transmedial als Vernetzung auf andere multimodale Kommunikationsumgebungen gelesen werden. Im vorliegenden Text wird anhand von Beispielen illustriert, wie Phraseologismen in Foren strategisch verwendet und stilistisch genutzt werden. Basierend auf einem eigens zusammengestellten Korpus wird text- und kulturanalytisch Bottom-up vorgegangen. Somit spiegeln diese Formen der (Text-)Vernetzung eine sich stetig andernde Umwelt und hinterlassen Spuren in einem kulturellen Verständnis.

Während in der Aussprache, in der Lexik und in der Grammatik die diatopische Variation auf dialektaler und standardsprachlicher Ebene schon gut dokumentiert ist, gibt es nur wenige Untersuchungen zur Arealität pragmatischer Aspekte. Der Beitrag berichtet von den ersten Ergebnissen eines diesbezüglichen Forschungsvorhabens und legt den Schwerpunkt auf einen Vergleich Zürich - Berlin. Nach einigen grundsätzlichen Überlegungen zur interpersonalen Pragmatik und Arealität kommunikativer Muster wird die Frage diskutiert, welche Erhebungsmethoden geeignet sind, um Variation in diesem Bereich systematisch zu erfassen. Sodann wird am Beispiel einer Stichprobenuntersuchung in Berliner und Zürcher Bäckereien aufgezeigt, welche Beobachtungen sich bereits auf schmaler Datenbasis anstellen lassen. Dabei liegt der Schwerpunkt auf einem kommunikativen Muster, das aus kulturanalytischer Sicht besonders interessant ist: das Grüssen und Verabschieden. Abschliessend wird dafür plädiert, die Pluriarealitätsforschung und die interpersonale Pragmatik enger miteinander zu verknüpfen.

Das Wetter ist auf Ansichtskarten allgegenwartig; es gehort - wie die Unterkunft oder die Verpflegung - zu dem, was man thematisieren kann, um die mit der Ansichtskarte verbundene Textfunktion des Feriengruses einzulosen. Im Beitrag wird auf der Grundlage eines umfangreichen Korpus von Ansichtskarten gezeigt, welche sprachlichen Formen die Thematisierung des Wetters annehmen kann und wie sich dabei ein Stereotyp des Ferienwetters manifestiert, das in seiner musterhaften Auspragung der sprachliche Indikator und Faktor einer mit dem modernen Tourismus massenhaft verbreiteten Alltagserfahrung ist.

Die linguistische Kulturanalyse ist eine relativ junge Ausprägung sprachwissenschaftlicher Forschung, die sich derzeit zunehmend etabliert. Sie geht von der Annahme aus, dass sich Sprachliches und Kulturelles gegenseitig hervorbringen, und untersucht dieses Verhältnis theoretisch und empirisch. Der Band Linguistische Kulturanalyse versammelt 17 Beiträge, die sich einerseits mit grundlegenden kulturanalytischen Konzepten und Annahmen auseinandersetzen und andererseits das Potenzial der linguistischen Kulturanalyse an lexikalischen, morphosyntaktischen, praktikenbezogenen, textuellen und diskursiven Beispielen des Sprachgebrauchs veranschaulichen. Damit stellt der Band den State of the Art der linguistischen Kulturanalyse dar und entwirft zugleich deren Zukunftsperspektiven.