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1. Severity-adjusted evaluation of initial dialysis on short-term health outcomes in urea cycle disorders

Author

Schulze, Andreas, Ficicioglu, Can, Harding, Cary O., Lam, Christina, Coughlin, Curtis R., 2nd, Wong, Derek, Diaz, George A., Berry, Gerard T., Enns, Gregory M., Wilkening, Greta, Seminara, Jennifer, Konczal, Laura, Lawrence Merritt, J., 2nd, Burrage, Lindsay C., Breilyn, Margo, Baumgartner, Matthias R., Mew, Nicholas Ah., Gallagher, Renata C., McCandless, Shawn E., Berry, Susan A., Stricker, Tamar, Zielonka, Matthias, Kölker, Stefan, Garbade, Sven F., Gleich, Florian, Nagamani, Sandesh C.S., Gropman, Andrea L., Druck, Ann-Catrin, Ramdhouni, Nesrine, Göde, Laura, Hoffmann, Georg F., and Posset, Roland

Published
2024
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3. Severity-adjusted evaluation of liver transplantation on health outcomes in urea cycle disorders

Author

Mew, Nicholas Ah, Seminara, Jennifer, Burrage, Lindsay C., Berry, Gerard T., Breilyn, Margo, Schulze, Andreas, Harding, Cary O., Berry, Susan A., Wong, Derek, McCandless, Shawn E., Baumgartner, Matthias R., Konczal, Laura, Ficicioglu, Can, Diaz, George A., Coughlin, Curtis R., 2nd, Enns, Gregory M., Gallagher, Renata C., Lam, Christina, Stricker, Tamar, Wilkening, Greta, Dionisi-Vici, Carlo, Dobbelaere, Dries, Blasco-Alonso, Javier, Burlina, Alberto B., Freisinger, Peter, van Hasselt, Peter M., Skouma, Anastasia, Lund, Allan M., Vara, Roshni, Sarajlija, Adrijan, Morris, Andrew A., Chakrapani, Anupam, Barić, Ivo, Augoustides-Savvopoulou, Persephone, Chien, Yin-Hsiu, Cortès-Saladelafont, Elisenda, Eyskens, Francois, Gramer, Gwendolyn, Zeman, Jiri, Karall, Daniela, Couce, Maria L., Mühlhausen, Chris, Pedrón-Giner, Consuelo, Spiekerkoetter, Ute, Sykut-Cegielska, Jolanta, Wagenmakers, Margreet, Wijburg, Frits A., Posset, Roland, Garbade, Sven F., Gleich, Florian, Scharre, Svenja, Okun, Jürgen G., Gropman, Andrea L., Nagamani, Sandesh C.S., Druck, Ann-Catrin, Epp, Friederike, Hoffmann, Georg F., Kölker, Stefan, and Zielonka, Matthias

Published
2024
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4. Impact of supplementation with L-citrulline/arginine after liver transplantation in individuals with Urea Cycle Disorders

Author

Schulze, Andreas, García-Cazorla, Angeles, Ficicioglu, Can, Harding, Cary O., Lam, Christina, Coughlin, Curtis R., 2<ce:sup loc='post">nd</ce:sup>, Le Mons, Cynthia, Wong, Derek, Dobbelaere, Dries, Diaz, George A., Berry, Gerard T., Enns, Gregory M., Wilkening, Greta, Lawrence Merritt, J., 2<ce:sup loc='post">nd</ce:sup>, Seminara, Jennifer, Konczal, Laura, Burrage, Lindsay C., Breilyn, Margo, Lindner, Martin, Baumgartner, Matthias R., Mew, Nicholas Ah., Gallagher, Renata C., McCandless, Shawn E., Berry, Susan A., Stricker, Tamar, Posset, Roland, Garbade, Sven F., Gleich, Florian, Nagamani, Sandesh C.S., Gropman, Andrea L., Epp, Friederike, Ramdhouni, Nesrine, Druck, Ann-Catrin, Hoffmann, Georg F., Kölker, Stefan, and Zielonka, Matthias

Published
2024
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5. Impact of genetic and non-genetic factors on phenotypic diversity in NBAS-associated disease

Author

Hammann, Nicole, Lenz, Dominic, Baric, Ivo, Crushell, Ellen, Vici, Carlo Dionisi, Distelmaier, Felix, Feillet, Francois, Freisinger, Peter, Hempel, Maja, Khoreva, Anna L., Laass, Martin W., Lacassie, Yves, Lainka, Elke, Larson-Nath, Catherine, Li, Zhongdie, Lipiński, Patryk, Lurz, Eberhard, Mégarbané, André, Nobre, Susana, Olivieri, Giorgia, Peters, Bianca, Prontera, Paolo, Schlieben, Lea D., Seroogy, Christine M., Sobacchi, Cristina, Suzuki, Shigeru, Tran, Christel, Vockley, Jerry, Wang, Jian-She, Wagner, Matias, Prokisch, Holger, Garbade, Sven F., Kölker, Stefan, Hoffmann, Georg F., and Staufner, Christian

Published
2024
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9. aRgus: Multilevel visualization of non-synonymous single nucleotide variants & advanced pathogenicity score modeling for genetic vulnerability assessment

Author

Schröter, Julian, Dattner, Tal, Hüllein, Jennifer, Jayme, Alejandra, Heuveline, Vincent, Hoffmann, Georg F., Kölker, Stefan, Lenz, Dominic, Opladen, Thomas, Popp, Bernt, Schaaf, Christian P., Staufner, Christian, Syrbe, Steffen, Uhrig, Sebastian, Hübschmann, Daniel, and Brennenstuhl, Heiko

Published
2023
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14. Natural History and Developmental Trajectories of Individuals With Disease-Causing Variants in STXBP1

Author

Thalwitzer, Kim M, Driedger, Jan H, Xian, Julie, Saffari, Afshin, Zacher, Pia, Bölsterli, Bigna K, McKeown Ruggiero, Sarah, Sullivan, Katie Rose, Datta, Alexandre N, Kellinghaus, Christoph, Althaus, Jurgen, Wiemer-Kruel, Adelheid, van Baalen, Andreas, Pampel, Armin, Alber, Michael, Braakman, Hilde M H, Debus, Otfried M, Denecke, Jonas, Hobbiebrunken, Elke, Breitweg, Ina, Diehl, Danielle, Eitel, Hans, Gburek-Augustat, Janina, Preisel, Martin, Schlump, Jan-Ulrich, Laufs, Mirjam, Mammadova, Dilbar, Wurst, Carsten, Prager, Christine, Löhr-Nilles, Christa, Martin, Peter, Garbade, Sven F, Platzer, Konrad, Benkel-Herrenbrueck, Ira, Egler, Kerstin, Fazeli, Walid, Lemke, Johannes R, Runkel, Eva, Klein, Barbara, Linden, Tobias, Schröter, Julian, Steffeck, Heike, Thies, Bastian, von Deimling, Florian, Illsinger, Sabine, Borggraefe, Ingo, Classen, Georg, Wieczorek, Dagmar, Ramantani, Georgia, Koelker, Stefan, Hoffmann, Georg F, Ries, Markus, Helbig, Ingo, and Syrbe, Steffen

Abstract

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 scores (GMFCS) 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 (IQR = 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 two individuals presenting with close to age-appropriate motor development. 29/61 (48%) individuals 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 epilepsy, in particular epileptic spasms, and neonatal or early-onset, presented with less favorable motor and language functional outcomes compared to individuals without epilepsy. These findings identify children at risk for severe disease and can serve as comparator for future interventional studies in STXBP1-related disorders. © 2023 American Academy of Neurology.

Published
2023

15. Cathepsin D as biomarker in cerebrospinal fluid of nusinersen-treated patients with spinal muscular atrophy

Author

Schorling, David C., Kölbel, Heike, Hentschel, Andreas, Pechmann, Astrid, Meyer, Nancy, Wirth, Brunhilde, Rombo, Roman, Sickmann, Albert, Kirschner, Janbernd, Schara‐Schmidt, Ulrike, Lochmüller, Hanns, Roos, Andreas, Abele, Thea Beatrice, Andres, Barbara, Angelova‐Toshkina, Daniela, Baum, Petra, Baum, Tobias, Baumann, Matthias, Baumgartner, Manuela, Baur, Ute, Becker, Benedikt, Behring, Bettina, Bernert, Günther, Birsak, Theresa, Bellut, Julia, Bertsche, Astrid, Blankenburg, Markus, Blaschek, Astrid, Braun, Nathalie, Braun, Sarah, Burgenmeister, Nadine, Claus, Nicole, Cordts, Isabell, de Vries, Heike, Deba, Timo, Marina, Adela Della, Denecke, Jonas, Deschauer, Marcus, Dörnbrack, Katharina, Driemeyer, Joenna, Eckenweiler, Matthias, Eisenkölbl, Astrid, Fiedler, Barbara, Fischer, Michal, Flotats‐Bastardas, Marina, Freigang, Maren, Friese, Johannes, Gaiser, Philippa, Gebert, Axel, Geitmann, Stephanie, Goldhahn, Klaus, Grässl, Michael, Gröning, Kristina, Grosskreutz, Julian, Gruber‐Sedlmayr, Ursula, Guillemot, Helene, Günther, René, von der Hagen, Maja, Hagenacker, Tim, Hahn, Andreas, Hartmann, Hans, Hiebeler, Miriam, Hobbiebrunken, Elke, Friedrich Hoffmann, Georg, Holtkamp, Britta, Holzwarth, Dorothea, Horber, Veronka, Husain, Ralf A., Illsinger, Sabine, Jansen, Eva, Johannsen, Jessika, Kaindl, Angela, Kaiser, Nadja, Klamroth, Jennifer, Christoph Koch, Jan, Köhler, Cornelia, Koelker, Stefan, Kolzter, Kirsten, Korschinsky, Brigitte, Küpper, Hanna, Langer, Thorsten, Lehnert, Ilka, Lingor, Paul, Löscher, Wolfgang N., LoudoviciüKrug, Dana, Martakis, Kyriakos, Mayer, Iris, Metelmann, Moritz, Meyer, Sascha, von Moers, Arpad, Mueller‐Kaempffer, Katharina, Müller, Monika, Müller, Petra, Müller‐Felber, Wolfgang, Neuwirth, Christoph, Niederschweiberer, Johanna, Nolte, Anja, Odorfer, Thorsten, Omran, Heymut, Pauschek, Josefine, Pickrodt, Katrin, Plecko, Barbara, Pühringer, Manuel, Quinten, Anna Lisa, Rappold, Mika, Reihle, Christof, Reinhardt, Tabea, Rödiger, Annekathrin, Roetmann, Gerda, Saffari, Afshin, Schimmel, Mareike, Schlachter, Kurt, Schneider, Joanna, Schoene‐Bake, Christoph, Schreiber, Gudrun, Schwartz, Oliver, Schwerin‐Nagel, Anette, Schwersenz, Inge, Smitka, Martin, Stein, Sabine, Steinbach, Robert, Steiner, Elisabeth, Steuernagel, Daniela, Stögmann, Eva, Stolte, Benjamin, Stoltenburg, Corinna, Stüve, Burkhard, Tassoni, Adrian, Theophil, Manuela, Thiele, Simone, Topakian, Raffi, Trollmann, Regina, Türk, Matthias, van der Stam, Lieske, Vill, Katharina, Vogt, Sibylle, Vollmann, Peter, Walter, Maggie C., Warken, Birgit, Weber, Markus, Weiler, Markus, Weiß, Claudia, Weiss, Deike, Weiss, Simone, Wenzel, Franziska, Wider, Sabine, Wiebe, Nils, Wiegand, Gert, Wilichowski, Ekkehard, Wilken, Bernd, Wochner, Katarzyna, Zeiner, Fiona, Zeisler, Daniela, Zeller, Daniel, Zemlin, Michael, and Ziegler, Andreas

Subjects
Adult, Proteomics, Adolescent, Oligonucleotides, Medizin, Cathepsin D, Atròfia muscular espinal -- Tractament, Muscular Atrophy, Spinal, Neurology, Humans, Neurology (clinical), Child, Biomarkers, Aged
Abstract

Data de publicació electrònica: 23-03-2022 Background and purpose: The therapeutic landscape of spinal muscular atrophy (SMA) has changed dramatically during the past 4 years, but treatment responses differ remarkably between individuals, and therapeutic decision-making remains challenging, underlining the persistent need for validated biomarkers. Methods: We applied untargeted proteomic analyses to determine biomarkers in cerebrospinal fluid (CSF) samples of SMA patients under treatment with nusinersen. Identified candidate proteins were validated in CSF samples of SMA patients by Western blot and enzyme-linked immunosorbent assay. Furthermore, levels of peripheral neurofilament heavy and light chain were determined. Results: Untargeted proteomic analysis of CSF samples of three SMA type 1 patients revealed the lysosomal protease cathepsin D as a candidate biomarker. Subsequent validation analysis in a larger cohort of 31 pediatric SMA patients (type 1, n = 12; type 2, n = 9; type 3, n = 6; presymptomatically treated, n = 4; age = 0-16 years) revealed a significant decline of cathepsin D levels in SMA patients aged ≥2 months at the start of treatment. Although evident in all older age categories, this decline was only significant in the group of patients who showed a positive motor response. Moreover, downregulation of cathepsin D was evident in muscle biopsies of SMA patients. Conclusions: We identified a decline of cathepsin D levels in CSF samples of SMA patients under nusinersen treatment that was more pronounced in the group of "treatment responders" than in "nonresponders." We believe that our results indicate a suitability of cathepsin D levels as a possible biomarker in SMA also in older patients, in combination with analysis of peripheral neurofilament light chain in adolescents or alone in adult patients. Funding: H.L. receives support from the Canadian Institutes of Health Research (Foundation Grant FDN-167281), the Canadian Institutes of Health Research and Muscular Dystrophy Canada (Network Catalyst Grant for NMD4C), the Canada Foundation for Innovation (CFI-JELF 38412), and the Canada Research Chairs program (Canada Research Chair in Neuromuscular Genomics and Health, 950-232279). This work was also supported by a grant of the French Muscular Dystrophy Association (AFM-Téléthon;#21466) to A.R. The work of B.W. is supported by the German Research Foundation (Wi945/17-1, SFB 1451 [project-ID 431549029–A01] and GRK1960 [project ID 233886668]), the European Research Council under the European Union's Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement 956185 (SMABEYOND), and the Center for Molecular Medicine Cologne (project No C18)

Published
2022

17. Issues with European guidelines for phenylketonuria

Author

Burgard, Peter, Ullrich, Kurt, Ballhausen, Diana, Hennermann, Julia B, Hollak, Carla E M, Langeveld, Mirjam, Karall, Daniela, Konstantopoulou, Vassiliki, Maier, Esther M, Lang, Frauke, Lachmann, Robin, Murphy, Elaine, Garbade, Sven, Hoffmann, Georg F, Kölker, Stefan, Lindner, Martin, and Zschocke, Johannes

Published
2017
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22. Recessive mutations in EPG5 cause Vici syndrome, a multisystem disorder with defective autophagy.

Author

Cullup, Thomas, Kho, Ay Lin, Dionisi-Vici, Carlo, Brandmeier, Birgit, Smith, Frances, Urry, Zoe, Simpson, Michael A, Yau, Shu, Bertini, Enrico, McClelland, Verity, Al-Owain, Mohammed, Koelker, Stefan, Koerner, Christian, Hoffmann, Georg F, Wijburg, Frits A, Hoedt, Amber E ten, Rogers, R Curtis, Manchester, David, Miyata, Rie, and Hayashi, Masaharu

Subjects
IMMUNODEFICIENCY, GENETIC mutation, AUTOPHAGY, HOMOLOGY (Biology), HYPOPIGMENTATION, CARDIOMYOPATHIES
Abstract

Vici syndrome is a recessively inherited multisystem disorder characterized by callosal agenesis, cataracts, cardiomyopathy, combined immunodeficiency and hypopigmentation. To investigate the molecular basis of Vici syndrome, we carried out exome and Sanger sequence analysis in a cohort of 18 affected individuals. We identified recessive mutations in EPG5 (previously KIAA1632), indicating a causative role in Vici syndrome. EPG5 is the human homolog of the metazoan-specific autophagy gene epg-5, encoding a key autophagy regulator (ectopic P-granules autophagy protein 5) implicated in the formation of autolysosomes. Further studies showed a severe block in autophagosomal clearance in muscle and fibroblasts from individuals with mutant EPG5, resulting in the accumulation of autophagic cargo in autophagosomes. These findings position Vici syndrome as a paradigm of human multisystem disorders associated with defective autophagy and suggest a fundamental role of the autophagy pathway in the immune system and the anatomical and functional formation of organs such as the brain and heart. [ABSTRACT FROM AUTHOR]

Published
2013
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23. The incidence of urea cycle disorders.

Author

Summar, Marshall L., Koelker, Stefan, Freedenberg, Debra, Le Mons, Cynthia, Haberle, Johannes, Lee, Hye-Seung, and Kirmse, Brian

Subjects
*GENETIC disorders, *ENZYME deficiency, *UREA, *LYASES, *NEONATAL diseases, *LONGITUDINAL method
Abstract

Abstract: A key question for urea cycle disorders is their incidence. In the United States two UCDs, argininosuccinic synthetase and lyase deficiency, are currently detected by newborn screening. We used newborn screening data on over 6million births and data from the large US and European longitudinal registries to determine how common these conditions are. The incidence for the United States is predicted to be 1 urea cycle disorder patient for every 35,000 births presenting about 113 new patients per year across all age groups. [Copyright &y& Elsevier]

Published
2013
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24. Impact of short- and medium-chain organic acids, acylcarnitines, and acyl-CoAs onmitochondrial energy metabolism

Author

Sauer, Sven Wolfgang, Okun, Juergen G., Hoffmann, Georg F., Koelker, Stefan, and Morath, Marina A.

Subjects
*ORGANIC acids, *ENERGY metabolism, *COENZYMES, *CARNITINE
Abstract

Abstract: Accumulation of organic acids as well as their CoA and carnitine esters in tissues and body fluids is a common finding in organic acidurias, beta-oxidation defects, Reye syndrome, and Jamaican vomiting sickness. Pathomechanistic approaches for these disorders have been often focused on the effect of accumulating organic acids on mitochondrial energy metabolism, whereas little is known about the pathophysiologic role of short- and medium-chain acyl-CoAs and acylcarnitines. Therefore, we investigated the impact of short- and medium-chain organic acids, acylcarnitines, and acyl-CoAs on central components of mitochondrial energy metabolism, namely alpha-ketoglutarate dehydrogenase complex, pyruvate dehydrogenase complex, and single enzyme complexes I-V of respiratory chain. Although at varying degree, all acyl-CoAs had an inhibitory effect on pyruvate dehydrogenase complex and alpha-ketoglutarate dehydrogenase complex activity. Effect sizes were critically dependent on chain length and number of functional groups. Unexpectedly, octanoyl-CoA was shown to inhibit complex III. The inhibition was noncompetitive regarding reduced ubiquinone and uncompetitive regarding cytochrome c. In addition, octanoyl-CoA caused a blue shift in the gamma band of the absorption spectrum of reduced complex III. This effect may play a role in the pathogenesis of medium-chain and multiple acyl-CoA dehydrogenase deficiency, Reye syndrome, and Jamaican vomiting sickness which are inherited and acquired conditions of intracellular accumulation of octanoyl-CoA. [Copyright &y& Elsevier]

Published
2008
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25. Natural History and Developmental Trajectories of Individuals With Disease-Causing Variants in STXBP1 .

Author

Thalwitzer KM, Driedger JH, Xian J, Saffari A, Zacher P, Bölsterli BK, Ruggiero SM, Sullivan KR, Datta AN, Kellinghaus C, Althaus J, Wiemer-Kruel A, van Baalen A, Pampel A, Alber M, Braakman HMH, Debus OM, Denecke J, Hobbiebrunken E, Breitweg I, Diehl D, Eitel H, Gburek-Augustat J, Preisel M, Schlump JU, Laufs M, Mammadova D, Wurst C, Prager C, Löhr-Nilles C, Martin P, Garbade SF, Platzer K, Benkel-Herrenbrueck I, Egler K, Fazeli W, Lemke JR, Runkel E, Klein B, Linden T, Schröter J, Steffeck H, Thies B, von Deimling F, Illsinger S, Borggraefe I, Classen G, Wieczorek D, Ramantani G, Koelker S, Hoffmann GF, Ries M, Helbig I, and Syrbe S

Subjects
Child, Child, Preschool, Humans, Cross-Sectional Studies, Munc18 Proteins genetics, Mutation, Retrospective Studies, Seizures, Spasm, Speech Disorders, Adult, Epilepsy, Spasms, Infantile genetics
Abstract

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 epilepsy, in particular epileptic spasms, and neonatal or early-onset presented with less favorable motor and language functional outcomes compared with individuals without epilepsy. These findings identify children at risk for severe disease and can serve as comparator for future interventional studies in STXBP1 -related disorders., (© 2023 American Academy of Neurology.)

Published
2023
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