Browsing by Author "Kuhlenbäumer, Gregor"

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    Common Variants Near ZIC1 and ZIC4 in Autopsy-Confirmed Multiple System Atrophy
    (Wiley, 2022-10) Hopfner, Franziska; Tietz, Anja K.; Ruf, Viktoria C.; Ross, Owen A.; Koga, Shunsuke; Dickson, Dennis; Aguzzi, Adriano; Attems, Johannes; Beach, Thomas; Beller, Allison; Cheshire, William P.; van Deerlin, Vivianna; Desplats, Paula; Deuschl, Günther; Duyckaerts, Charles; Ellinghaus, David; Evsyukov, Valentin; Flanagan, Margaret Ellen; Franke, Andre; Frosch, Matthew P.; Gearing, Marla; Gelpi, Ellen; van Gerpen, Jay A.; Ghetti, Bernardino; Glass, Jonathan D.; Grinberg, Lea T.; Halliday, Glenda; Helbig, Ingo; Höllerhage, Matthias; Huitinga, Inge; Irwin, David John; Keene, Dirk C.; Kovacs, Gabor G.; Lee, Edward B.; Levin, Johannes; Martí, Maria J.; Mackenzie, Ian; McKeith, Ian; Mclean, Catriona; Mollenhauer, Brit; Neumann, Manuela; Newell, Kathy L.; Pantelyat, Alex; Pendziwiat, Manuela; Peters, Annette; Porcel, Laura Molina; Rabano, Alberto; Matěj, Radoslav; Rajput, Alex; Rajput, Ali; Reimann, Regina; Scott, William K.; Seeley , William; Selvackadunco, Sashika; Simuni, Tanya; Stadelmann, Christine; Svenningsson, Per; Thomas, Alan; Trenkwalder, Claudia; Troakes, Claire; Trojanowski, John Q.; Uitti, Ryan J.; White, Charles L.; Wszolek, Zbigniew K.; Xie, Tao; Ximelis, Teresa; Justo, Yebenes; Alzheimer’s Disease Genetics Consortium; Müller, Ulrich; Schellenberg, Gerard D.; Herms, Jochen; Kuhlenbäumer, Gregor; Höglinger, Günter; Pathology and Laboratory Medicine, School of Medicine
    Background: Multiple System Atrophy is a rare neurodegenerative disease with alpha-synuclein aggregation in glial cytoplasmic inclusions and either predominant olivopontocerebellar atrophy or striatonigral degeneration, leading to dysautonomia, parkinsonism, and cerebellar ataxia. One prior genome-wide association study in mainly clinically diagnosed patients with Multiple System Atrophy failed to identify genetic variants predisposing for the disease. Objective: Since the clinical diagnosis of Multiple System Atrophy yields a high rate of misdiagnosis when compared to the neuropathological gold standard, we studied only autopsy-confirmed cases. Methods: We studied common genetic variations in Multiple System Atrophy cases (N = 731) and controls (N = 2898). Results: The most strongly disease-associated markers were rs16859966 on chromosome 3, rs7013955 on chromosome 8, and rs116607983 on chromosome 4 with P-values below 5 × 10−6, all of which were supported by at least one additional genotyped and several imputed single nucleotide polymorphisms. The genes closest to the chromosome 3 locus are ZIC1 and ZIC4 encoding the zinc finger proteins of cerebellum 1 and 4 (ZIC1 and ZIC4). Interpretation: Since mutations of ZIC1 and ZIC4 and paraneoplastic autoantibodies directed against ZIC4 are associated with severe cerebellar dysfunction, we conducted immunohistochemical analyses in brain tissue of the frontal cortex and the cerebellum from 24 Multiple System Atrophy patients. Strong immunohistochemical expression of ZIC4 was detected in a subset of neurons of the dentate nucleus in all healthy controls and in patients with striatonigral degeneration, whereas ZIC4-immunoreactive neurons were significantly reduced inpatients with olivopontocerebellar atrophy. These findings point to a potential ZIC4-mediated vulnerability of neurons in Multiple System Atrophy.
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    Relevance of genetic testing in the gene-targeted trial era: the Rostock Parkinson's disease study
    (Oxford University Press, 2024) Westenberger, Ana; Skrahina, Volha; Usnich, Tatiana; Beetz, Christian; Vollstedt, Eva-Juliane; Laabs, Björn-Hergen; Paul, Jefri J.; Curado, Filipa; Skobalj, Snezana; Gaber, Hanaa; Olmedillas, Maria; Bogdanovic, Xenia; Ameziane, Najim; Schell, Nathalie; Aasly, Jan Olav; Afshari, Mitra; Agarwal, Pinky; Aldred, Jason; Alonso-Frech, Fernando; Anderson, Roderick; Araújo, Rui; Arkadir, David; Avenali, Micol; Balal, Mehmet; Benizri, Sandra; Bette, Sagari; Bhatia, Perminder; Bonello, Michael; Braga-Neto, Pedro; Brauneis, Sarah; Costa Cardoso, Francisco Eduardo; Cavallieri, Francesco; Classen, Joseph; Cohen, Lisa; Coletta, Della; Crosiers, David; Cullufi, Paskal; Dashtipour, Khashayar; Demirkiran, Meltem; de Carvalho Aguiar, Patricia; De Rosa, Anna; Djaldetti, Ruth; Dogu, Okan; Dos Santos Ghilardi, Maria Gabriela; Eggers, Carsten; Elibol, Bulent; Ellenbogen, Aaron; Ertan, Sibel; Fabiani, Giorgio; Falkenburger, Björn H.; Farrow, Simon; Fay-Karmon, Tsviya; Ferencz, Gerald J.; Fonoff, Erich Talamoni; Fragoso, Yara Dadalti; Genç, Gençer; Gorospe, Arantza; Grandas, Francisco; Gruber, Doreen; Gudesblatt, Mark; Gurevich, Tanya; Hagenah, Johann; Hanagasi, Hasmet A.; Hassin-Baer, Sharon; Hauser, Robert A.; Hernández-Vara, Jorge; Herting, Birgit; Hinson, Vanessa K.; Hogg, Elliot; Hu, Michele T.; Hummelgen, Eduardo; Hussey, Kelly; Infante, Jon; Isaacson, Stuart H.; Jauma, Serge; Koleva-Alazeh, Natalia; Kuhlenbäumer, Gregor; Kühn, Andrea; Litvan, Irene; López-Manzanares, Lydia; Luxmore, McKenzie; Manandhar, Sujeena; Marcaud, Veronique; Markopoulou, Katerina; Marras, Connie; McKenzie, Mark; Matarazzo, Michele; Merello, Marcelo; Mollenhauer, Brit; Morgan, John C.; Mullin, Stephen; Musacchio, Thomas; Myers, Bennett; Negrotti, Anna; Nieves, Anette; Nitsan, Zeev; Oskooilar, Nader; Öztop-Çakmak, Özgür; Pal, Gian; Pavese, Nicola; Percesepe, Antonio; Piccoli, Tommaso; Pinto de Souza, Carolina; Prell, Tino; Pulera, Mark; Raw, Jason; Reetz, Kathrin; Reiner, Johnathan; Rosenberg, David; Ruiz-Lopez, Marta; Ruiz Martinez, Javier; Sammler, Esther; Santos-Lobato, Bruno Lopes; Saunders-Pullman, Rachel; Schlesinger, Ilana; Schofield, Christine M.; Schumacher-Schuh, Artur F.; Scott, Burton; Sesar, Ángel; Shafer, Stuart J.; Sheridan, Ray; Silverdale, Monty; Sophia, Rani; Spitz, Mariana; Stathis, Pantelis; Stocchi, Fabrizio; Tagliati, Michele; Tai, Yen F.; Terwecoren, Annelies; Thonke, Sven; Tönges, Lars; Toschi, Giulia; Tumas, Vitor; Urban, Peter Paul; Vacca, Laura; Vandenberghe, Wim; Valente, Enza Maria; Valzania, Franco; Vela-Desojo, Lydia; Weill, Caroline; Weise, David; Wojcieszek, Joanne; Wolz, Martin; Yahalom, Gilad; Yalcin-Cakmakli, Gul; Zittel, Simone; Zlotnik, Yair; Kandaswamy, Krishna K.; Balck, Alexander; Hanssen, Henrike; Borsche, Max; Lange, Lara M.; Csoti, Ilona; Lohmann, Katja; Kasten, Meike; Brüggemann, Norbert; Rolfs, Arndt; Klein, Christine; Bauer, Peter; Neurology, School of Medicine
    Estimates of the spectrum and frequency of pathogenic variants in Parkinson's disease (PD) in different populations are currently limited and biased. Furthermore, although therapeutic modification of several genetic targets has reached the clinical trial stage, a major obstacle in conducting these trials is that PD patients are largely unaware of their genetic status and, therefore, cannot be recruited. Expanding the number of investigated PD-related genes and including genes related to disorders with overlapping clinical features in large, well-phenotyped PD patient groups is a prerequisite for capturing the full variant spectrum underlying PD and for stratifying and prioritizing patients for gene-targeted clinical trials. The Rostock Parkinson's disease (ROPAD) study is an observational clinical study aiming to determine the frequency and spectrum of genetic variants contributing to PD in a large international cohort. We investigated variants in 50 genes with either an established relevance for PD or possible phenotypic overlap in a group of 12 580 PD patients from 16 countries [62.3% male; 92.0% White; 27.0% positive family history (FH+), median age at onset (AAO) 59 years] using a next-generation sequencing panel. Altogether, in 1864 (14.8%) ROPAD participants (58.1% male; 91.0% White, 35.5% FH+, median AAO 55 years), a PD-relevant genetic test (PDGT) was positive based on GBA1 risk variants (10.4%) or pathogenic/likely pathogenic variants in LRRK2 (2.9%), PRKN (0.9%), SNCA (0.2%) or PINK1 (0.1%) or a combination of two genetic findings in two genes (∼0.2%). Of note, the adjusted positive PDGT fraction, i.e. the fraction of positive PDGTs per country weighted by the fraction of the population of the world that they represent, was 14.5%. Positive PDGTs were identified in 19.9% of patients with an AAO ≤ 50 years, in 19.5% of patients with FH+ and in 26.9% with an AAO ≤ 50 years and FH+. In comparison to the idiopathic PD group (6846 patients with benign variants), the positive PDGT group had a significantly lower AAO (4 years, P = 9 × 10-34). The probability of a positive PDGT decreased by 3% with every additional AAO year (P = 1 × 10-35). Female patients were 22% more likely to have a positive PDGT (P = 3 × 10-4), and for individuals with FH+ this likelihood was 55% higher (P = 1 × 10-14). About 0.8% of the ROPAD participants had positive genetic testing findings in parkinsonism-, dystonia/dyskinesia- or dementia-related genes. In the emerging era of gene-targeted PD clinical trials, our finding that ∼15% of patients harbour potentially actionable genetic variants offers an important prospect to affected individuals and their families and underlines the need for genetic testing in PD patients. Thus, the insights from the ROPAD study allow for data-driven, differential genetic counselling across the spectrum of different AAOs and family histories and promote a possible policy change in the application of genetic testing as a routine part of patient evaluation and care in PD.