Dokument-ID Dokumenttyp Verfasser/Autoren Herausgeber Haupttitel Abstract Auflage Verlagsort Verlag Erscheinungsjahr Seitenzahl Schriftenreihe Titel Schriftenreihe Bandzahl ISBN Quelle der Hochschulschrift Konferenzname Quelle:Titel Quelle:Jahrgang Quelle:Heftnummer Quelle:Erste Seite Quelle:Letzte Seite URN DOI Abteilungen OPUS4-13363 Wissenschaftlicher Artikel Jarius, Sven; Ruprecht, Klemens; Wildemann, Brigitte; Kuempfel, Tania; Ringelstein, Marius; Geis, Christian; Kleiter, Ingo; Kleinschnitz, Christoph; Berthele, Achim; Brettschneider, Johannes; Hellwig, Kerstin; Hemmer, Bernhard; Linker, Ralf A.; Lauda, Florian; Hayrettin, Christoph A.; Tumani, Hayrettin; Melms, Arthur; Trebst, Corinna; Stangel, Martin; Marziniak, Martin; Hoffmann, Frank; Schippling, Sven; Faiss, Jürgen H.; Neuhaus, Oliver; Ettrich, Barbara; Zentner, Christian; Guthke, Kersten; Hofstadt-van Oy, Ulrich; Reuss, Reinhard; Pellkofer, Hannah; Ziemann, Ulf; Kern, Peter; Wandinger, Klaus P.; Bergh, Florian Then; Boettcher, Tobias; Langel, Stefan; Liebetrau, Martin; Rommer, Paulus S.; Niehaus, Sabine; Münch, Christoph; Winkelmann, Alexander; Zettl, Uwe K; Metz, Imke; Veauthier, Christian; Sieb, Jörn P.; Wilke, Christian; Hartung, Hans P.; Aktas, Orhan; Paul, Friedemann Contrasting disease patterns in seropositive and seronegative neuromyelitis optica: A multicentre study of 175 patients Background: The diagnostic and pathophysiological relevance of antibodies to aquaporin-4 (AQP4-Ab) in patients with neuromyelitis optica spectrum disorders (NMOSD) has been intensively studied. However, little is known so far about the clinical impact of AQP4-Ab seropositivity. Objective: To analyse systematically the clinical and paraclinical features associated with NMO spectrum disorders in Caucasians in a stratified fashion according to the patients' AQP4-Ab serostatus. Methods: Retrospective study of 175 Caucasian patients (AQP4-Ab positive in 78.3%). Results: Seropositive patients were found to be predominantly female (p < 0.0003), to more often have signs of co-existing autoimmunity (p < 0.00001), and to experience more severe clinical attacks. A visual acuity of <= 0.1 during acute optic neuritis (ON) attacks was more frequent among seropositives (p < 0.002). Similarly, motor symptoms were more common in seropositive patients, the median Medical Research Council scale (MRC) grade worse, and MRC grades <= 2 more frequent, in particular if patients met the 2006 revised criteria (p < 0.005, p < 0.006 and p < 0.01, respectively), the total spinal cord lesion load was higher (p < 0.006), and lesions >= 6 vertebral segments as well as entire spinal cord involvement more frequent (p < 0.003 and p < 0.043). By contrast, bilateral ON at onset was more common in seronegatives (p < 0.007), as was simultaneous ON and myelitis (p < 0.001); accordingly, the time to diagnosis of NMO was shorter in the seronegative group (p < 0.029). The course of disease was more often monophasic in seronegatives (p < 0.008). Seropositives and seronegatives did not differ significantly with regard to age at onset, time to relapse, annualized relapse rates, outcome from relapse (complete, partial, no recovery), annualized EDSS increase, mortality rate, supratentorial brain lesions, brainstem lesions, history of carcinoma, frequency of preceding infections, oligoclonal bands, or CSF pleocytosis. Both the time to relapse and the time to diagnosis was longer if the disease started with ON (p < 0.002 and p < 0.013). Motor symptoms or tetraparesis at first myelitis and > 1 myelitis attacks in the first year were identified as possible predictors of a worse outcome. 2012 Journal of Neuroinflammation 9 14 urn:nbn:de:bvb:20-opus-133636 10.1186/1742-2094-9-14 Neurologische Klinik und Poliklinik OPUS4-16540 Wissenschaftlicher Artikel Sadovnick, A. Dessa; Traboulsee, Anthony L.; Bernales, Cecily Q.; Ross, Jay P.; Forwell, Amanda L.; Yee, Irene M.; Guillot-Noel, Lena; Fontaine, Bertrand; Cournu-Rebeix, Isabelle; Alcina, Antonio; Fedetz, Maria; Izquierdo, Guillermo; Matesanz, Fuencisla; Hilven, Kelly; Dubois, Bénédicte; Goris, An; Astobiza, Ianire; Alloza, Iraide; Antigüedad, Alfredo; Vandenbroeck, Koen; Akkad, Denis A.; Aktas, Orhan; Blaschke, Paul; Buttmann, Mathias; Chan, Andrew; Epplen, Joerg T.; Gerdes, Lisa-Ann; Kroner, Antje; Kubisch, Christian; Kümpfel, Tania; Lohse, Peter; Rieckmann, Peter; Zettl, Uwe K.; Zipp, Frauke; Bertram, Lars; Lill, Christina M.; Fernandez, Oscar; Urbaneja, Patricia; Leyva, Laura; Alvarez-Cermeño, Jose Carlos; Arroyo, Rafael; Garagorri, Aroa M.; García-Martínez, Angel; Villar, Luisa M.; Urcelay, Elena; Malhotra, Sunny; Montalban, Xavier; Comabella, Manuel; Berger, Thomas; Fazekas, Franz; Reindl, Markus; Schmied, Mascha C.; Zimprich, Alexander; Vilariño-Güell, Carles Analysis of Plasminogen Genetic Variants in Multiple Sclerosis Patients Multiple sclerosis (MS) is a prevalent neurological disease of complex etiology. Here, we describe the characterization of a multi-incident MS family that nominated a rare missense variant (p.G420D) in plasminogen (PLG) as a putative genetic risk factor for MS. Genotyping of PLG p.G420D (rs139071351) in 2160 MS patients, and 886 controls from Canada, identified 10 additional probands, two sporadic patients and one control with the variant. Segregation in families harboring the rs139071351 variant, identified p.G420D in 26 out of 30 family members diagnosed with MS, 14 unaffected parents, and 12 out of 30 family members not diagnosed with disease. Despite considerably reduced penetrance, linkage analysis supports cosegregation of PLG p.G420D and disease. Genotyping of PLG p.G420D in 14446 patients, and 8797 controls from Canada, France, Spain, Germany, Belgium, and Austria failed to identify significant association with disease (P = 0.117), despite an overall higher prevalence in patients (OR = 1.32; 95% CI = 0.93-1.87). To assess whether additional rare variants have an effect on MS risk, we sequenced PLG in 293 probands, and genotyped all rare variants in cases and controls. This analysis identified nine rare missense variants, and although three of them were exclusively observed in MS patients, segregation does not support pathogenicity. PLG is a plausible biological candidate for MS owing to its involvement in immune system response, blood-brain barrier permeability, and myelin degradation. Moreover, components of its activation cascade have been shown to present increased activity or expression in MS patients compared to controls; further studies are needed to clarify whether PLG is involved in MS susceptibility. 2016 2073-2079 G3: Genes Genomes Genetics 6 7 urn:nbn:de:bvb:20-opus-165405 10.1534/g3.116.030841 Neurologische Klinik und Poliklinik OPUS4-20076 Wissenschaftlicher Artikel Gómez-Fernández, Paloma; Lopez de Lapuente Portilla, Aitzkoa; Astobiza, Ianire; Mena, Jorge; Urtasun, Andoni; Altmann, Vivian; Matesanz, Fuencisla; Otaegui, David; Urcelay, Elena; Antigüedad, Alfredo; Malhotra, Sunny; Montalban, Xavier; Castillo-Triviño, Tamara; Espino-Paisán, Laura; Aktas, Orhan; Buttmann, Mathias; Chan, Andrew; Fontaine, Bertrand; Gourraud, Pierre-Antoine; Hecker, Michael; Hoffjan, Sabine; Kubisch, Christian; Kümpfel, Tania; Luessi, Felix; Zettl, Uwe K.; Zipp, Frauke; Alloza, Iraide; Comabella, Manuel; Lill, Christina M.; Vandenbroeck, Koen The rare IL22RA2 signal peptide coding variant rs28385692 decreases secretion of IL-22BP isoform-1, -2 and -3 and is associated with risk for multiple sclerosis The IL22RA2 locus is associated with risk for multiple sclerosis (MS) but causative variants are yet to be determined. In a single nucleotide polymorphism (SNP) screen of this locus in a Basque population, rs28385692, a rare coding variant substituting Leu for Pro at position 16 emerged significantly (p = 0.02). This variant is located in the signal peptide (SP) shared by the three secreted protein isoforms produced by IL22RA2 (IL-22 binding protein-1(IL-22BPi1), IL-22BPi2 and IL-22BPi3). Genotyping was extended to a Europe-wide case-control dataset and yielded high significance in the full dataset (p = 3.17 × 10\(^{-4}\)). Importantly, logistic regression analyses conditioning on the main known MS-associated SNP at this locus, rs17066096, revealed that this association was independent from the primary association signal in the full case-control dataset. In silico analysis predicted both disruption of the alpha helix of the H-region of the SP and decreased hydrophobicity of this region, ultimately affecting the SP cleavage site. We tested the effect of the p.Leu16Pro variant on the secretion of IL-22BPi1, IL-22BPi2 and IL-22BPi3 and observed that the Pro16 risk allele significantly lowers secretion levels of each of the isoforms to around 50%-60% in comparison to the Leu16 reference allele. Thus, our study suggests that genetically coded decreased levels of IL-22BP isoforms are associated with augmented risk for MS. 2020 Cells 9 1 urn:nbn:de:bvb:20-opus-200769 10.3390/cells9010175 Neurologische Klinik und Poliklinik