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1. Decreasing ganglioside synthesis delays motor and cognitive symptom onset in Spg11 knockout mice

Author

Fortier, Manon, Cauhapé, Margaux, Buono, Suzie, Becker, Julien, Menuet, Alexia, Branchu, Julien, Ricca, Ivana, Mero, Serena, Dorgham, Karim, El Hachimi, Khalid-Hamid, Dobrenis, Kostantin, Colsch, Benoit, Samaroo, Dominic, Devaux, Morgan, Durr, Alexandra, Stevanin, Giovanni, Santorelli, Filippo M., Colombo, Sophie, Cowling, Belinda, and Darios, Frédéric

Published
2024
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2. Motor neuron pathology in CANVAS due to RFC1 expansions

Author

Huin, Vincent, Coarelli, Giulia, Guemy, Clément, Boluda, Susana, Debs, Rabab, Mochel, Fanny, Stojkovic, Tanya, Grabli, David, Maisonobe, Thierry, Gaymard, Bertrand, Lenglet, Timothée, Tard, Céline, Davion, Jean-Baptiste, Sablonnière, Bernard, Monin, Marie-Lorraine, Ewenczyk, Claire, Viala, Karine, Charles, Perrine, Ber, Isabelle Le, Reilly, Mary, Houlden, Henry, Cortese, Andrea, Seilhean, Danielle, Brice, Alexis, and Durr, Alexandra

Subjects
Quantitative Biology - Neurons and Cognition
Abstract

CANVAS caused by RFC1 biallelic expansions is a major cause of inherited sensory neuronopathy. Detection of RFC1 expansion is challenging and CANVAS can be associated with atypical features. We clinically and genetically characterized 50 patients, selected based on the presence of sensory neuronopathy confirmed by EMG. We screened RFC1 expansion by PCR, repeat-primed PCR, and Southern blotting of long-range PCR products, a newly developed method. Neuropathological characterization was performed on the brain and spinal cord of one patient. Most patients (88%) carried a biallelic (AAGGG)n expansion in RFC1. In addition to the core CANVAS phenotype (sensory neuronopathy, cerebellar syndrome, and vestibular impairment), we observed chronic cough (97%), oculomotor signs (85%), motor neuron involvement (55%), dysautonomia (50%), and parkinsonism (10%). Motor neuron involvement was found for 24 of 38 patients (63.1%). First motor neuron signs, such as brisk reflexes, extensor plantar responses, and/or spasticity, were present in 29% of patients, second motor neuron signs, such as fasciculations, wasting, weakness, or a neurogenic pattern on EMG in 18%, and both in 16%. Mixed motor and sensory neuronopathy was observed in 19% of patients. Among six non-RFC1 patients, one carried a heterozygous AAGGG expansion and a pathogenic variant in GRM1. Neuropathological examination of one RFC1 patient with an enriched phenotype, including parkinsonism, dysautonomia, and cognitive decline, showed posterior column and lumbar posterior root atrophy. Degeneration of the vestibulospinal and spinocerebellar tracts was mild. We observed marked astrocytic gliosis and axonal swelling of the synapse between first and second motor neurons in the anterior horn at the lumbar level. The cerebellum showed mild depletion of Purkinje cells, with empty baskets, torpedoes, and astrogliosis characterized by a disorganization of the Bergmann's radial glia. We found neuronal loss in the vagal nucleus. The pars compacta of the substantia nigra was depleted, with widespread Lewy bodies in the locus coeruleus, substantia nigra, hippocampus, entorhinal cortex, and amygdala. We propose new guidelines for the screening of RFC1 expansion, considering different expansion motifs. Here, we developed a new method to more easily detect pathogenic RFC1 expansions. We report frequent motor neuron involvement and different neuronopathy subtypes. Parkinsonism was more prevalent in this cohort than in the general population, 10% versus the expected 1% (p < .001). We describe, for the first time, the spinal cord pathology in CANVAS, showing the alteration of posterior columns and roots, astrocytic gliosis and axonal swelling, suggesting motor neuron synaptic dysfunction.

Published
2022
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3. Image Collation: Matching illustrations in manuscripts

Author

Kaoua, Ryad, Shen, Xi, Durr, Alexandra, Lazaris, Stavros, Picard, David, and Aubry, Mathieu

Subjects
Computer Science - Computer Vision and Pattern Recognition
Abstract

Illustrations are an essential transmission instrument. For an historian, the first step in studying their evolution in a corpus of similar manuscripts is to identify which ones correspond to each other. This image collation task is daunting for manuscripts separated by many lost copies, spreading over centuries, which might have been completely re-organized and greatly modified to adapt to novel knowledge or belief and include hundreds of illustrations. Our contributions in this paper are threefold. First, we introduce the task of illustration collation and a large annotated public dataset to evaluate solutions, including 6 manuscripts of 2 different texts with more than 2 000 illustrations and 1 200 annotated correspondences. Second, we analyze state of the art similarity measures for this task and show that they succeed in simple cases but struggle for large manuscripts when the illustrations have undergone very significant changes and are discriminated only by fine details. Finally, we show clear evidence that significant performance boosts can be expected by exploiting cycle-consistent correspondences. Our code and data are available on http://imagine.enpc.fr/~shenx/ImageCollation., Comment: accepted to ICDAR 2021

Published
2021

4. CAG repeat mosaicism is gene specific in spinocerebellar ataxias

Author

Kacher, Radhia, Lejeune, François-Xavier, David, Isabelle, Boluda, Susana, Coarelli, Giulia, Leclere-Turbant, Sabrina, Heinzmann, Anna, Marelli, Cecilia, Charles, Perrine, Goizet, Cyril, Kabir, Nisha, Hilab, Rania, Jornea, Ludmila, Six, Julie, Dommergues, Marc, Fauret, Anne-Laure, Brice, Alexis, Humbert, Sandrine, and Durr, Alexandra

Published
2024
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5. Reply: Early-onset phenotype of bi-allelic GRN mutations

Author

Huin, Vincent, Barbier, Mathieu, Durr, Alexandra, and Ber, Isabelle Le

Subjects
Quantitative Biology - Genomics, Quantitative Biology - Neurons and Cognition
Abstract

We would like to reply to Neuray et al. who report a series of five new patients from four unrelated families with bi-allelic mutations of GRN. Their work nicely completes the few existing reports of similar cases, and refers to our recent publication describing six homozygous GRN pathogenic variant carriers with divergent phenotypes and ages at onset (Huin et al., 2020). In summary, the Letter from Neuray et al., reports valuable findings that lead to better define CLN11 due to bi-allelic GRN pathogenic variants. Despite the small sample number that does not allow statistical analysis, the authors underlined the occurrence of cognitive deterioration and epilepsy. Further study of the CLN11 families with functional brain imaging and neuropsychological examinations may be highly informative for the understanding and the clinical characterization of this rare disease., Comment: Brain - A Journal of Neurology , Oxford University Press (OUP), 2020

Published
2021
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6. TMEM240 mutations cause spinocerebellar ataxia 21 with mental retardation and severe cognitive impairment

Author

Delplanque, Jérôme, Devos, David, Huin, Vincent, Genet, Alexandre, Sand, Olivier, Moreau, Caroline, Goizet, Cyril, Charles, Perrine, Anheim, Mathieu, Monin, Marie Lorraine, Buée, Luc, Destée, Alain, Grolez, Guillaume, Delmaire, Christine, Dujardin, Kathy, Dellacherie, Delphine, Brice, Alexis, Stevanin, Giovanni, Strubi-Vuillaume, Isabelle, Durr, Alexandra, and Sablonnière, Bernard

Subjects
Quantitative Biology - Genomics
Abstract

Autosomal dominant cerebellar ataxia corresponds to a clinically and genetically heterogeneous group of neurodegenerative disorders that primarily affect the cerebellum. Here, we report the identification of the causative gene in spinocerebellar ataxia 21, an autosomal-dominant disorder previously mapped to chromosome 7p21.3-p15.1. This ataxia was firstly characterized in a large French family with slowly progressive cerebellar ataxia, accompanied by severe cognitive impairment and mental retardation in two young children. Following the recruitment of 12 additional young family members, linkage analysis enabled us to definitively map the disease locus to chromosome 1p36.33-p36.32. The causative mutation, (c.509C4T/p.P170L) in the transmembrane protein gene TMEM240, was identified by whole exome sequencing and then was confirmed by Sanger sequencing and co-segregation analyses. Index cases from 368 French families with autosomal-dominant cerebellar ataxia were also screened for mutations. In seven cases, we identified a range of missense mutations (c.509C4T/p.P170L, c.239C4T/p.T80M, c.346C4T/p.R116C, c.445G4A/p.E149K, c.511C4T/p.R171W), and a stop mutation (c.489C4G/p.Y163*) in the same gene. TMEM240 is a small, strongly conserved transmembrane protein of unknown function present in cerebellum and brain. Spinocerebellar ataxia 21 may be a particular early-onset disease associated with severe cognitive impairment.

Published
2020
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7. Homozygous GRN mutations: unexpected phenotypes and new insights into pathological and molecular mechanisms

Author

Huin, Vincent, Barbier, Mathieu, Bottani, Armand, Lobrinus, Johannes, Clot, Fabienne, Lamari, Foudil, Chat, Laureen, Rucheton, Benoît, Fluchère, Frédérique, Auvin, Stéphane, Myers, Peter, Gelot, Antoinette, Camuzat, Agnès, Caillaud, Catherine, Jornéa, Ludmila, Forlani, Sylvie, Saracino, Dario, Duyckaerts, Charles, Brice, Alexis, Durr, Alexandra, and Ber, Isabelle Le

Subjects
Quantitative Biology - Biomolecules, Quantitative Biology - Genomics, Quantitative Biology - Neurons and Cognition
Abstract

Homozygous mutations in the progranulin gene (GRN) are associated with neuronal ceroid lipofuscinosis 11 (CLN11), a rare lysosomal-storage disorder characterized by cerebellar ataxia, seizures, retinitis pigmentosa, and cognitive disorders, usually beginning between 13 and 25 years of age. This is a rare condition, previously reported in only four families. In contrast, heterozygous GRN mutations are a major cause of frontotemporal dementia associated with neuronal cytoplasmic TDP-43 inclusions. We identified homozygous GRN mutations in six new patients. The phenotypic spectrum is much broader than previously reported, with two remarkably distinct presentations, depending on the age of onset. A childhood/juvenile form is characterized by classical CLN11 symptoms at an early age at onset. Unexpectedly, other homozygous patients presented a distinct delayed phenotype of frontotemporal dementia and parkinsonism after 50 years; none had epilepsy or cerebellar ataxia. Another major finding of this study is that all GRN mutations may not have the same impact on progranulin protein synthesis. A hypomorphic effect of some mutations is supported by the presence of residual levels of plasma progranulin and low levels of normal transcript detected in one case with a homozygous splice-site mutation and late onset frontotemporal dementia. This is a new critical finding that must be considered in therapeutic trials based on replacement strategies. The first neuropathological study in a homozygous carrier provides new insights into the pathological mechanisms of the disease. Hallmarks of neuronal ceroid lipofuscinosis were present. The absence of TDP-43 cytoplasmic inclusions markedly differs from observations of heterozygous mutations, suggesting a pathological shift between lysosomal and TDP-43 pathologies depending on the mono or bi-allelic status. An intriguing observation was the loss of normal TDP-43 staining in the nucleus of some neurons, which could be the first stage of the TDP-43 pathological process preceding the formation of typical cytoplasmic inclusions. Finally, this study has important implications for genetic counselling and molecular diagnosis. Semi-dominant inheritance of GRN mutations implies that specific genetic counseling should be delivered to children and parents of CLN11 patients, as they are heterozygous carriers with a high risk of developing dementia. More broadly, this study illustrates the fact that genetic variants can lead to different phenotypes according to their mono- or bi-allelic state, which is a challenge for genetic diagnosis.

Published
2020
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9. Clinical and genetic keys to cerebellar ataxia due to FGF14 GAA expansions

Author

Méreaux, Jean-Loup, Davoine, Claire-Sophie, Pellerin, David, Coarelli, Giulia, Coutelier, Marie, Ewenczyk, Claire, Monin, Marie-Lorraine, Anheim, Mathieu, Le Ber, Isabelle, Thobois, Stéphane, Gobert, Florent, Guillot-Noël, Léna, Forlani, Sylvie, Jornea, Ludmila, Heinzmann, Anna, Sangare, Aude, Gaymard, Bertrand, Guyant-Maréchal, Lucie, Charles, Perrine, Marelli, Cecilia, Honnorat, Jérôme, Degos, Bertrand, Tison, François, Sangla, Sophie, Simonetta-Moreau, Marion, Salachas, François, Tchikviladzé, Maya, Castelnovo, Giovanni, Mochel, Fanny, Klebe, Stephan, Castrioto, Anna, Fenu, Silvia, Méneret, Aurélie, Bourdain, Frédéric, Wandzel, Marion, Roth, Virginie, Bonnet, Céline, Riant, Florence, Stevanin, Giovanni, Noël, Sandrine, Fauret-Amsellem, Anne-Laure, Bahlo, Melanie, Lockhart, Paul J., Brais, Bernard, Renaud, Mathilde, Brice, Alexis, and Durr, Alexandra

Published
2024
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10. Individual perception of environmental factors that influence lower limbs spasticity in inherited spastic paraparesis

Author

Lallemant-Dudek, Pauline, MD, Parodi, Livia, PhD, Coarelli, Giulia, MD, Heinzmann, Anna, MD, Charles, Perrine, MD PhD, Ewenczyk, Claire, MD, PhD, Fenu, Silvia, MD, Monin, Marie-Lorraine, MD, Corcia, Philippe, MD PhD, Depienne, Christel, PhD, Mochel, Fanny, MD, PhD, Benard, Jean, PhD, Tezenas du Montcel, Sophie, MD, and Durr, Alexandra, MD, PhD

Published
2023
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12. Extreme phenotypic heterogeneity in non-expansion spinocerebellar ataxias

Author

Cunha, Paulina, Petit, Emilien, Coutelier, Marie, Coarelli, Giulia, Mariotti, Caterina, Faber, Jennifer, Van Gaalen, Judith, Damasio, Joana, Fleszar, Zofia, Tosi, Michele, Rocca, Clarissa, De Michele, Giovanna, Minnerop, Martina, Ewenczyk, Claire, Santorelli, Filippo M., Heinzmann, Anna, Bird, Thomas, Amprosi, Matthias, Indelicato, Elisabetta, Benussi, Alberto, Charles, Perrine, Stendel, Claudia, Romano, Silvia, Scarlato, Marina, Le Ber, Isabelle, Bassi, Maria Teresa, Serrano, Mercedes, Schmitz-Hübsch, Tanja, Doss, Sarah, Van Velzen, Gijs A.J., Thomas, Quentin, Trabacca, Antonio, Ortigoza-Escobar, Juan Dario, D'Arrigo, Stefano, Timmann, Dagmar, Pantaleoni, Chiara, Martinuzzi, Andrea, Besse-Pinot, Elsa, Marsili, Luca, Cioffi, Ettore, Nicita, Francesco, Giorgetti, Alejandro, Moroni, Isabella, Romaniello, Romina, Casali, Carlo, Ponger, Penina, Casari, Giorgio, De Bot, Susanne T., Ristori, Giovanni, Blumkin, Lubov, Borroni, Barbara, Goizet, Cyril, Marelli, Cecilia, Boesch, Sylvia, Anheim, Mathieu, Filla, Alessandro, Houlden, Henry, Bertini, Enrico, Klopstock, Thomas, Synofzik, Matthis, Riant, Florence, Zanni, Ginevra, Magri, Stefania, Di Bella, Daniela, Nanetti, Lorenzo, Sequeiros, Jorge, Oliveira, Jorge, Van de Warrenburg, Bart, Schöls, Ludger, Taroni, Franco, Brice, Alexis, and Durr, Alexandra

Published
2023
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13. A Solve-RD ClinVar-based reanalysis of 1522 index cases from ERN-ITHACA reveals common pitfalls and misinterpretations in exome sequencing

Author

Abbott, Kristin M., Banka, Siddharth, de Boer, Elke, Ciolfi, Andrea, Clayton-Smith, Jill, Dallapiccola, Bruno, Denommé-Pichon, Anne-Sophie, Faivre, Laurence, Gilissen, Christian, Haack, Tobias B., Havlovicova, Marketa, Hoischen, Alexander, Jackson, Adam, Kerstjens, Mieke, Kleefstra, Tjitske, Martín, Estrella López, Macek, Milan, Jr., Matalonga, Leslie, Maystadt, Isabelle, Morleo, Manuela, Nigro, Vicenzo, Pinelli, Michele, Pizzi, Simone, Posada, Manuel, Radio, Francesca C., Renieri, Alessandra, Riess, Olaf, Rooryck, Caroline, Ryba, Lukas, Agathe, Jean-Madeleine de Sainte, Santen, Gijs W.E., Schwarz, Martin, Tartaglia, Marco, Thauvin, Christel, Torella, Annalaura, Trimouille, Aurélien, Verloes, Alain, Vissers, Lisenka, Vitobello, Antonio, Votypka, Pavel, Zguro, Kristina, Boer, Elke de, Cohen, Enzo, Danis, Daniel, Gao, Fei, Horvath, Rita, Johari, Mridul, Johanson, Lennart, Li, Shuang, Morsy, Heba, Nelson, Isabelle, Paramonov, Ida, te Paske, Iris B.A.W., Robinson, Peter, Savarese, Marco, Steyaert, Wouter, Töpf, Ana, van der Velde, Joeri K., Vandrovcova, Jana, Graessner, Holm, Zurek, Birte, Ellwanger, Kornelia, Ossowski, Stephan, Demidov, German, Sturm, Marc, Schulze-Hentrich, Julia M., Schüle, Rebecca, Xu, Jishu, Kessler, Christoph, Wayand, Melanie, Synofzik, Matthis, Wilke, Carlo, Traschütz, Andreas, Schöls, Ludger, Hengel, Holger, Lerche, Holger, Kegele, Josua, Heutink, Peter, Brunner, Han, Scheffer, Hans, Hoogerbrugge, Nicoline, ‘t Hoen, Peter A.C., Vissers, Lisenka E.L.M., Sablauskas, Karolis, de Voer, Richarda M., Kamsteeg, Erik-Jan, van de Warrenburg, Bart, van Os, Nienke, Paske, Iris te, Janssen, Erik, Steehouwer, Marloes, Yaldiz, Burcu, Brookes, Anthony J., Veal, Colin, Gibson, Spencer, Maddi, Vatsalya, Mehtarizadeh, Mehdi, Riaz, Umar, Warren, Greg, Dizjikan, Farid Yavari, Shorter, Thomas, Straub, Volker, Bettolo, Chiara Marini, Manera, Jordi Diaz, Hambleton, Sophie, Engelhardt, Karin, Alexander, Elizabeth, Duffourd, Yannis, Bruel, Ange-Line, Peyron, Christine, Pélissier, Aurore, Beltran, Sergi, Gut, Ivo Glynne, Laurie, Steven, Piscia, Davide, Papakonstantinou, Anastasios, Bullich, Gemma, Corvo, Alberto, Fernandez-Callejo, Marcos, Hernández, Carles, Picó, Daniel, Lochmüller, Hanns, Gumus, Gulcin, Bros-Facer, Virginie, Rath, Ana, Hanauer, Marc, Lagorce, David, Hongnat, Oscar, Chahdil, Maroua, Lebreton, Emeline, Stevanin, Giovanni, Durr, Alexandra, Davoine, Claire-Sophie, Guillot-Noel, Léna, Heinzmann, Anna, Coarelli, Giulia, Bonne, Gisèle, Evangelista, Teresinha, Allamand, Valérie, Ben Yaou, Rabah, Metay, Corinne, Eymard, Bruno, Atalaia, Antonio, Stojkovic, Tanya, Turnovec, Marek, Thomasová, Dana, Kremliková, Radka Pourová, Franková, Vera, Havlovicová, Markéta, Lišková, Petra, Doležalová, Pavla, Parkinson, Helen, Keane, Thomas, Freeberg, Mallory, Thomas, Coline, Spalding, Dylan, Robert, Glenn, Costa, Alessia, Patch, Christine, Hanna, Mike, Houlden, Henry, Reilly, Mary, Efthymiou, Stephanie, Cali, Elisa, Magrinelli, Francesca, Sisodiya, Sanjay M., Rohrer, Jonathan, Muntoni, Francesco, Zaharieva, Irina, Sarkozy, Anna, Timmerman, Vincent, Baets, Jonathan, de Vries, Geert, De Winter, Jonathan, Beijer, Danique, de Jonghe, Peter, Van de Vondel, Liedewei, De Ridder, Willem, Weckhuysen, Sarah, Nigro, Vincenzo, Mutarelli, Margherita, Varavallo, Alessandra, Banfi, Sandro, Musacchia, Francesco, Piluso, Giulio, Ferlini, Alessandra, Selvatici, Rita, Gualandi, Francesca, Bigoni, Stefania, Rossi, Rachele, Neri, Marcella, Aretz, Stefan, Spier, Isabel, Sommer, Anna Katharina, Peters, Sophia, Oliveira, Carla, Pelaez, Jose Garcia, Matos, Ana Rita, José, Celina São, Ferreira, Marta, Gullo, Irene, Fernandes, Susana, Garrido, Luzia, Ferreira, Pedro, Carneiro, Fátima, Swertz, Morris A., Johansson, Lennart, van der Vries, Gerben, Neerincx, Pieter B., Ruvolo, David, Kerstjens Frederikse, Wilhemina S., Zonneveld-Huijssoon, Eveline, Roelofs-Prins, Dieuwke, van Gijn, Marielle, Köhler, Sebastian, Metcalfe, Alison, Drunat, Séverine, Heron, Delphine, Mignot, Cyril, Keren, Boris, Lacombe, Didier, Trimouille, Aurelien, Capella, Gabriel, Valle, Laura, Holinski-Feder, Elke, Laner, Andreas, Steinke-Lange, Verena, Cilio, Maria-Roberta, Carpancea, Evelina, Depondt, Chantal, Lederer, Damien, Sznajer, Yves, Duerinckx, Sarah, Mary, Sandrine, Macaya, Alfons, Cazurro-Gutiérrez, Ana, Pérez-Dueñas, Belén, Munell, Francina, Jarava, Clara Franco, Masó, Laura Batlle, Marcé-Grau, Anna, Colobran, Roger, Hackman, Peter, Udd, Bjarne, Hemelsoet, Dimitri, Dermaut, Bart, Schuermans, Nika, Poppe, Bruce, Verdin, Hannah, Osorio, Andrés Nascimento, Depienne, Christel, Roos, Andreas, Cordts, Isabell, Deschauer, Marcus, Striano, Pasquale, Zara, Federico, Riva, Antonella, Iacomino, Michele, Uva, Paolo, Scala, Marcello, Scudieri, Paolo, Başak, Ayşe Nazlı, Claeys, Kristl, Boztug, Kaan, Haimel, Matthias, W.E, Gijs, Ruivenkamp, Claudia A.L., Natera de Benito, Daniel, Thompson, Rachel, Polavarapu, Kiran, Grimbacher, Bodo, Zaganas, Ioannis, Kokosali, Evgenia, Lambros, Mathioudakis, Evangeliou, Athanasios, Spilioti, Martha, Kapaki, Elisabeth, Bourbouli, Mara, Radio, Francesca Clementina, Balicza, Peter, Molnar, Maria Judit, De la Paz, Manuel Posada, Sánchez, Eva Bermejo, Delgado, Beatriz Martínez, Alonso García de la Rosa, F. Javier, Schröck, Evelin, Rump, Andreas, Mei, Davide, Vetro, Annalisa, Balestrini, Simona, Guerrini, Renzo, Chinnery, Patrick F., Ratnaike, Thiloka, Schon, Katherine, Maver, Ales, Peterlin, Borut, Münchau, Alexander, Lohmann, Katja, Herzog, Rebecca, Pauly, Martje, May, Patrick, Beeson, David, Cossins, Judith, Furini, Simone, Fallerini, Chiara, Benetti, Elisa, Afenjar, Alexandra, Goldenberg, Alice, Masurel, Alice, Phan, Alice, Dieux-Coeslier, Anne, Fargeot, Anne, Guerrot, Anne-Marie, Toutain, Annick, Molin, Arnaud, Sorlin, Arthur, Putoux, Audrey, Jouret, Béatrice, Laudier, Béatrice, Demeer, Bénédicte, Doray, Bérénice, Bonniaud, Bertille, Isidor, Bertrand, Gilbert-Dussardier, Brigitte, Leheup, Bruno, Reversade, Bruno, Paul, Carle, Vincent-Delorme, Catherine, Neiva, Cecilia, Poirsier, Céline, Quélin, Chloé, Chiaverini, Christine, Coubes, Christine, Francannet, Christine, Colson, Cindy, Desplantes, Claire, Wells, Constance, Goizet, Cyril, Sanlaville, Damien, Amram, Daniel, Lehalle, Daphné, Geneviève, David, Gaillard, Dominique, Zivi, Einat, Sarrazin, Elisabeth, Steichen, Elisabeth, Schaefer, Élise, Lacaze, Elodie, Jacquemin, Emmanuel, Bongers, Ernie, Kilic, Esra, Colin, Estelle, Giuliano, Fabienne, Prieur, Fabienne, Laffargue, Fanny, Morice-Picard, Fanny, Petit, Florence, Cartault, François, Feillet, François, Baujat, Geneviève, Morin, Gilles, Diene, Gwenaëlle, Journel, Hubert, Perthus, Isabelle, Lespinasse, James, Alessandri, Jean-Luc, Amiel, Jeanne, Martinovic, Jelena, Delanne, Julian, Albuisson, Juliette, Lambert, Laëtitia, Perrin, Laurence, Ousager, Lilian Bomme, Van Maldergem, Lionel, Pinson, Lucile, Ruaud, Lyse, Samimi, Mahtab, Bournez, Marie, Bonnet-Dupeyron, Marie Noëlle, Vincent, Marie, Jacquemont, Marie-Line, Cordier-Alex, Marie-Pierre, Gérard-Blanluet, Marion, Willems, Marjolaine, Spodenkiewicz, Marta, Doco-Fenzy, Martine, Rossi, Massimiliano, Renaud, Mathilde, Fradin, Mélanie, Mathieu, Michèle, Holder-Espinasse, Muriel H., Houcinat, Nada, Hanna, Nadine, Leperrier, Nathalie, Chassaing, Nicolas, Philip, Nicole, Boute, Odile, Van Kien, Philippe Khau, Parent, Philippe, Bitoun, Pierre, Sarda, Pierre, Vabres, Pierre, Jouk, Pierre-Simon, Touraine, Renaud, El Chehadeh, Salima, Whalen, Sandra, Marlin, Sandrine, Passemard, Sandrine, Grotto, Sarah, Bellanger, Séverine Audebert, Blesson, Sophie, Nambot, Sophie, Naudion, Sophie, Lyonnet, Stanislas, Odent, Sylvie, Attie-Bitach, Tania, Busa, Tiffany, Drouin-Garraud, Valérie, Layet, Valérie, Bizaoui, Varoona, Cusin, Véronica, Capri, Yline, Alembik, Yves, Jean-Marçais, Nolwenn, López-Martín, Estrella, Macek, Milan, Mencarelli, Maria Antonietta, Moutton, Sébastien, Pfundt, Rolph, Safraou, Hana, Thauvin-Robinet, Christel, Thevenon, Julien, Tran Mau-Them, Frédéric, de Vries, Bert B.A., Willemsen, Marjolein H., and Philippe, Christophe

Published
2023
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14. Intermediate repeat expansions of TBP and STUB1: Genetic modifier or pure digenic inheritance in spinocerebellar ataxias?

Author

Barbier, Mathieu, Davoine, Claire-Sophie, Petit, Emilien, Porché, Maximilien, Guillot-Noel, Léna, Sayah, Sabrina, Fauret, Anne-Laure, Neau, Jean-Philippe, Guyant-Maréchal, Lucie, Deffond, Didier, Tranchant, Christine, Goizet, Cyril, Coarelli, Giulia, Castrioto, Anna, Klebe, Stephan, Ewenczyk, Claire, Heinzmann, Anna, Charles, Perrine, Tchikviladzé, Maya, Van Broeckhoven, Christine, Brice, Alexis, and Durr, Alexandra

Published
2023
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15. Safety and efficacy of riluzole in spinocerebellar ataxia type 2 in France (ATRIL): a multicentre, randomised, double-blind, placebo-controlled trial

Author

Coarelli, Giulia, Heinzmann, Anna, Ewenczyk, Claire, Fischer, Clara, Chupin, Marie, Monin, Marie-Lorraine, Hurmic, Hortense, Calvas, Fabienne, Calvas, Patrick, Goizet, Cyril, Thobois, Stéphane, Anheim, Mathieu, Nguyen, Karine, Devos, David, Verny, Christophe, Ricigliano, Vito A G, Mangin, Jean-François, Brice, Alexis, Tezenas du Montcel, Sophie, and Durr, Alexandra

Published
2022
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16. Hedgerow structural diversity is key to promoting biodiversity and ecosystem services: A systematic review of Central European studies.

Author

Kratschmer, Sophie, Hauer, Julia, Zaller, Johann G., Dürr, Alexandra, and Weninger, Thomas

Subjects
WINDBREAKS, shelterbelts, etc., ANIMAL diversity, ECOSYSTEM services, BIODIVERSITY, SEED dispersal, SPECIES diversity, ECOSYSTEMS
Abstract

• Relations among hedgerow structure, biodiversity & ecosystem services are unclear. • We performed a systematic review including 89 studies from Central Europe and UK from 1974 to 2022. • Arthropods & birds, were most often, earthworms & bats least often studied. • Structural diversity, layering & woody vegetation promoted biodiversity. • Connectivity, density & structural complexity improved ecosystem service provision. Agricultural intensification decreases the heterogeneity of the landscape and leads to a decline in hedgerows. As hedgerows provide important habitats for many taxa, this contributes to the loss of biodiversity in agroecosystems. However, the extent to which hedgerows, and in particular their habitat quality in terms of structural characteristics, also influence biodiversity-based ecosystem services is poorly studied. Here, we conducted a systematic review of the Scopus and other literature databases focusing on Central European and UK studies examining (1) the influence of hedgerow habitat quality on the biodiversity of arthropods, earthworms, birds, bats and small mammals and (2) the relationship between selected hedgerow parameters, animal taxa, and ecosystem services such as pollination, seed dispersal, pest and disease control and soil quality regulation. A total of 2260 studies (cut-off date: 13 September 2022) published between 1974 and 2022 were found. After sorting based on inclusion criteria related to the research focus, 89 studies remained for evaluation. Arthropods, birds, and small mammals were studied most frequently, earthworms and bats least frequently. The selected studies showed that structural diversity, layering, woody biomass and density were strongly positively correlated with animal species diversity, while hedgerow length, width and age showed less relevant relationships. Hedgerow connectivity, density, structural diversity, and layering were strongly positive associated with the provision of ecosystem services. We conclude that the structural diversity of hedgerows needs to be increased if their impact on biodiversity and ecosystem service provision is to be improved. It is therefore recommended that hedgerow management measures should specifically consider the ecological importance of the structural diversity of hedgerows. [ABSTRACT FROM AUTHOR]

Published
2024
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19. Progression characteristics of the European Friedreich's Ataxia Consortium for Translational Studies (EFACTS): a 4-year cohort study

Author

Labrum, Robyn, Thomas-Black, Gilbert, Manso, Katarina, Solanky, Nita, Gellera, Cinzia, Mongelli, Alessia, Castaldo, Anna, Fichera, Mario, Palau, Francesc, O'Callaghan, Mar, Biet, Marie, Monin, Marie Lorraine, Eigentler, Andreas, Indelicato, Elisabetta, Amprosi, Matthias, Radelfahr, Florentine, Bischoff, Almut T., Holtbernd, Florian, Brcina, Nikolina, Hohenfeld, Christian, Koutsis, Georgios, Breza, Marianthi, Bertini, Enrico, Vasco, Gessica, Reetz, Kathrin, Dogan, Imis, Hilgers, Ralf-Dieter, Giunti, Paola, Parkinson, Michael H, Mariotti, Caterina, Nanetti, Lorenzo, Durr, Alexandra, Ewenczyk, Claire, Boesch, Sylvia, Nachbauer, Wolfgang, Klopstock, Thomas, Stendel, Claudia, Rodríguez de Rivera Garrido, Francisco Javier, Rummey, Christian, Schöls, Ludger, Hayer, Stefanie N, Klockgether, Thomas, Giordano, Ilaria, Didszun, Claire, Rai, Myriam, Pandolfo, Massimo, and Schulz, Jörg B

Published
2021
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21. Conversion of individuals at risk for spinocerebellar ataxia types 1, 2, 3, and 6 to manifest ataxia (RISCA): a longitudinal cohort study

Author

Jacobi, Heike, du Montcel, Sophie Tezenas, Romanzetti, Sandro, Harmuth, Florian, Mariotti, Caterina, Nanetti, Lorenzo, Rakowicz, Maria, Makowicz, Grzegorz, Durr, Alexandra, Monin, Marie-Lorraine, Filla, Alessandro, Roca, Alessandro, Schöls, Ludger, Hengel, Holger, Infante, Jon, Kang, Jun-Suk, Timmann, Dagmar, Casali, Carlo, Masciullo, Marcella, Baliko, Laszlo, Melegh, Bela, Nachbauer, Wolfgang, Bürk-Gergs, Katrin, Schulz, Jörg B, Riess, Olaf, Reetz, Kathrin, and Klockgether, Thomas

Published
2020
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22. Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis.

Author

van Rheenen, Wouter, Shatunov, Aleksey, Dekker, Annelot M, McLaughlin, Russell L, Diekstra, Frank P, Pulit, Sara L, van der Spek, Rick AA, Võsa, Urmo, de Jong, Simone, Robinson, Matthew R, Yang, Jian, Fogh, Isabella, van Doormaal, Perry Tc, Tazelaar, Gijs HP, Koppers, Max, Blokhuis, Anna M, Sproviero, William, Jones, Ashley R, Kenna, Kevin P, van Eijk, Kristel R, Harschnitz, Oliver, Schellevis, Raymond D, Brands, William J, Medic, Jelena, Menelaou, Androniki, Vajda, Alice, Ticozzi, Nicola, Lin, Kuang, Rogelj, Boris, Vrabec, Katarina, Ravnik-Glavač, Metka, Koritnik, Blaž, Zidar, Janez, Leonardis, Lea, Grošelj, Leja Dolenc, Millecamps, Stéphanie, Salachas, François, Meininger, Vincent, de Carvalho, Mamede, Pinto, Susana, Mora, Jesus S, Rojas-García, Ricardo, Polak, Meraida, Chandran, Siddharthan, Colville, Shuna, Swingler, Robert, Morrison, Karen E, Shaw, Pamela J, Hardy, John, Orrell, Richard W, Pittman, Alan, Sidle, Katie, Fratta, Pietro, Malaspina, Andrea, Topp, Simon, Petri, Susanne, Abdulla, Susanne, Drepper, Carsten, Sendtner, Michael, Meyer, Thomas, Ophoff, Roel A, Staats, Kim A, Wiedau-Pazos, Martina, Lomen-Hoerth, Catherine, Van Deerlin, Vivianna M, Trojanowski, John Q, Elman, Lauren, McCluskey, Leo, Basak, A Nazli, Tunca, Ceren, Hamzeiy, Hamid, Parman, Yesim, Meitinger, Thomas, Lichtner, Peter, Radivojkov-Blagojevic, Milena, Andres, Christian R, Maurel, Cindy, Bensimon, Gilbert, Landwehrmeyer, Bernhard, Brice, Alexis, Payan, Christine AM, Saker-Delye, Safaa, Dürr, Alexandra, Wood, Nicholas W, Tittmann, Lukas, Lieb, Wolfgang, Franke, Andre, Rietschel, Marcella, Cichon, Sven, Nöthen, Markus M, Amouyel, Philippe, Tzourio, Christophe, Dartigues, Jean-François, Uitterlinden, Andre G, Rivadeneira, Fernando, Estrada, Karol, Hofman, Albert, Curtis, Charles, and Blauw, Hylke M

Subjects
PARALS Registry, SLALOM Group, SLAP Registry, FALS Sequencing Consortium, SLAGEN Consortium, NNIPPS Study Group, Humans, Amyotrophic Lateral Sclerosis, Genetic Predisposition to Disease, Proteins, Cytoskeletal Proteins, Myelin Proteins, Case-Control Studies, Cohort Studies, Mutation, Netherlands, Munc18 Proteins, Genome-Wide Association Study, Neurosciences, Rare Diseases, Brain Disorders, Biotechnology, Prevention, Human Genome, Neurodegenerative, Genetics, ALS, Aetiology, 2.1 Biological and endogenous factors, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

To elucidate the genetic architecture of amyotrophic lateral sclerosis (ALS) and find associated loci, we assembled a custom imputation reference panel from whole-genome-sequenced patients with ALS and matched controls (n = 1,861). Through imputation and mixed-model association analysis in 12,577 cases and 23,475 controls, combined with 2,579 cases and 2,767 controls in an independent replication cohort, we fine-mapped a new risk locus on chromosome 21 and identified C21orf2 as a gene associated with ALS risk. In addition, we identified MOBP and SCFD1 as new associated risk loci. We established evidence of ALS being a complex genetic trait with a polygenic architecture. Furthermore, we estimated the SNP-based heritability at 8.5%, with a distinct and important role for low-frequency variants (frequency 1-10%). This study motivates the interrogation of larger samples with full genome coverage to identify rare causal variants that underpin ALS risk.

Published
2016

24. Hecken und ihre Ökosystemleistungen Einführung und Anwendung des Bewertungssystems Heck.in.

Author

Dürr, Alexandra, Weninger, Thomas, Loicht, Johanna, and Strauss, Peter

Abstract

In rural landscapes, hedgerows and windbreaks play a critical role in providing various ecosystem services. The functionality of these landscape elements depends on their structural characteristics and their placement in the landscape. Heck.in is a practically applicable evaluation system for hedgerows and windbreaks in cultural landscapes, based on scientific findings. It allows the quantification of ecosystem services. For this purpose, correlations between structural and site indicators with the provision of ecosystem services are described based on scientific findings and are summarized in a quantitative assessment scheme. By using Heck.in, an assessment of hedgerows can easily be carried out by both experts and non-specialists. The result is presented in the form of a graph and quantitative values covering 13 different ecosystem services. This allows identification of outstanding services as well as weak points in individual hedgerows, assessment of the impact of maintenance measures on functionality, and the making of comparisons. The scoring system was successfully tested in a regional study and proved to be practicable and differentiating. Future applications of Heck.in could be in planning processes, scientific studies, and educational campaigns for people of different ages and interest groups. [ABSTRACT FROM AUTHOR]

Published
2024
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25. Spinocerebellar ataxia type 7 (SCA7)

Author

Stevanin, Giovanni, primary, David, Gilles, additional, Abbas, Nacer, additional, Dürr, Alexandra, additional, Holmberg, Monica, additional, Duyckaerts, Charles, additional, Giunti, Paola., additional, Cancel, Géraldine, additional, Ruberg, Merle, additional, Mandel, Jean-Louis, additional, and Brice, Alexis, additional

Published
2020
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26. PTPA variants and impaired PP2A activity in early-onset parkinsonism with intellectual disability

Author

Fevga, Christina, Tesson, Christelle, Carreras Mascaro, Ana, Courtin, Thomas, Van Coller, Riaan, Sakka, Salma, Ferraro, Federico, Farhat, Nouha, Bardien, Soraya, Damak, Mariem, Carr, Jonathan, Ferrien, Melanie, Boumeester, Valerie, Hundscheid, Jasmijn, Grillenzoni, Nicola, Kessissoglou, Irini A., Kuipers, Demy J.S., Quadri, Marialuisa, Agid, Yves, Anheim, Mathieu, Borg, Michel, Brice, Alexis, Broussolle, Emmanuel, Corvol, Jean Christophe, Damier, Philippe, Defebvre, Luc, Dürr, Alexandra, Durif, Franck, Houeto, Jean Luc, Krack, Paul, Klebe, Stephan, Lesage, Suzanne, Lohmann, Ebba, Martinez, Maria, Mangone, Graziella, Mariani, Louise Laure, Pollak, Pierre, Rascol, Olivier, Tison, François, Tranchant, Christine, Verin, Marc, Viallet, François, Vidailhet, Marie, Emre, Murat, Hanagasi, Hasmet, Bilgic, Basar, Lu, Bedia Marangozog, Benmahdjoub, Mustapha, Arezki, Mohammed, Bouchetara, Sofiane A., Benhassine, Traki, Tazir, Meriem, Djebara, Mouna Ben, Gouider, Riadh, Romdhan, Sawssan Ben, Mhiri, Chokri, Bouhouche, Ahmed, Bonifati, Vincenzo, Mandemakers, Wim, Kievit, Anneke J.A., Boon, Agnita J.W., Ferreira, Joaquim J., Guedes, Leonor Correia, Hanagasi, Hasmet A., Tufekcioglu, Zeynep, Elibol, Bulent, Dog.u, Okan, Gultekin, Murat, Chien, Hsin F., Barbosa, Egberto, Jardim, Laura Bannach, Rieder, Carlos R.M., Chang, Hsiu Chen, Lu, Chin Song, Wu-Chou, Yah Huei, Yeh, Tu Hsueh, Lopiano, Leonardo, Tassorelli, Cristina, Pacchetti, Claudio, Comi, Cristoforo, Raudino, Francesco, Bertolasi, Laura, Tinazzi, Michele, Bonizzato, Alberto, Ferracci, Carlo, Marconi, Roberto, Guidi, Marco, Onofrj, Marco, Thomas, Astrid, Vanacore, Nicola, Meco, Giuseppe, Fabrizio, Edito, Fabbrini, Giovanni, Berardelli, Alfredo, Stocchi, Fabrizio, Vacca, Laura, Barone, Paolo, Picillo, Marina, De Michele, Giuseppe, Criscuolo, Chiara, De Mari, Michele, Dell'aquila, Claudia, Iliceto, Giovanni, Toni, Vincenzo, Trianni, Giorgio, Saddi, Valeria, Cossu, Gianni, Melis, Maurizio, Hassan, Bassem A., Breedveld, Guido J., Erasmus University Medical Center [Rotterdam] (Erasmus MC), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Génétique médicale [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Faculty of Health Sciences [Pretoria], University of Pretoria [South Africa], Hopital Habib Bourguiba - Habib Bourguiba Hospital [Sfax], Stellenbosch University, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Motivation, cerveau et comportement = Motivation, Brain and Behavior [ICM Paris] (MBB), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Tesson, Christelle, Clinical Genetics, and Neurology

Subjects
[SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, intellectual disability, PTPA, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], PPP2R4, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, parkinsonism, PP2A
Abstract

The protein phosphatase 2A complex (PP2A), the major Ser/Thr phosphatase in the brain, is involved in a number of signalling pathways and functions, including the regulation of crucial proteins for neurodegeneration, such as alpha-synuclein, tau and LRRK2. Here, we report the identification of variants in the PTPA/PPP2R4 gene, encoding a major PP2A activator, in two families with early-onset parkinsonism and intellectual disability. We carried out clinical studies and genetic analyses, including genome-wide linkage analysis, whole-exome sequencing, and Sanger sequencing of candidate variants. We next performed functional studies on the disease-associated variants in cultured cells and knock-down of ptpa in Drosophila melanogaster. We first identified a homozygous PTPA variant, c.893T>G (p.Met298Arg), in patients from a South African family with early-onset parkinsonism and intellectual disability. Screening of a large series of additional families yielded a second homozygous variant, c.512C>A (p.Ala171Asp), in a Libyan family with a similar phenotype. Both variants co-segregate with disease in the respective families. The affected subjects display juvenile-onset parkinsonism and intellectual disability. The motor symptoms were responsive to treatment with levodopa and deep brain stimulation of the subthalamic nucleus. In overexpression studies, both the PTPA p.Ala171Asp and p.Met298Arg variants were associated with decreased PTPA RNA stability and decreased PTPA protein levels; the p.Ala171Asp variant additionally displayed decreased PTPA protein stability. Crucially, expression of both variants was associated with decreased PP2A complex levels and impaired PP2A phosphatase activation. PTPA orthologue knock-down in Drosophila neurons induced a significant impairment of locomotion in the climbing test. This defect was age-dependent and fully reversed by L-DOPA treatment. We conclude that bi-allelic missense PTPA variants associated with impaired activation of the PP2A phosphatase cause autosomal recessive early-onset parkinsonism with intellectual disability. Our findings might also provide new insights for understanding the role of the PP2A complex in the pathogenesis of more common forms of neurodegeneration.

Published
2023

27. Survival in patients with spinocerebellar ataxia types 1, 2, 3, and 6 (EUROSCA): a longitudinal cohort study

Author

Diallo, Alhassane, Jacobi, Heike, Cook, Arron, Labrum, Robyn, Durr, Alexandra, Brice, Alexis, Charles, Perrine, Marelli, Cecilia, Mariotti, Caterina, Nanetti, Lorenzo, Panzeri, Marta, Rakowicz, Maria, Sobanska, Anna, Sulek, Anna, Schmitz-Hübsch, Tanja, Schöls, Ludger, Hengel, Holger, Melegh, Bela, Filla, Alessandro, Antenora, Antonella, Infante, Jon, Berciano, José, van de Warrenburg, Bart P, Timmann, Dagmar, Boesch, Sylvia, Pandolfo, Massimo, Schulz, Jörg B, Bauer, Peter, Giunti, Paola, Kang, Jun-Suk, Klockgether, Thomas, and Tezenas du Montcel, Sophie

Published
2018
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28. Hereditary Spastic Paraplegia Type 43 (SPG43) is Caused by Mutation in C19orf12

Author

Landouré, Guida, Zhu, Peng‐Peng, Lourenço, Charles M, Johnson, Janel O, Toro, Camilo, Bricceno, Katherine V, Rinaldi, Carlo, Meilleur, Katherine G, Sangaré, Modibo, Diallo, Oumarou, Pierson, Tyler M, Ishiura, Hiroyuki, Tsuji, Shoji, Hein, Nichole, Fink, John K, Stoll, Marion, Nicholson, Garth, Gonzalez, Michael A, Speziani, Fiorella, Dürr, Alexandra, Stevanin, Giovanni, Biesecker, Leslie G, Center, for the NIH Intramural Sequencing, Accardi, John, Landis, Dennis MD, Gahl, William A, Traynor, Bryan J, Marques, Wilson, Züchner, Stephan, Blackstone, Craig, Fischbeck, Kenneth H, and Burnett, Barrington G

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Genetics, Rare Diseases, Neurosciences, Human Genome, Clinical Research, Neurodegenerative, Aetiology, 2.1 Biological and endogenous factors, Adolescent, Amino Acid Sequence, Brain, Homozygote, Humans, Intracellular Space, Magnetic Resonance Imaging, Male, Mitochondrial Proteins, Molecular Sequence Data, Mutation, Protein Transport, Sequence Alignment, Sequence Deletion, Spastic Paraplegia, Hereditary, SPG43, NBIA, C19orf12, hereditary spastic paraplegia, NIH Intramural Sequencing Center, Clinical Sciences, Genetics & Heredity, Clinical sciences
Abstract

We report here the genetic basis for a form of progressive hereditary spastic paraplegia (SPG43) previously described in two Malian sisters. Exome sequencing revealed a homozygous missense variant (c.187G>C; p.Ala63Pro) in C19orf12, a gene recently implicated in neurodegeneration with brain iron accumulation (NBIA). The same mutation was subsequently also found in a Brazilian family with features of NBIA, and we identified another NBIA patient with a three-nucleotide deletion (c.197_199del; p.Gly66del). Haplotype analysis revealed that the p.Ala63Pro mutations have a common origin, but MRI scans showed no brain iron deposition in the Malian SPG43 subjects. Heterologous expression of these SPG43 and NBIA variants resulted in similar alterations in the subcellular distribution of C19orf12. The SPG43 and NBIA variants reported here as well as the most common C19orf12 missense mutation reported in NBIA patients are found within a highly conserved, extended hydrophobic domain in C19orf12, underscoring the functional importance of this domain.

Published
2013

31. Genome-wide association study identifies a new susceptibility locus inPLA2G4Cfor Multiple System Atrophy

Author

Nakahara, Yasuo, primary, Mitsui, Jun, additional, Date, Hidetoshi, additional, Porto, Kristine Joyce, additional, Hayashi, Yasuhiro, additional, Yamashita, Atsushi, additional, Kusakabe, Yoshio, additional, Matsukawa, Takashi, additional, Ishiura, Hiroyuki, additional, Yasuda, Tsutomu, additional, Iwata, Atsushi, additional, Goto, Jun, additional, Ichikawa, Yaeko, additional, Momose, Yoshio, additional, Takahashi, Yuji, additional, Toda, Tatsushi, additional, Ohta, Rikifumi, additional, Yoshimura, Jun, additional, Morishita, Shinichi, additional, Gustavsson, Emil K, additional, Christy, Darren, additional, Maczis, Melissa, additional, Farrer, Matthew J., additional, Kim, Han-Joon, additional, Park, Sung-Sup, additional, Jeon, Beomseok, additional, Zhang, Jin, additional, Gu, Weihong, additional, Scholz, Sonja W., additional, Singleton, Andrew B., additional, Houlden, Henry, additional, Yabe, Ichiro, additional, Sasaki, Hidenao, additional, Matsushima, Masaaki, additional, Takashima, Hiroshi, additional, Kikuchi, Akio, additional, Aoki, Masashi, additional, Hara, Kenju, additional, Kakita, Akiyoshi, additional, Yamada, Mitsunori, additional, Takahashi, Hitoshi, additional, Onodera, Osamu, additional, Nishizawa, Masatoyo, additional, Watanabe, Hirohisa, additional, Ito, Mizuki, additional, Sobue, Gen, additional, Ishikawa, Kinya, additional, Mizusawa, Hidehiro, additional, Kanai, Kazuaki, additional, Kuwabara, Satoshi, additional, Arai, Kimihito, additional, Koyano, Shigeru, additional, Kuroiwa, Yoshiyuki, additional, Hasegawa, Kazuko, additional, Yuasa, Tatsuhiko, additional, Yasui, Kenichi, additional, Nakashima, Kenji, additional, Ito, Hijiri, additional, Izumi, Yuishin, additional, Kaji, Ryuji, additional, Kato, Takeo, additional, Kusunoki, Susumu, additional, Osaki, Yasushi, additional, Horiuchi, Masahiro, additional, Yamamoto, Ken, additional, Shimada, Mihoko, additional, Miyagawa, Taku, additional, Kawai, Yosuke, additional, Nishida, Nao, additional, Tokunaga, Katsushi, additional, Dürr, Alexandra, additional, Brice, Alexis, additional, Filla, Alessandro, additional, Klockgether, Thomas, additional, Wüllner, Ullrich, additional, Tanner, Caroline M., additional, Kukull, Walter A., additional, Lee, Virginia M.-Y., additional, Masliah, Eliezer, additional, Low, Phillip A., additional, Sandroni, Paola, additional, Ozelius, Laurie, additional, Foroud, Tatiana, additional, and Tsuji, Shoji, additional

Published
2023
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32. Heck.in. Hecken und ihre Ökosystemleistungen - eine Bewertung anhand von Indikatoren

Author

Dürr Alexandra, Loicht Johanna, Strauss Peter, Hösl Rosemarie, and Weninger Thomas

Subjects
Windbreak, Hedgerow, Soil Protection, Landscape Ecology, Ecosystem Services, Ecological Assessment
Abstract

Structural elements in rural landscapes, such as hedgerows and windbreaks, provide a range of ecosystem services.The potential for their functionality is determined by structural characteristics and placement in the landscape.Heck.in is a scientifically based and ready-to-use assessment system for hedgerows or windbreaks in rural landscapes that quantifies the fulfillment of ecosystem services. The relationships between structural and locational indicators with ecosystem service delivery have been described based on results from scientific work around the world and combined into a quantitative assessment scheme. With this scheme a hedgerow can be easily evaluated by interested laymen, as a result a classification of 13 different ecosystem services is given in graphical and quantitative form. On this basis, particularly pronounced services or weak points of individual hedges can be made visible, the impact of maintenance measures on functionality can be estimated and comparisons can be made. The application can be made in scientific studies, planning procedures or in the context of training campaigns with all age and interest groups. ZIP-Package contains: - Manual and project description - long version (100 p) - Technical manual for field assessment (24 p) - Form for hedgerow assessment - Model file for hedgerow assessment ************************************************************************************************************************************* Strukturelemente in ländlichen Landschaften, wie Hecken und Windschutzstreifen, erfüllen eine Reihe von Ökosystemleistungen.Das Potenzial für ihre Funktionalität wird durch strukturelle Eigenschaften und die Anordnung in der Landschaft bestimmt.Heck.in ist ein wissenschaftlich fundiertes und anwendungsbereites Bewertungssystem für Hecken oder Windschutzstreifen in ländlichen Landschaften, das die Erfüllung von Ökosystemleistungen quantifiziert. Die Zusammenhänge zwischen strukturellen und Lageindikatoren mit der Erbringung von Ökosystemleistungen wurden auf der Basis von Ergebnissen aus wissenschaftlichen Arbeiten aus aller Welt beschrieben und in einem quantitativen Bewertungsschema zusammengeführt. Mit diesem Schema kann eine Hecke von interessierten Laien einfach bewertet werden, als Ergebnis wird eine Klassifizierung von 13 verschiedenen Ökosystemleistungen in graphischer und quantitativer Form ausgegeben. Auf dieser Basis können besonders ausgeprägte Leistungen oder Schwachpunkte einzelner Hecken sichtbar gemacht werden, die Auswirkung von Pflegemaßnahmen auf die Funktionalität abgeschätzt werden und Vergleiche können gezogen werden. Die Anwendung kann in wissenschaftlichen Studien, Planungsverfahren oder im Rahmen von Schulungsaktionen mit allen Alters- und Interessensgruppen erfolgen. ZIP-Package beinhaltet: - Manual und Projektbeschreibung - Langfassung(100 p) - Kurzfassung /Kartieranleitung(24 p) - Formular für Heckenbewertung - Eingabe- und Berechnungsdatei mit Bewertungsmodell

Published
2023
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33. De Novo and Dominantly Inherited <scp> SPTAN1 </scp> Mutations Cause Spastic Paraplegia and Cerebellar Ataxia

Author

Van de Vondel, Liedewei, De Winter, Jonathan, Deconinck, Tine, Vural, Atay, Ertan, Sibel, Dogu, Okan, Uysal, Hilmi, Brankovic, Vesna, Herzog, Rebecca, Brice, Alexis, Dürr, Alexandra, Klebe, Stephan, Beijer, Danique, Stock, Friedrich, Bischoff, Almut Turid, Rattay, Tim W, Sobrido, María-Jesús, De Michele, Giovanna, De Jonghe, Peter, Klopstock, Thomas, Lohmann, Katja, Zanni, Ginevra, Santorelli, Filippo M, Coarelli, Giulia, Timmerman, Vincent, Haack, Tobias B, Züchner, Stephan, Consortium, PREPARE, Schüle, Rebecca, Stevanin, Giovanni, Synofzik, Matthis, Basak, A Nazli, Baets, Jonathan, Wayand, Melanie, Palvadeau, Robin, Pauly, Martje G, Klein, Katrin, Rautenberg, Maren, Guillot-Noël, Léna, and PREPARE Consortium

Subjects
spastic paraplegia, Cerebellar Ataxia, genetics [Spectrin], Medizin, genetics [Mutation], genetics [Carrier Proteins], Article, genetics [Paraplegia], genetics [Spastic Paraplegia, Hereditary], Intellectual Disability, Humans, ddc:610, Paraplegia, genetics [Cerebellar Ataxia], Spastic Paraplegia, Hereditary, ataxia, Microfilament Proteins, rare diseases, Spectrin, Pedigree, spectrin, Phenotype, Neurology, Mutation, next-generation sequencing, Human medicine, Neurology (clinical), genetics [Intellectual Disability], genetics [Microfilament Proteins], Carrier Proteins
Abstract

Background Pathogenic variants in SPTAN1 have been linked to a remarkably broad phenotypical spectrum. Clinical presentations include epileptic syndromes, intellectual disability, and hereditary motor neuropathy. Objectives We investigated the role of SPTAN1 variants in rare neurological disorders such as ataxia and spastic paraplegia. Methods We screened 10,000 NGS datasets across two international consortia and one local database, indicative of the level of international collaboration currently required to identify genes causative for rare disease. We performed in silico modeling of the identified SPTAN1 variants. Results We describe 22 patients from 14 families with five novel SPTAN1 variants. Of six patients with cerebellar ataxia, four carry a de novo SPTAN1 variant and two show a sporadic inheritance. In this group, one variant (p.Lys2083del) is recurrent in four patients. Two patients have novel de novo missense mutations (p.Arg1098Cys, p.Arg1624Cys) associated with cerebellar ataxia, in one patient accompanied by intellectual disability and epilepsy. We furthermore report a recurrent missense mutation (p.Arg19Trp) in 15 patients with spastic paraplegia from seven families with a dominant inheritance pattern in four and a de novo origin in one case. One further patient carrying a de novo missense mutation (p.Gln2205Pro) has a complex spastic ataxic phenotype. Through protein modeling we show that mutated amino acids are located at crucial interlinking positions, interconnecting the three-helix bundle of a spectrin repeat. Conclusions We show that SPTAN1 is a relevant candidate gene for ataxia and spastic paraplegia. We suggest that for the mutations identified in this study, disruption of the interlinking of spectrin helices could be a key feature of the pathomechanism. © 2022 International Parkinson and Movement Disorder Society

Published
2022

36. No genetic association between attention-deficit/hyperactivity disorder (ADHD) and Parkinson’s disease in nine ADHD candidate SNPs

Author

Geissler, Julia M., Romanos, Marcel, Gerlach, Manfred, Berg, Daniela, Schulte, Claudia, Nalls, Mike, Plagnol, Vincent, Hernandez, Dena G., Sharma, Manu, Sheerin, Una-Marie, Saad, Mohamad, Simón-Sánchez, Javier, Schulte, Claudia, Lesage, Suzanne, Sveinbjörnsdóttir, Sigurlaug, Arepalli, Sampath, Barker, Roger, Ben-Shlomo, Yoav, Berendse, Henk W., Berg, Daniela, Bhatia, Kailash, de Bie, Rob M. A., Biffi, Alessandro, Bloem, Bas, Bochdanovits, Zoltan, Bonin, Michael, Bras, Jose M., Brockmann, Kathrin, Brooks, Janet, Burn, David J., Charlesworth, Gavin, Chen, Honglei, Chinnery, Patrick F., Chong, Sean, Clarke, Carl E., Cookson, Mark R., Cooper, J. Mark, Corvol, Jean Christophe, Counsell, Carl, Damier, Philippe, Dartigues, Jean-François, Deloukas, Panos, Deuschl, Günther, Dexter, David T., van Dijk, Karin D., Dillman, Allissa, Durif, Frank, Dürr, Alexandra, Edkins, Sarah, Evans, Jonathan R., Foltynie, Thomas, Gao, Jianjun, Gardner, Michelle, Gibbs, J. Raphael, Goate, Alison, Gray, Emma, Guerreiro, Rita, Gústafsson, Ómar, Harris, Clare, van Hilten, Jacobus J., Hofman, Albert, Hollenbeck, Albert, Holton, Janice, Hu, Michele, Huang, Xuemei, Huber, Heiko, Hudson, Gavin, Hunt, Sarah E., Huttenlocher, Johanna, Illig, Thomas, Jónsson, Pálmi V., Lambert, Jean-Charles, Langford, Cordelia, Lees, Andrew, Lichtner, Peter, Limousin, Patricia, Lopez, Grisel, Lorenz, Delia, McNeill, Alisdair, Moorby, Catriona, Moore, Matthew, Morris, Huw R., Morrison, Karen E., Mudanohwo, Ese, O’Sullivan, Sean S., Pearson, Justin, Perlmutter, Joel S., Pétursson, Hjörvar, Pollak, Pierre, Post, Bart, Potter, Simon, Ravina, Bernard, Revesz, Tamas, Riess, Olaf, Rivadeneira, Fernando, Rizzu, Patrizia, Ryten, Mina, Sawcer, Stephen, Schapira, Anthony, Scheffer, Hans, Shaw, Karen, Shoulson, Ira, Sidransky, Ellen, Smith, Colin, Spencer, Chris C. A., Stefánsson, Hreinn, Steinberg, Stacy, Stockton, Joanna D., Strange, Amy, Talbot, Kevin, Tanner, Carlie M., Tashakkori-Ghanbaria, Avazeh, Tison, François, Trabzuni, Daniah, Traynor, Bryan J., Uitterlinden, André G., Velseboer, Daan, Vidailhet, Marie, Walker, Robert, van de Warrenburg, Bart, Wickremaratchi, Mirdhu, Williams, Nigel, Williams-Gray, Caroline H., Winder-Rhodes, Sophie, Stefánsson, Kári, Martinez, Maria, Hardy, John, Heutink, Peter, Brice, Alexis, Gasser, Thomas, Singleton, Andrew B., Wood, Nicholas W., and International Parkinson Disease Genomics Consortium members

Published
2017
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37. Solving unsolved rare neurological diseases-a Solve-RD viewpoint

Author

Schüle, Rebecca, Timmann, Dagmar, Erasmus, Corrie E., Reichbauer, Jennifer, Wayand, Melanie, Solve-RD-DITF-RND Baets Jonathan Balicza Peter Chinnery Patrick Dürr Alexandra Haack Tobias Hengel Holger Horvath Rita Houlden Henry Kamsteeg Erik-Jan Kamsteeg Christoph Lohmann Katja Macaya Alfons Marcé-Grau Anna Maver Ales Molnar Judit Münchau Alexander Peterlin Borut Riess Olaf Schöls Ludger European Reference Network for Rare Neurological Diseases, Tübingen, Germany Schüle Rebecca European Reference Network for Rare Neurological Diseases, Tübingen, Germany Stevanin Giovanni Synofzik Matthis European Reference Network for Rare Neurological Diseases, Tübingen, Germany Timmerman Vincent van de Warrenburg Bart Department of Neurology, Donders Centre for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen, The Netherlands van Os Nienke Vandrovcova Jana Wayand Melanie German Center for Neurodegenerative Diseases (DZNE), University of Tübingen, Tübingen, Germany Wilke Carlo German Center for Neurodegenerative Diseases (DZNE), University of Tübingen, Tübingen, Germany, Baets, Jonathan, Balicza, Peter, Chinnery, Patrick, Dürr, Alexandra, Haack, Tobias, Hengel, Holger, Horvath, Rita, Houlden, Henry, Kamsteeg, Erik-Jan, Kamsteeg, Christoph, Lohmann, Katja, Macaya, Alfons, Marcé-Grau, Anna, Maver, Ales, Molnar, Judit, Münchau, Alexander, Peterlin, Borut, Riess, Olaf, Schöls, Ludger, Stevanin, Giovanni, Synofzik, Matthis, Timmerman, Vincent, van de Warrenburg, Bart, van Os, Nienke, Vandrovcova, Jana, Wilke, Carlo, Bevot, Andrea, Zuchner, Stephan, Beltran, Sergi, Laurie, Steven, Matalonga, Leslie, Graessner, Holm, The Solve-RD Consortium Graessner Holm Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany Zurek Birte Ellwanger Kornelia Ossowski Stephan Demidov German Sturm Marc Schulze-Hentrich Julia M. Heutink Peter Brunner Han Scheffer Hans Hoogerbrugge Nicoline Hoischen Alexander ’t Hoen Peter A. C. Vissers Lisenka E. L. M. Gilissen Christian Steyaert Wouter Sablauskas Karolis de Voer Richarda M. Janssen Erik de Boer Elke Steehouwer Marloes Yaldiz Burcu Kleefstra Tjitske Brookes Anthony J. Veal Colin Gibson Spencer Wadsley Marc Mehtarizadeh Mehdi Riaz Umar Warren Greg Dizjikan Farid Yavari Shorter Thomas Töpf Ana Straub Volker Bettolo Chiara Marini Specht Sabine Clayton-Smith Jill Banka Siddharth Alexander Elizabeth Jackson Adam Faivre Laurence Thauvin Christel Vitobello Antonio Denommé-Pichon Anne-Sophie Duffourd Yannis Tisserant Emilie Bruel Ange-Line Peyron Christine Pélissier Aurore Beltran Sergi Facultat de Biologia, Departament de Genètica, Microbiologia i Estadística, Universitat de Barcelona (UB), Barcelona, Spain Gut Ivo Glynne Laurie Steven CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain Piscia Davide Matalonga Leslie CNAG-CRG, Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology (BIST), Barcelona, Spain Papakonstantinou Anastasios Bullich Gemma Corvo Alberto Garcia Carles Fernandez-Callejo Marcos Hernández Carles Picó Daniel Paramonov Ida Lochmüller Hanns Gumus Gulcin Bros-Facer Virginie Rath Ana Hanauer Marc Olry Annie Lagorce David Havrylenko Svitlana Izem Katia Rigour Fanny Durr Alexandra Davoine Claire-Sophie Guillot-Noel Léna Heinzmann Anna Coarelli Giulia Bonne Gisèle Evangelista Teresinha Allamand Valérie Nelson Isabelle Yaou Rabah Ben Metay Corinne Eymard Bruno Cohen Enzo Atalaia Antonio Stojkovic Tanya Macek Milan Jr. Turnovec Marek Thomasová Dana Kremliková Radka Pourová Franková Vera Havlovicová Markéta Kremlik Vlastimil Parkinson Helen Keane Thomas Spalding Dylan Senf Alexander Robinson Peter Danis Daniel Robert Glenn Costa Alessia Patch Christine Hanna Mike Houlden Henry Reilly Mary Vandrovcova Jana Muntoni Francesco Zaharieva Irina Sarkozy Anna de Jonghe Peter Nigro Vincenzo Banfi Sandro Torella Annalaura Musacchia Francesco Piluso Giulio Ferlini Alessandra Selvatici Rita Rossi Rachele Neri Marcella Aretz Stefan Spier Isabel Sommer Anna Katharina Peters Sophia Oliveira Carla Pelaez Jose Garcia Matos Ana Rita José Celina São Ferreira Marta Gullo Irene Fernandes Susana Garrido Luzia Ferreira Pedro Carneiro Fátima Swertz Morris A. Johansson Lennart van der Velde Joeri K. van der Vries Gerben Neerincx Pieter B. Roelofs-Prins Dieuwke Köhler Sebastian Metcalfe Alison Verloes Alain Drunat Séverine Rooryck Caroline Trimouille Aurelien Castello Raffaele Morleo Manuela Pinelli Michele Varavallo Alessandra De la Paz Manuel Posada Sánchez Eva Bermejo Martín Estrella López Delgado Beatriz Martínez de la Rosa F. Javier Alonso García Ciolfi Andrea Dallapiccola Bruno Pizzi Simone Radio Francesca Clementina Tartaglia Marco Renieri Alessandra Benetti Elisa Balicza Peter Molnar Maria Judit Maver Ales Peterlin Borut Münchau Alexander Lohmann Katja Herzog Rebecca Pauly Martje Macaya Alfons Marcé-Grau Anna Osorio Andres Nascimiento de Benito Daniel Natera Lochmüller Hanns Thompson Rachel Polavarapu Kiran Beeson David Cossins Judith Cruz Pedro M. Rodriguez Hackman Peter Johari Mridul Savarese Marco Udd Bjarne Horvath Rita Capella Gabriel Valle Laura Holinski-Feder Elke Laner Andreas Steinke-Lange Verena Schröck Evelin Rump Andreas, Zurek, Birte, Ellwanger, Kornelia, Ossowski, Stephan, Demidov, German, Sturm, Marc, Schulze-Hentrich, Julia M., Heutink, Peter, Brunner, Han, Scheffer, Hans, Hoogerbrugge, Nicoline, Hoischen, Alexander, ’t Hoen, Peter A. C., Vissers, Lisenka E. L. M., Gilissen, Christian, Steyaert, Wouter, Sablauskas, Karolis, de Voer, Richarda M., Janssen, Erik, de Boer, Elke, Steehouwer, Marloes, Yaldiz, Burcu, Kleefstra, Tjitske, Brookes, Anthony J., Veal, Colin, Gibson, Spencer, Wadsley, Marc, Mehtarizadeh, Mehdi, Riaz, Umar, Warren, Greg, Dizjikan, Farid Yavari, Shorter, Thomas, Töpf, Ana, Straub, Volker, Bettolo, Chiara Marini, Specht, Sabine, Clayton-Smith, Jill, Banka, Siddharth, Alexander, Elizabeth, Jackson, Adam, Faivre, Laurence, Thauvin, Christel, Vitobello, Antonio, Denommé-Pichon, Anne-Sophie, Duffourd, Yannis, Tisserant, Emilie, Bruel, Ange-Line, Peyron, Christine, Pélissier, Aurore, Gut, Ivo Glynne, Piscia, Davide, Papakonstantinou, Anastasios, Bullich, Gemma, Corvo, Alberto, Garcia, Carles, Fernandez-Callejo, Marcos, Hernández, Carles, Picó, Daniel, Paramonov, Ida, Lochmüller, Hanns, Gumus, Gulcin, Bros-Facer, Virginie, Rath, Ana, Hanauer, Marc, Olry, Annie, Lagorce, David, Havrylenko, Svitlana, Izem, Katia, Rigour, Fanny, Durr, Alexandra, Davoine, Claire-Sophie, Guillot-Noel, Léna, Heinzmann, Anna, Coarelli, Giulia, Bonne, Gisèle, Evangelista, Teresinha, Allamand, Valérie, Nelson, Isabelle, Yaou, Rabah Ben, Metay, Corinne, Eymard, Bruno, Cohen, Enzo, Atalaia, Antonio, Stojkovic, Tanya, Macek, Milan, Turnovec, Marek, Thomasová, Dana, Kremliková, Radka Pourová, Franková, Vera, Havlovicová, Markéta, Kremlik, Vlastimil, Parkinson, Helen, Keane, Thomas, Spalding, Dylan, Senf, Alexander, Robinson, Peter, Danis, Daniel, Robert, Glenn, Costa, Alessia, Patch, Christine, Hanna, Mike, Reilly, Mary, Muntoni, Francesco, Zaharieva, Irina, Sarkozy, Anna, de Jonghe, Peter, Nigro, Vincenzo, Banfi, Sandro, Torella, Annalaura, Musacchia, Francesco, Piluso, Giulio, Ferlini, Alessandra, Selvatici, Rita, Rossi, Rachele, Neri, Marcella, Aretz, Stefan, Spier, Isabel, Sommer, Anna Katharina, Peters, Sophia, Oliveira, Carla, Pelaez, Jose Garcia, Matos, Ana Rita, José, Celina São, Ferreira, Marta, Gullo, Irene, Fernandes, Susana, Garrido, Luzia, Ferreira, Pedro, Carneiro, Fátima, Swertz, Morris A., Johansson, Lennart, van der Velde, Joeri K., van der Vries, Gerben, Neerincx, Pieter B., Roelofs-Prins, Dieuwke, Köhler, Sebastian, Metcalfe, Alison, Verloes, Alain, Drunat, Séverine, Rooryck, Caroline, Trimouille, Aurelien, Castello, Raffaele, Morleo, Manuela, Pinelli, Michele, Varavallo, Alessandra, De la Paz, Manuel Posada, Sánchez, Eva Bermejo, Martín, Estrella López, Delgado, Beatriz Martínez, de la Rosa, F. Javier Alonso García, Ciolfi, Andrea, Dallapiccola, Bruno, Pizzi, Simone, Radio, Francesca Clementina, Tartaglia, Marco, Renieri, Alessandra, Benetti, Elisa, Molnar, Maria Judit, Herzog, Rebecca, Pauly, Martje, Osorio, Andres Nascimiento, de Benito, Daniel Natera, Thompson, Rachel, Polavarapu, Kiran, Beeson, David, Cossins, Judith, Cruz, Pedro M. Rodriguez, Hackman, Peter, Johari, Mridul, Savarese, Marco, Udd, Bjarne, Capella, Gabriel, Valle, Laura, Holinski-Feder, Elke, Laner, Andreas, Steinke-Lange, Verena, Schröck, Evelin, Rump, Andreas, Solve-RD-DITF-RND, Solve-RD Consortium, Schule, R., Timmann, D., Erasmus, C. E., Reichbauer, J., Wayand, M., van de Warrenburg, B., Schols, L., Wilke, C., Bevot, A., Zuchner, S., Beltran, S., Laurie, S., Matalonga, L., Graessner, H., Synofzik, M., Nigro, V., Banfi, S., Torella, A., Piluso, G., Medicum, University of Helsinki, Department of Medical and Clinical Genetics, Klinische Genetica, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA Klinische Genetica (5), Wilke, Carlo [0000-0002-7250-8597], Beltran, Sergi [0000-0002-2810-3445], Laurie, Steven [0000-0003-3913-5829], Graessner, Holm [0000-0001-9803-7183], Synofzik, Matthis [0000-0002-2280-7273], and Apollo - University of Cambridge Repository

Subjects
genetics [Rare Diseases], lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Medizin, Datasets as Topic, 0302 clinical medicine, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Medicine, Genetics (clinical), 0303 health sciences, methods [Genomics], Management science, Neurodevelopmental disorders, Neurodegenerative diseases, 030305 genetics & heredity, 1184 Genetics, developmental biology, physiology, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Genomics, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], genetics [Nervous System Diseases], 3. Good health, Chemistry, Practice Guidelines as Topic, Malalties rares, pathology [Rare Diseases], methods [Genetic Testing], Movement disorders, Other Research Donders Center for Medical Neuroscience [Radboudumc 0], Socio-culturale, standards [Exome Sequencing], standards [Genetic Testing], pathology [Nervous System Diseases], 03 medical and health sciences, Rare Diseases, Viewpoint, Exome Sequencing, Genetics, Humans, Genetic Testing, ddc:610, Biology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, Sistema nerviós -- Malalties, methods [Exome Sequencing], standards [Genomics], 3111 Biomedicine, Human medicine, Nervous System Diseases, business, Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19], 030217 neurology & neurosurgery
Abstract

Rare genetic neurological disorders (RND; ORPHA:71859) are a heterogeneous group of disorders comprising >1700 distinct genetic disease entities. However, genetic discoveries have not yet translated into dramatic increases of diagnostic yield and indeed rates of molecular genetic diagnoses have been stuck at about 30–50% across NGS modalities and RND phenotypes [1, 2]. Existence of yet unknown disease genes as well as shortcomings of commonly employed NGS technologies and analysis pipelines in detecting certain variant types are typically cited to explain the low diagnosis rates. To increase the diagnostic yield in RNDs - one of the four focus disease groups in Solve-RD - we follow two major approaches, that we will here present and exemplify: (i) systematic state-of the art re-analysis of large cohorts of unsolved whole-exome/genome sequencing (WES/WGS) RND datasets; and (ii) novel-omics approaches. Based on the way Solve-RD systematically organizes researchers’ expertise to channel this approach [3], the European Reference Network for Rare Neurological Diseases (ERN-RND) has established its own Data Interpretation Task Force (DITF) within SOLVE-RD, which is currently composed of clinical and genetic experts from 29 sites in 15 European countries. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under Grant Agreement No. 779257. Data were analysed using the RD‐Connect Genome‐Phenome Analysis Platform, which received funding from EU projects RD‐Connect, Solve-RD and EJP-RD (Grant Numbers FP7 305444, H2020 779257, H2020 825575), Instituto de Salud Carlos III (Grant Numbers PT13/0001/0044, PT17/0009/0019; Instituto Nacional de Bioinformática, INB) and ELIXIR Implementation Studies. The study was further funded by the Federal Ministry of Education and Research, Germany, through the TreatHSP network (01GM1905 to RS and LS), the National Institute of Neurological Diseases and Stroke (R01NS072248 to SZ and RS), the European Joint Program on Rare Diseases-EJP-RD COFUND-EJP N° 825575 through funding for the PROSPAX consortium (441409627 to MS, RS and BvW). CW was supported by the PATE program of the Medical Faculty, University of Tübingen. CEE received support from the Dutch Princess Beatrix Muscle Fund and the Dutch Spieren voor Spieren Muscle fund. Authors on this paper are members of the European Reference Network for Rare Neurological Diseases (ERN-RND, Project ID 739510)

Published
2021

38. Analysis of the Striato-Thalamo-Cortical Connectivity on the Cortical Surface to Infer Biomarkers of Huntington’s Disease

Author

Marrakchi-Kacem, Linda, Delmaire, Christine, Tucholka, Alan, Roca, Pauline, Guevara, Pamela, Poupon, Fabrice, Yelnik, Jérôme, Durr, Alexandra, Mangin, Jean-François, Lehericy, Stéphane, Poupon, Cyril, Hutchison, David, editor, Kanade, Takeo, editor, Kittler, Josef, editor, Kleinberg, Jon M., editor, Mattern, Friedemann, editor, Mitchell, John C., editor, Naor, Moni, editor, Nierstrasz, Oscar, editor, Pandu Rangan, C., editor, Steffen, Bernhard, editor, Sudan, Madhu, editor, Terzopoulos, Demetri, editor, Tygar, Doug, editor, Vardi, Moshe Y., editor, Weikum, Gerhard, editor, Jiang, Tianzi, editor, Navab, Nassir, editor, Pluim, Josien P. W., editor, and Viergever, Max A., editor

Published
2010
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40. Exome Sequencing Links Corticospinal Motor Neuron Disease to Common Neurodegenerative Disorders

Author

Novarino, Gaia, Fenstermaker, Ali G., Zaki, Maha S., Hofree, Matan, Silhavy, Jennifer L., Heiberg, Andrew D., Abdellateef, Mostafa, Rosti, Basak, Scott, Eric, Mansour, Lobna, Masri, Amira, Kayserili, Hulya, Al-Aama, Jumana Y., Abdel-Salam, Ghada M. H., Karminejad, Ariana, Kara, Majdi, Kara, Bulent, Bozorgmehri, Bita, Ben-Omran, Tawfeg, Mojahedi, Faezeh, Mahmoud, Iman Gamal El Din, Bouslam, Naima, Bouhouche, Ahmed, Benomar, Ali, Hanein, Sylvain, Raymond, Laure, Forlani, Sylvie, Mascaro, Massimo, Selim, Laila, Shehata, Nabil, Al-Allawi, Nasir, Bindu, P.S., Azam, Matloob, Gunel, Murat, Caglayan, Ahmet, Bilguvar, Kaya, Tolun, Aslihan, Issa, Mahmoud Y., Schroth, Jana, Spencer, Emily G., Rosti, Rasim O., Akizu, Naiara, Vaux, Keith K., Johansen, Anide, Koh, Alice A., Megahed, Hisham, Durr, Alexandra, Brice, Alexis, Stevanin, Giovanni, Gabriel, Stacy B., Ideker, Trey, and Gleeson, Joseph G.

Published
2014

41. Excessive burden of lysosomal storage disorder gene variants in Parkinson’s disease

Author

Robak, Laurie A, Jansen, Iris E, van Rooij, Jeroen, Uitterlinden, André G, Kraaij, Robert, Jankovic, Joseph, Heutink, Peter, Shulman, Joshua M, Nalls, Mike A, Plagnol, Vincent, Hernandez, Dena G, Sharma, Manu, Sheerin, Una-Marie, Saad, Mohamad, Simón-Sánchez, Javier, Schulte, Claudia, Lesage, Suzanne, Sveinbjörnsdóttir, Sigurlaug, Arepalli, Sampath, Barker, Roger, Ben-, Yoav, Berendse, Henk W, Berg, Daniela, Bhatia, Kailash, de Bie, Rob M A, Biffi, Alessandro, Bloem, Bas, Bochdanovits, Zoltan, Bonin, Michael, Bras, Jose M, Brockmann, Kathrin, Brooks, Janet, Burn, David J, Majounie, Elisa, Charlesworth, Gavin, Lungu, Codrin, Chen, Honglei, Chinnery, Patrick F, Chong, Sean, Clarke, Carl E, Cookson, Mark R, Mark Cooper, J, Corvol, Jean Christophe, Counsell, Carl, Damier, Philippe, Dartigues, Jean-François, Deloukas, Panos, Deuschl, Günther, Dexter, David T, van Dijk, Karin D, Dillman, Allissa, Durif, Frank, Dürr, Alexandra, Edkins, Sarah, Evans, Jonathan R, Foltynie, Thomas, Dong, Jing, Gardner, Michelle, Raphael Gibbs, J, Goate, Alison, Gray, Emma, Guerreiro, Rita, Harris, Clare, van Hilten, Jacobus J, Hofman, Albert, Hollenbeck, Albert, Holton, Janice, Hu, Michele, Huang, Xuemei, Wurster, Isabel, Mätzler, Walter, Hudson, Gavin, Hunt, Sarah E, Huttenlocher, Johanna, Illig, Thomas, Jónsson, Pálmi V, Lambert, Jean-Charles, Langford, Cordelia, Lees, Andrew, Lichtner, Peter, Limousin, Patricia, Lopez, Grisel, Lorenz, Delia, Lungu, Codrin, McNeill, Alisdair, Moorby, Catriona, Moore, Matthew, Morris, Huw R, Morrison, Karen E, Escott-Price, Valentina, Mudanohwo, Ese, O’Sullivan, Sean S, Pearson, Justin, Perlmutter, Joel S, Pétursson, Hjörvar, Pollak, Pierre, Post, Bart, Potter, Simon, Ravina, Bernard, Revesz, Tamas, Riess, Olaf, Rivadeneira, Fernando, Rizzu, Patrizia, Ryten, Mina, Sawcer, Stephen, Schapira, Anthony, Scheffer, Hans, Shaw, Karen, Shoulson, Ira, Shulman, Joshua, Sidransky, Ellen, Smith, Colin, Spencer, Chris C A, Stefánsson, Hreinn, Bettella, Francesco, Stockton, Joanna D, Strange, Amy, Talbot, Kevin, Tanner, Carlie M, Tashakkori-Ghanbaria, Avazeh, Tison, François, Trabzuni, Daniah, Traynor, Bryan J, Uitterlinden, André G, Velseboer, Daan, Vidailhet, Marie, Walker, Robert, van de Warrenburg, Bart, Wickremaratchi, Mirdhu, Williams, Nigel, Williams-Gray, Caroline H, Winder-Rhodes, Sophie, Stefánsson, Kári, Martinez, Maria, Wood, Nicholas W, Hardy, John, Heutink, Peter, Brice, Alexis, Gasser, Thomas, and Singleton, Andrew B

Published
2017
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42. Differences in Survival across Monogenic Forms of Parkinson's Disease.

Author

Lanore, Aymeric, Casse, Fanny, Tesson, Christelle, Courtin, Thomas, Menon, Poornima Jayadev, Sambin, Sara, Mangone, Graziella, Mariani, Louise‐Laure, Lesage, Suzanne, Brice, Alexis, Elbaz, Alexis, Corvol, Jean‐Christophe, Agid, Yves, Anheim, Mathieu, Borg, Michel, Broussolle, Emmanuel, Damier, Philippe, Defebvre, Luc, Dürr, Alexandra, and Durif, Franck

Subjects
PARKINSON'S disease, GENETIC counseling, DARDARIN, OVERALL survival, VITAL records (Births, deaths, etc.), MOVEMENT disorders
Abstract

Objective: Survival of patients with monogenic Parkinson's disease may depend on the causative genes associated with the disease. In this study, we compare survival of patients with Parkinson's disease according to the presence of SNCA, PRKN, LRRK2, or GBA mutations. Methods: Data from the French Parkinson Disease Genetics national multicenter cohort study were used. Patients with sporadic and familial Parkinson's disease were recruited between 1990 and 2021. Patients were genotyped for the presence of mutations in the SNCA, PRKN, LRRK2, or GBA genes. Vital status was collected from the National death register for participants born in France. Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed using multivariable Cox proportional hazards regression. Results: Of the 2,037 patients with Parkinson's disease, 889 had died after a follow‐up of up to 30 years. Patients with PRKN (n = 100, HR = 0.41; p = 0.001) and LRRK2 mutations (n = 51, HR = 0.49; p = 0.023) had longer survival than those without any mutation, whereas patients with SNCA (n = 20, HR = 9.88; p < 0.001) or GBA mutations (n = 173, HR = 1.33; p = 0.048) had shorter survival. Interpretation: Survival differs across genetic forms of Parkinson's disease, with higher mortality for patients with SNCA or GBA mutations, and lower mortality for those with PRKN or LRRK2 mutations. Differences in severity and disease progression among monogenic forms of Parkinson's disease likely explain these findings, which has important consequences for genetic counselling and choice of end points for future clinical trials for targeted therapies. ANN NEUROL 2023;94:123–132 [ABSTRACT FROM AUTHOR]

Published
2023
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43. Biological and clinical characteristics of individuals at risk for spinocerebellar ataxia types 1, 2, 3, and 6 in the longitudinal RISCA study: analysis of baseline data

Author

Jacobi, Heike, Reetz, Kathrin, du Montcel, Sophie Tezenas, Bauer, Peter, Mariotti, Caterina, Nanetti, Lorenzo, Rakowicz, Maria, Sulek, Anna, Durr, Alexandra, Charles, Perrine, Filla, Alessandro, Antenora, Antonella, Schöls, Ludger, Schicks, Julia, Infante, Jon, Kang, Jun-Suk, Timmann, Dagmar, Fabio, Roberto Di, Masciullo, Marcella, Baliko, Laszlo, Melegh, Bela, Boesch, Sylvia, Bürk, Katrin, Peltz, Annkathrin, Schulz, Jörg B, Dufaure-Garé, Isabelle, and Klockgether, Thomas

Published
2013
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46. Potential endpoints for clinical trials in premanifest and early Huntington's disease in the TRACK-HD study: analysis of 24 month observational data

Author

Tabrizi, Sarah J, Reilmann, Ralf, Roos, Raymund AC, Durr, Alexandra, Leavitt, Blair, Owen, Gail, Jones, Rebecca, Johnson, Hans, Craufurd, David, Hicks, Stephen L, Kennard, Christopher, Landwehrmeyer, Bernhard, Stout, Julie C, Borowsky, Beth, Scahill, Rachael I, Frost, Chris, and Langbehn, Douglas R

Published
2012
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47. Ökologische Bewertung von niederösterreichischen Hecken: Vergleich zweier Methoden

Author

Dürr, Alexandra

Abstract

Hecken sind wichtige Bestandteile von Kulturlandschaften weltweit. Sie erbringen eine Vielzahl an Ökosystemleistungen (ÖSL). Jedoch erbringt nicht jede Hecke diese Leistungen in gleichem Maße. Das Heck.in Bewertungsschema wurde entwi-ckelt, um den Erfüllungsgrad verschiedener ÖSL einer Hecke zu erfassen. Hierfür wird auf möglichst einfach zu erfassende Indikatoren zurückgegriffen. Ziel dieser Arbeit ist die Evaluierung eines Teils dieses Schemas – die Bewertung der Habitatleistungen (Nahrungsquelle, Korridor, Ruhe- und Fortpflanzungsstät-te). Hierfür wurden fünfzig niederösterreichische Hecken mit dem Schema aufge-nommen und bewertet. Die Ergebnisse wurden dann mit einer parallel dazu erho-benen Biotopbewertung verglichen. Zudem wurde der qualitative Zustand der un-tersuchten Hecken beleuchtet. Die Mittelwerte der Ergebnisse beider Bewertungsmethoden sind nahezu iden-tisch, Differenzen bestehen jedoch in der Verteilung der Ergebnisse. Abweichun-gen könnten auf methodische Unterschiede zurückzuführen sein, z.B. eine abstu-fende Bewertung in Heck.in vs. Ja-/Nein-Entscheidungen in der Biotopbewer-tung. Auch die verschiedenen Blickwinkel (Heck.in: tierökologisch, Biotopbewer-tung: botanisch) und der Einfluss der Korridorleistung könnten Gründe sein. Die Qualität der Habitatleistungen der untersuchten Hecken unterscheidet sich zwischen Hecken aus traditionellen Heckenlandschaften und seit 1970 angelegten Bodenschutzanlagen in den ÖSL Nahrungsquellen und Ruhe- und Fortpflanzungs-stätte, sowie in den Gesamt-Habitatleistungen signifikant. Lediglich die Korri-dorleistung wird in beiden Gruppen gleichermaßen erbracht. Die insgesamt am schlechtesten bewerteten Indikatoren sind: Saum, Totholz, Heckendichte und Netzwerk. Sie bieten damit das größte Verbesserungspotenzial. Für ‚Saum‘ und ‚Totholz‘ sind verbesserte Managementpraktiken an der Einzelhecke nötig, für ‚Heckendichte‘ und ‚Netzwerk‘ ist eine großräumigere Planung notwendig., Hedgerows are important components of cultural landscapes worldwide and pro-vide a variety of ecosystem services (ESS). However, not every hedgerow provides these services to the same extent. The Heck.in assessment scheme was developed to rate the degree to which each hedgerow fulfills different ESS of a hedgerow by relying on easy-recordable indicators. The aim of this thesis is to evaluate one part of this scheme – the assessment of habitat services (food source, corridor, resting and breeding site). To this end, fif-ty hedges in Lower Austria were recorded and evaluated with the scheme. The re-sults were then compared to a biotope assessment made at the same time. Fur-thermore, the qualitative condition of the examined hedgerows was analyzed. The mean values of the results of both assessment methods are almost identical, but a difference was found in the distribution of the results. Discrepancies could be due to methodological differences, for example graded scoring in Heck.in vs. yes/no decisions in the biotope assessment. The different perspectives (Heck.in: faunistic, biotope assessment: botanical) and the influence of corridor perfor-mance could also be reasons. The quality of habitat services of the studied hedgerows differs significantly be-tween hedgerows in traditional hedgerow landscapes and shelter belts established since 1970 in the ESS food source and resting and breeding sites, as well as in the overall habitat services. Only the ESS corridor are equally performed in both groups. The lowest scoring indicators overall are: Margin, deadwood, hedgerow density, and network. They therefore offer the greatest potential for improve-ment. For the indicators margin and deadwood, improved management practices are needed at the single hedge, and for hedge density and network, more large-scale planning is needed.

Published
2022
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49. Delayed-Onset Friedreichʼs Ataxia Revisited

Author

Lecocq, Claire, Charles, Perrine, Azulay, Jean-Philippe, Meissner, Wassilios, Rai, Myriam, NʼGuyen, Karine, Péréon, Yann, Fabre, Nelly, Robin, Elsa, Courtois, Sylvie, Guyant-Maréchal, Lucie, Zagnoli, Fabien, Rudolf, Gabrielle, Renaud, Mathilde, Sévin-Allouet, Mathieu, Lesne, Fabien, Alaerts, Nick, Goizet, Cyril, Calvas, Patrick, Eusebio, Alexandre, Guissart, Claire, Derkinderen, Pascal, Tison, Francois, Brice, Alexis, Koenig, Michel, Pandolfo, Massimo, Tranchant, Christine, Dürr, Alexandra, and Anheim, Mathieu

Published
2016
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