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1. Identification of a DAGLB Mutation in a Non-Chinese Patient with Parkinson's Disease

Author

Tesson, Christelle, Bouchetara, Mohamed Sofiane, Ferrien, Mélanie, Lesage, Suzanne, and Brice, Alexis

Subjects
Quantitative Biology - Neurons and Cognition
Abstract

Liu et al. recently reported that biallelic mutations in DAGLB are responsible for autosomal recessive early-onset Parkinson's disease. They identified six patients carrying DAGLB mutations, all of Chinese origin and presenting with typical Parkinson disease. No additional cases outside China have been reported so far.To assess the causality of DAGLB in our cohort, we used data mining in the exomes of 684 index cases with either autosomal recessive or sporadic early onset Parkinson disease (< 50 years). We identified a homozygous p.Pro357Leu missense variant in a single consanguineous PD case. This mutation predicted deleterious, affects a conserved amino acid localized in the catalytic domain of the protein nearby the pathological p.Asp363Gly mutation described in the previous paper. As the most frequent genes involved in AR-PD (PRKN, PINK1), the DAGLB-associated disease presents and evolves like typical PD.This work reinforces the fact that DAGLB is involved in early onset Parkinson disease, but given the fact that we identified a single patient among 684 index cases screened, we conclude that DAGLB is a very rare cause of early onset autosomal recessive Parkinson disease. However, we demonstrate that, mutations in DAGLB are not limited to the Chinese population but can also account for PD in North Africa.We feel that these new data indicate that DAGLB variants should be considered in non-Chinese cases with early-onset typical Parkinson disease.

Published
2023
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2. Genotype–phenotype correlation in PRKN-associated Parkinson’s disease

Author

Menon, Poornima Jayadev, Sambin, Sara, Criniere-Boizet, Baptiste, Courtin, Thomas, Tesson, Christelle, Casse, Fanny, Ferrien, Melanie, Mariani, Louise-Laure, Carvalho, Stephanie, Lejeune, Francois-Xavier, Rebbah, Sana, Martet, Gaspard, Houot, Marion, Lanore, Aymeric, Mangone, Graziella, Roze, Emmanuel, Vidailhet, Marie, Aasly, Jan, Gan Or, Ziv, Yu, Eric, Dauvilliers, Yves, Zimprich, Alexander, Tomantschger, Volker, Pirker, Walter, Álvarez, Ignacio, Pastor, Pau, Di Fonzo, Alessio, Bhatia, Kailash P., Magrinelli, Francesca, Houlden, Henry, Real, Raquel, Quattrone, Andrea, Limousin, Patricia, Korlipara, Prasad, Foltynie, Thomas, Grosset, Donald, Williams, Nigel, Narendra, Derek, Lin, Hsin-Pin, Jovanovic, Carna, Svetel, Marina, Lynch, Timothy, Gallagher, Amy, Vandenberghe, Wim, Gasser, Thomas, Brockmann, Kathrin, Morris, Huw R., Borsche, Max, Klein, Christine, Corti, Olga, Brice, Alexis, Lesage, Suzanne, and Corvol, Jean Christophe

Published
2024
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4. RAB32 Ser71Arg in autosomal dominant Parkinson's disease: linkage, association, and functional analyses

Author

Gustavsson, Emil K, Follett, Jordan, Trinh, Joanne, Barodia, Sandeep K, Real, Raquel, Liu, Zhiyong, Grant-Peters, Melissa, Fox, Jesse D, Appel-Cresswell, Silke, Stoessl, A Jon, Rajput, Alex, Rajput, Ali H, Auer, Roland, Tilney, Russel, Sturm, Marc, Haack, Tobias B, Lesage, Suzanne, Tesson, Christelle, Brice, Alexis, Vilariño-Güell, Carles, Ryten, Mina, Goldberg, Matthew S, West, Andrew B, Hu, Michele T, Morris, Huw R, Sharma, Manu, Gan-Or, Ziv, Samanci, Bedia, Lis, Pawel, Periñan, Maria Teresa, Amouri, Rim, Ben Sassi, Samia, Hentati, Faycel, Tonelli, Francesca, Alessi, Dario R, and Farrer, Matthew J

Published
2024
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5. A pathogenic variant in RAB32 causes autosomal dominant Parkinsons disease and activates LRRK2 kinase

Author

Gustavsson, Emil K, primary, Follett, Jordan, additional, Trinh, Joanne, additional, Barodia, Sandeep K, additional, Real, Raquel, additional, Liu, Zhiyong, additional, Grant-Peters, Melissa, additional, Fox, Jesse D, additional, Appel-Cresswell, Silke, additional, Stoessl, Jon A, additional, Rajput, Alex, additional, Rajput, Ali H, additional, Auer, Roland, additional, Tilney, Russel, additional, Sturm, Marc, additional, Haack, Tobias B, additional, Lesage, Suzanne, additional, Tesson, Christelle, additional, Brice, Alexis, additional, Vilarino-Gueell, Carles, additional, Ryten, Mina, additional, Goldberg, Matthew S, additional, West, Andrew B, additional, Hu, Michele T, additional, Morris, Huw R, additional, Sharma, Manu, additional, Gan-Or, Ziv, additional, Samanci, Bedia, additional, Lis, Pawel, additional, Tocino, Teresa, additional, Amouri, Rim, additional, Ben Sassi, Samia, additional, Hentati, Faycel, additional, Tonelli, Francesca, additional, Alessi, Dario R, additional, and Farrer, Matthew J, additional

Published
2024
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6. A Pathogenic Variant in Rab32 Causes Autosomal Dominant Parkinson's Disease and Activates LRRK2 Kinase

Author

Gustavsson, Emil K., primary, Follett, Jordan, additional, Trinh, Joanne, additional, Barodia, Sandeep K., additional, Real, Raquel, additional, Liu, Zhiyong, additional, Grant-Peters, Melissa, additional, Fox, Jesse D., additional, Cresswell, Silke, additional, Stoessl, A. Jon, additional, Rajput, Alex, additional, Rajput, Ali H., additional, Auer, Roland, additional, Tilney, Russel, additional, Sturm, Marc, additional, Haack, Tobias B., additional, Lesage, Suzanne, additional, Tesson, Christelle, additional, Brice, Alexis, additional, Vilarino-Guell, Carles, additional, Ryten, Mina, additional, Goldberg, Matthew S., additional, West, Andrew B., additional, Hu, Michele T., additional, Morris, Huw R., additional, Sharma, Manu, additional, Gan-Or, Ziv, additional, Samanci, Bedia, additional, Lis, Pawel, additional, Tocino, Teressa P., additional, Amouri, Rim, additional, Sassi, Samir Ben, additional, Hentati, Faycel, additional, anon, Global Parkinson’s Genetics, additional, Tonelli, Francesca, additional, Alessi, Dario R., additional, and Farrer, Matthew J., additional

Published
2024
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7. 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

10. Embracing Monogenic Parkinson's Disease: The MJFF Global Genetic PD Cohort

Author

Vollstedt, Eva-Juliane, Schaake, Susen, Lohmann, Katja, Padmanabhan, Shalini, Brice, Alexis, Lesage, Suzanne, Tesson, Christelle, Vidailhet, Marie, Wurster, Isabel, Hentati, Faycel, Mirelman, Anat, Giladi, Nir, Marder, Karen, Waters, Cheryl, Fahn, Stanley, Kasten, Meike, Brüggemann, Norbert, Borsche, Max, Foroud, Tatiana, Tolosa, Eduardo, Garrido, Alicia, Annesi, Grazia, Gagliardi, Monica, Bozi, Maria, Stefanis, Leonidas, Ferreira, Joaquim J, Correia Guedes, Leonor, Avenali, Micol, Petrucci, Simona, Clark, Lorraine, Fedotova, Ekaterina Y, Abramycheva, Natalya Y, Alvarez, Victoria, Menéndez-González, Manuel, Jesús Maestre, Silvia, Gómez-Garre, Pilar, Mir, Pablo, Belin, Andrea Carmine, Ran, Caroline, Lin, Chin-Hsien, Kuo, Ming-Che, Crosiers, David, Wszolek, Zbigniew K, Ross, Owen A, Jankovic, Joseph, Nishioka, Kenya, Funayama, Manabu, Clarimon, Jordi, Williams-Gray, Caroline H, Camacho, Marta, Cornejo-Olivas, Mario, Torres-Ramirez, Luis, Wu, Yih-Ru, Lee-Chen, Guey-Jen, Morgadinho, Ana, Pulkes, Teeratorn, Termsarasab, Pichet, Berg, Daniela, Kuhlenbäumer, Gregor, Kühn, Andrea A, Borngräber, Friederike, De Michele, Giuseppe, De Rosa, Anna, Zimprich, Alexander, Puschmann, Andreas, Mellick, George D, Dorszewska, Jolanta, Carr, Jonathan, Ferese, Rosangela, Gambardella, Stefano, Chase, Bruce, Markopoulou, Katerina, Satake, Wataru, Toda, Tatsushi, Rossi, Malco, Merello, Marcelo, Lynch, Timothy, Olszewska, Diana A, Lim, Shen-Yang, Ahmad-Annuar, Azlina, Tan, Ai Huey, Al-Mubarak, Bashayer, Hanagasi, Hasmet, Koziorowski, Dariusz, Ertan, Sibel, Genç, Gençer, De Carvalho Aguiar, Patricia, Barkhuizen, Melinda, Pimentel, Marcia MG, Saunders-Pullman, Rachel, Van De Warrenburg, Bart, Bressman, Susan, Toft, Mathias, Appel-Cresswell, Silke, Lang, Anthony E, Skorvanek, Matej, Boon, Agnita JW, Krüger, Rejko, Sammler, Esther M, Tumas, Vitor, Zhang, Bao-Rong, Garraux, Gaetan, Chung, Sun Ju, Kim, Yun Joong, Winkelmann, Juliane, Sue, Carolyn M, Tan, Eng-King, Damásio, Joana, Klivényi, Péter, Kostic, Vladimir S, Arkadir, David, Martikainen, Mika, Borges, Vanderci, Hertz, Jens Michael, Brighina, Laura, Spitz, Mariana, Suchowersky, Oksana, Riess, Olaf, Das, Parimal, Mollenhauer, Brit, Gatto, Emilia M, Petersen, Maria Skaalum, Hattori, Nobutaka, Wu, Ruey-Meei, Illarioshkin, Sergey N, Valente, Enza Maria, Aasly, Jan O, Aasly, Anna, Alcalay, Roy N, Thaler, Avner, Farrer, Matthew J, Brockmann, Kathrin, Corvol, Jean-Christophe, Klein, Christine, MJFF Global Genetic Parkinson's Disease Study Group, Vollstedt, Ej, Schaake, S, Lohmann, K, Padmanabhan, S, Brice, A, Lesage, S, Tesson, C, Vidailhet, M, Wurster, I, Hentati, F, Mirelman, A, Giladi, N, Marder, K, Waters, C, Fahn, S, Kasten, M, Brüggemann, N, Borsche, M, Foroud, T, Tolosa, E, Garrido, A, Annesi, G, Gagliardi, M, Bozi, M, Stefanis, L, Ferreira, Jj, Correia Guedes, L, Avenali, M, Petrucci, S, Clark, L, Fedotova, Ey, Abramycheva, Ny, Alvarez, V, Menéndez-González, M, Jesús Maestre, S, Gómez-Garre, P, Mir, P, Belin, Ac, Ran, C, Lin, Ch, Kuo, Mc, Crosiers, D, Wszolek, Zk, Ross, Oa, Jankovic, J, Nishioka, K, Funayama, M, Clarimon, J, Williams-Gray, Ch, Camacho, M, Cornejo-Olivas, M, Torres-Ramirez, L, Wu, Yr, Lee-Chen, Gj, Morgadinho, A, Pulkes, T, Termsarasab, P, Berg, D, Kuhlenbäumer, G, Kühn, Aa, Borngräber, F, de Michele, G, De Rosa, A, Zimprich, A, Puschmann, A, Mellick, Gd, Dorszewska, J, Carr, J, Ferese, R, Gambardella, S, Chase, B, Markopoulou, K, Satake, W, Toda, T, Rossi, M, Merello, M, Lynch, T, Olszewska, Da, Lim, Sy, Ahmad-Annuar, A, Tan, Ah, Al-Mubarak, B, Hanagasi, H, Koziorowski, D, Ertan, S, Genç, G, de Carvalho Aguiar, P, Barkhuizen, M, Pimentel, Mmg, Saunders-Pullman, R, van de Warrenburg, B, Bressman, S, Toft, M, Appel-Cresswell, S, Lang, Ae, Skorvanek, M, Boon, Ajw, Krüger, R, Sammler, Em, Tu, Repositório da Universidade de Lisboa, Clinical Genetics, Neurology, Internal Medicine, Aasly, Anna, Aasly, Jan O, Abramycheva, Natalya Y, Ahmad-Annuar, Azlina, Albanese, Alberto, Alcalay, Roy N, Aldakheel, Amaal, Alkhairallah, Thamer, Al-Mubarak, Bashayer, Al-Tassan, Nada, Alvarez, Victoria, Amami, Paolo, Annesi, Grazia, Appel-Cresswell, Silke, Leite, Marco Antonio Araujo, Arkadir, David, Avenali, Micol, Ferraz, Henrique Ballalai, Bardien, Soraya, Barkhuizen, Melinda, Barrett, Matthew J, Başak, A Nazlı, Berg, Daniela, Bilgic, Basar, Bloem, Bastiaan R, Bonifati, Vincenzo, Boon, Agnita J W, Borges, Vanderci, Borngräber, Friederike, Borsche, Max, Bozi, Maria, Bressman, Susan, Brice, Alexis, Brighina, Laura, Brockmann, Kathrin, Brüggemann, Norbert, Camacho, Marta, Belin, Andrea Carmine, Carr, Jonathan, Cesarini, Martin Emiliano, Cornejo-Olivas, Mario, Chase, Bruce, Chung, Sun Ju, Guedes, Leonor Correia, Clarimon, Jordi, Clark, Lorraine, Corvol, Jean-Christophe, Crosiers, David, Das, Parimal, de Carvalho Aguiar, Patricia, Damásio, Joana, de Michele, Giuseppe, De Rosa, Anna, Dieguez, Elena, Dorszewska, Jolanta, Ertan, Sibel, Fahn, Stanley, Farrer, Matthew J, Fedotova, Ekaterina Y, Ferese, Rosangela, Ferreira, Joaquim J, Foroud, Tatiana, Funayama, Manabu, Fung, Victor S C, Gagliardi, Monica, Gambardella, Stefano, Garraux, Gaetan, Garrido, Alicia, Gatto, Emilia M, Genç, Gençer, Giladi, Nir, Gómez-Garre, Pilar, Hanagasi, Hasmet, Hattori, Nobutaka, Hentati, Faycel, Hertz, Jens Michael, Illarioshkin, Sergey N, Jankovic, Joseph, Januario, Cristina, Maestre, Silvia Jesús, Kaasinen, Valtteri, Kasten, Meike, Kataoka, Hiroshi, Kievit, Anneke A, Kim, Yun Joong, Klein, Christine, Klivényi, Péter, Kostic, Vladimir S, Koziorowski, Dariusz, Krüger, Rejko, Kühn, Andrea, Kuhlenbäumer, Gregor, Kuo, Ming-Che, Lang, Anthony E, Lee-Chen, Guey-Jen, Lesage, Suzanne, Lim, Jia Lun, Lim, Shen-Yang, Lin, Chin-Hsien, Lohmann, Katja, Lynch, Timothy, Marder, Karen, Markopoulou, Katerina, Martikainen, Mika, May, Patrick, McCarthy, Allan, Mellick, George D, Menéndez-González, Manuel, Merello, Marcelo, Mir, Pablo, Mirelman, Anat, Mollenhauer, Brit, Briceno, Hugo Morales, Morgadinho, Ana, Morris, Huw, Mosejova, Alexandra, Nishioka, Kenya, Çakmak, Özgür Öztop, Olszewska, Diana A, Orr-Urtreger, Avi, Pachchek, Sinthuja, Padmanabhan, Shalini, Periñán, Maria Teresa, Petrucci, Simona, Pimentel, Marcia M G, Procopio, Radha, Pulkes, Teeratorn, Puschmann, Andreas, Ran, Caroline, Riess, Olaf, Ross, Owen A, Rossi, Malco, Ruiz-Martinez, Javier, Sammler, Esther M, Pereira, João Santos, Satake, Wataru, Saunders-Pullman, Rachel, Schaake, Susen, Petersen, Maria Skaalum, Skorvanek, Matej, Stefanis, Leonidas, Soto-Beasley, Alexandra I, Sousa, Mário, Spitz, Mariana, Suchowersky, Oksana, Sue, Carolyn M, Tan, Ai Huey, Tan, Eng-King, Thaler, Avner, Tepgeç, Fatih, Termsarasab, Pichet, Tesson, Christelle, Toda, Tatsushi, Toft, Mathias, Tolosa, Eduardo, Torres-Ramirez, Luis, Tumas, Vitor, Uyguner, Oya, Valente, Enza Maria, van de Warrenburg, Bart, Vidailhet, Marie, Vollstedt, Eva-Juliane, Walton, Ronald L, Waters, Cheryl, Williams-Gray, Caroline H, Winkelmann, Juliane, Wu, Yih-Ru, Wurster, Isabel, Wszolek, Zbigniew K, Wu, Ruey-Meei, Zhang, Bao-Rong, Zimprich, Alexander, Vollstedt, Eva-Juliane [0000-0002-6898-9201], Lohmann, Katja [0000-0002-5121-1460], Mirelman, Anat [0000-0002-1520-2292], Brüggemann, Norbert [0000-0001-5969-6899], Borsche, Max [0000-0002-9651-5986], Tolosa, Eduardo [0000-0002-3781-0854], Ferreira, Joaquim J [0000-0003-3950-5113], Alvarez, Victoria [0000-0002-1916-2523], Mir, Pablo [0000-0003-1656-302X], Kuo, Ming-Che [0000-0003-3688-0225], Ross, Owen A [0000-0003-4813-756X], Nishioka, Kenya [0000-0001-8607-9757], Williams-Gray, Caroline H [0000-0002-2648-9743], Camacho, Marta [0000-0002-1490-5703], Cornejo-Olivas, Mario [0000-0001-6313-5680], Wu, Yih-Ru [0000-0003-1191-2542], Termsarasab, Pichet [0000-0002-3260-3119], Borngräber, Friederike [0000-0001-9650-6820], Zimprich, Alexander [0000-0002-1668-5177], Gambardella, Stefano [0000-0002-3727-4502], Chase, Bruce [0000-0001-5491-7242], Olszewska, Diana A [0000-0002-1814-8834], Tan, Ai Huey [0000-0002-2979-3839], Barkhuizen, Melinda [0000-0002-9952-7085], Appel-Cresswell, Silke [0000-0002-5986-1468], Skorvanek, Matej [0000-0001-5497-8715], Sammler, Esther M [0000-0003-3218-7116], Zhang, Bao-Rong [0000-0002-8099-7407], Chung, Sun Ju [0000-0003-4118-8233], Apollo - University of Cambridge Repository, and MJFF Global Genetic Parkinson's Disease Study Group

Subjects
parkinson's disease, monogenic pd, monogenic PD, Parkinson's disease, Monogenic PD, Parkinson Disease, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], ddc, Neurology, genetics [Parkinson Disease], Mutation, Humans, Human medicine, ddc:610, Neurology (clinical), Research Article, Research Articles
Abstract

© 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited., Background: As gene-targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial-ready cohorts is limited. Objective: The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD-linked variants; (2) provide harmonized and quality-controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD. Methods: We conducted a worldwide, systematic online survey to collect individual-level data on individuals with PD-linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ-1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype-phenotype relationships were analyzed. Results: We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals, 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35, 429 PRKN, 75 PINK1, 13 DJ-1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34%) were indicated as not previously published. Conclusions: Within the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD-linked variants; (2) provide harmonized and quality-controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward clinical and genetic stratification of patients for gene-targeted clinical trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., Michael J. Fox Foundation for Parkinson's Research. Grant Number: ID 15015.02. NIHR Cambridge Biomedical Research Centre. Grant Number: BRC-1215-20014

Published
2023

11. Genotype-Phenotype correlation in Parkin-Parkinson’s disease (P3-11.012)

Author

Menon, Poornima Jayadev, primary, Sambin, Sara, additional, Criniere-Boizet, Baptiste, additional, Courtin, Thomas, additional, Casse, Fanny, additional, Tesson, Christelle, additional, Ferrien, Melanie, additional, Flamand-Roze, Emmanuel, additional, Lejeune, Francois-Xavier, additional, Lanore, Aymeric, additional, Mangone, Graziella, additional, Mariani, Louise-Laure, additional, Aasly, Jan, additional, Or, Ziv Gan, additional, Yu, Eric, additional, Dauvilliers, Yves, additional, Zimprich, Alexander, additional, Fernandez, Ignacio Alvarez, additional, Pastor, Pau, additional, Di Fonzo, Alessio, additional, Bhatia, Khailash, additional, Magrinelli, Francesca, additional, Houlden, Henry, additional, Real, Raquel, additional, Narendra, Derek, additional, Lin, Hsin-Pin, additional, Jovanovic, Carna, additional, Koks, Sulev, additional, Lynch, Timothy, additional, Gallagher, Amy, additional, Vandenberghe, Wim, additional, Gasser, Thomas, additional, Morris, Huw, additional, Klein, Christine, additional, Brockmann, Kathrin, additional, Corti, Olga, additional, Brice, Alexis, additional, Lesage, Suzanne, additional, and Corvol, Jean-Christophe, additional

Published
2023
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12. Intrafamilial and interfamilial heterogeneity of PINK1-associated Parkinson's disease in Sudan

Author

Bakhit, Yousuf, primary, Ibrahim, Mohamed O., additional, Tesson, Christelle, additional, Elhassan, Ali A., additional, Ahmed, Mohamed Anwer, additional, Alebeed, Mohamed A., additional, Elrasheed, Salma M., additional, Omar, Mawia A., additional, Abubaker, Rayan, additional, Eltom, Khalid, additional, Shaheen, Mutaz T., additional, Ibrahim, Yousuf A., additional, Almak, Murad E., additional, Ali, Hiba A., additional, Abugrain, Ahmed A., additional, Almahal, Mohamed A., additional, MohamedSharif, Abubaker A., additional, Tahir, Mohamed Y., additional, Malik, Sawazen M., additional, Eldirdiri Abdelrahman, Hazim, additional, Khidir, Reem J., additional, Mohamed, Malaz T., additional, Abdalla, Abdelmohaymin, additional, Elsayed, Liena E.O., additional, Lesage, Suzanne, additional, Corvol, Jean-Christophe, additional, Seidi, Osheik, additional, and Wüllner, Ullrich, additional

Published
2023
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13. Embracing Monogenic Parkinson's Disease: The MJFF Global Genetic PD Cohort

Author

Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Fonds National de la Recherche - FnR [sponsor], MJFF [sponsor], H2020 (Orchestra) [sponsor], Vollstedt, Eva-Juliane, Schaake, Susen, Lohmann, Katja, Padmanabhan, Shalini, Brice, Alexis, Lesage, Suzanne, Tesson, Christelle, Vidailhet, Marie, Wurster, Isabel, Hentati, Faycel, Mirelman, Anat, Giladi, Nir, Karen, Marder, Waters, Cheryl, Fahn, Stanley, Kasten, Meike, Brüggemann, Norbert, Borsche, Max, Foroud, Tatiana, Tolosa, Eduardo, Garrido, Alicia, Annesi, Grazia, Gagliardi, Monica, Bozi, Maria, Stefanis, Leonidas, Ferreira, Joaquim J., Correia Guedes, Leonor, Avenali, Micol, Petrucci, Simona, Clark, Lorraine, Fedotova, Ekaterina Y., Abramycheva, Natalya Y., Alvarez, Victoria, Menéndez-González, Manuel, Jesús Maestre, Silvia, Gómez-Garre, Pilar, Mir, Pablo, Belin, Andrea Carmine, Ran, Caroline, Lin, Chin-Hsien, Kuo, Ming-Che, Crosiers, David, Wszolek, Zbigniew K., Ross, Owen A., Jankovic, Joseph, Nishioka, Kenya, Funayama, Manabu, Clarimon, Jordi, Williams-Gray, Caroline H., Camacho, Marta, Cornejo-Olivas, Mario, Torres-Ramirez, Luis, Wu, Yih-Ru, Lee-Chen, Guey-Jen, Morgadinho, Ana, Pulkes, Teeratorn, Termsarasab, Pichet, Berg, Daniela, Gregor, Kuhlenbäumer, Kühn, Andrea A., Borngräber, Friederike, de Michele, Giuseppe, De Rosa, Anna, Zimprich, Alexander, Puschmann, Andreas, Mellick, George D., Jolanta, Dorszewska, Carr, Jonathan, Ferese, Rosangela, Stefano, Gambardella, Chase, Bruce, Markopoulou, Katerina, Wataru, Satake, Toda, Tatsushi, Rossi, Malco, Merello, Marcelo, Lynch, Timothy, Olszewska, Diana A., Lim, Shen-Yang, Ahmad-Annuar, Azlina, Tan, Ai Huey, Al-Mubarak, Bashayer, Hanagasi, Hasmet, Koziorowski, Dariusz, Ertan, Sibel, Gen c, Gen Cer, de Carvalho Aguiar, Patricia, Barkhuizen, Melinda, Pimentel, Marcia M. G., Saunders-Pullman, Rachel, van de Warrenburg, Bart, Bressman, Susan, Toft, Mathias, Appel-Cresswell, Silke, Lang, Anthony E., Skorvanek, Matej, Boon, Agnita J. W., Krüger, Rejko, Sammler, Esther M., Tumas, Vitor, Zhang, Bao-Rong, Garraux, Gaetan, Chung, Sun Ju, Joong, Kim Yun, Winkelmann, Juliane, Sue, Carolyn M., Eng-King, Tan, Damásio, Joana, Klivényi, Péter, Kostic, Vladimir S., Arkadir, David, Martikainen, Mika, Borges, Vanderci, Hertz, Jens Michael, Brighina, Laura, Spitz, Mariana, Suchowersky, Oksana, Riess, Olaf, Parimal, Das, Mollenhauer, Brit, Gatto, Emilia M., Skaalum, Petersen Maria, Wu, Ruey-Meei, Illarioshkin, Sergey N., Valente, Enza Maria, Aasly, Jan O., Aasly, Anna, N, Alcalay Roy, Thaler, Avner, Farrer, Matthew J., Kathrin, Brockmann, Corvol, Jean-Christophe, Klein, Christine, Albanese, Alberto, Alcalay, Roy N., Aldakheel, Amaal, Alkhairallah, Thamer, Bashayer, Al-Mubarak, Al-Tassan, Nada, Paolo, Amami, Araujo, Leite Marco Antonio, Ferraz, Henrique Ballalai, Bardien, Soraya, Melinda, Barkhuizen, Barrett, Matthew J., Ba sak, A. Nazl I, Bilgic, Basar, Bloem, Bastiaan R., Bonifati, Vincenzo, Brockmann, Kathrin, Cesarini, Martin Emiliano, Ju, Chung Sun, Guedes, Leonor Correia, Lorraine, Clark, Dieguez, Elena, Dorszewska, Jolanta, Fung, Victor S. C., Pilar, Gómez-Garre, Hattori, Nobutaka, Faycel, Hentati, Januario, Cristina, Maestre, Silvia Jesús, Kaasinen, Valtteri, Hiroshi, Kataoka, Kievit, Anneke A., Kim, Yun Joong, Christine, Klein, Kuhlenbäumer, Gregor, Lim, Jia Lun, Timothy, Lynch, Marder, Karen, May, Patrick, McCarthy, Allan, Briceno, Hugo Morales, Morris, Huw, Mosejova, Alexandra, Cakmak, Özgür Öztop, Orr-Urtreger, Avi, Pachchek, Sinthuja, Periñ\'an, Maria Teresa, Procopio, Radha, Ruiz-Martinez, Javier, Pereira, João Santos, Satake, Wataru, Soto-Beasley, Alexandra I., Sousa, Mário, Tan, Eng-King, Tepge c, Fatih, Uyguner, Oya, Walton, Ronald L., H, Williams-Gray Caroline, Isabel, Wurster, Bao-Rong, Zhang, Luxembourg Centre for Systems Biomedicine (LCSB): Clinical & Experimental Neuroscience (Krüger Group) [research center], Luxembourg Centre for Systems Biomedicine (LCSB): Bioinformatics Core (R. Schneider Group) [research center], Fonds National de la Recherche - FnR [sponsor], MJFF [sponsor], H2020 (Orchestra) [sponsor], Vollstedt, Eva-Juliane, Schaake, Susen, Lohmann, Katja, Padmanabhan, Shalini, Brice, Alexis, Lesage, Suzanne, Tesson, Christelle, Vidailhet, Marie, Wurster, Isabel, Hentati, Faycel, Mirelman, Anat, Giladi, Nir, Karen, Marder, Waters, Cheryl, Fahn, Stanley, Kasten, Meike, Brüggemann, Norbert, Borsche, Max, Foroud, Tatiana, Tolosa, Eduardo, Garrido, Alicia, Annesi, Grazia, Gagliardi, Monica, Bozi, Maria, Stefanis, Leonidas, Ferreira, Joaquim J., Correia Guedes, Leonor, Avenali, Micol, Petrucci, Simona, Clark, Lorraine, Fedotova, Ekaterina Y., Abramycheva, Natalya Y., Alvarez, Victoria, Menéndez-González, Manuel, Jesús Maestre, Silvia, Gómez-Garre, Pilar, Mir, Pablo, Belin, Andrea Carmine, Ran, Caroline, Lin, Chin-Hsien, Kuo, Ming-Che, Crosiers, David, Wszolek, Zbigniew K., Ross, Owen A., Jankovic, Joseph, Nishioka, Kenya, Funayama, Manabu, Clarimon, Jordi, Williams-Gray, Caroline H., Camacho, Marta, Cornejo-Olivas, Mario, Torres-Ramirez, Luis, Wu, Yih-Ru, Lee-Chen, Guey-Jen, Morgadinho, Ana, Pulkes, Teeratorn, Termsarasab, Pichet, Berg, Daniela, Gregor, Kuhlenbäumer, Kühn, Andrea A., Borngräber, Friederike, de Michele, Giuseppe, De Rosa, Anna, Zimprich, Alexander, Puschmann, Andreas, Mellick, George D., Jolanta, Dorszewska, Carr, Jonathan, Ferese, Rosangela, Stefano, Gambardella, Chase, Bruce, Markopoulou, Katerina, Wataru, Satake, Toda, Tatsushi, Rossi, Malco, Merello, Marcelo, Lynch, Timothy, Olszewska, Diana A., Lim, Shen-Yang, Ahmad-Annuar, Azlina, Tan, Ai Huey, Al-Mubarak, Bashayer, Hanagasi, Hasmet, Koziorowski, Dariusz, Ertan, Sibel, Gen c, Gen Cer, de Carvalho Aguiar, Patricia, Barkhuizen, Melinda, Pimentel, Marcia M. G., Saunders-Pullman, Rachel, van de Warrenburg, Bart, Bressman, Susan, Toft, Mathias, Appel-Cresswell, Silke, Lang, Anthony E., Skorvanek, Matej, Boon, Agnita J. W., Krüger, Rejko, Sammler, Esther M., Tumas, Vitor, Zhang, Bao-Rong, Garraux, Gaetan, Chung, Sun Ju, Joong, Kim Yun, Winkelmann, Juliane, Sue, Carolyn M., Eng-King, Tan, Damásio, Joana, Klivényi, Péter, Kostic, Vladimir S., Arkadir, David, Martikainen, Mika, Borges, Vanderci, Hertz, Jens Michael, Brighina, Laura, Spitz, Mariana, Suchowersky, Oksana, Riess, Olaf, Parimal, Das, Mollenhauer, Brit, Gatto, Emilia M., Skaalum, Petersen Maria, Wu, Ruey-Meei, Illarioshkin, Sergey N., Valente, Enza Maria, Aasly, Jan O., Aasly, Anna, N, Alcalay Roy, Thaler, Avner, Farrer, Matthew J., Kathrin, Brockmann, Corvol, Jean-Christophe, Klein, Christine, Albanese, Alberto, Alcalay, Roy N., Aldakheel, Amaal, Alkhairallah, Thamer, Bashayer, Al-Mubarak, Al-Tassan, Nada, Paolo, Amami, Araujo, Leite Marco Antonio, Ferraz, Henrique Ballalai, Bardien, Soraya, Melinda, Barkhuizen, Barrett, Matthew J., Ba sak, A. Nazl I, Bilgic, Basar, Bloem, Bastiaan R., Bonifati, Vincenzo, Brockmann, Kathrin, Cesarini, Martin Emiliano, Ju, Chung Sun, Guedes, Leonor Correia, Lorraine, Clark, Dieguez, Elena, Dorszewska, Jolanta, Fung, Victor S. C., Pilar, Gómez-Garre, Hattori, Nobutaka, Faycel, Hentati, Januario, Cristina, Maestre, Silvia Jesús, Kaasinen, Valtteri, Hiroshi, Kataoka, Kievit, Anneke A., Kim, Yun Joong, Christine, Klein, Kuhlenbäumer, Gregor, Lim, Jia Lun, Timothy, Lynch, Marder, Karen, May, Patrick, McCarthy, Allan, Briceno, Hugo Morales, Morris, Huw, Mosejova, Alexandra, Cakmak, Özgür Öztop, Orr-Urtreger, Avi, Pachchek, Sinthuja, Periñ\'an, Maria Teresa, Procopio, Radha, Ruiz-Martinez, Javier, Pereira, João Santos, Satake, Wataru, Soto-Beasley, Alexandra I., Sousa, Mário, Tan, Eng-King, Tepge c, Fatih, Uyguner, Oya, Walton, Ronald L., H, Williams-Gray Caroline, Isabel, Wurster, and Bao-Rong, Zhang

Abstract

BACKGROUND: As gene-targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial-ready cohorts is limited. OBJECTIVE: The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD-linked variants; (2) provide harmonized and quality-controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD. METHODS: We conducted a worldwide, systematic online survey to collect individual-level data on individuals with PD-linked variants in SNCA, LRRK2 VPS35, PRKN, PINK1, DJ-1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype-phenotype relationships were analyzed. RESULTS: We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35 429 PRKN, 75 PINK1, 13 DJ-1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34\%) were indicated as not previously published. CONCLUSIONS: Within the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD-linked variants; (2) provide harmonized and quality-controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward cl

Published
2023

14. Intrafamilial and interfamilial heterogeneity of PINK1-associated Parkinson's disease in Sudan

Author

Bakhit, Yousuf, Ibrahim, Mohamed O., Tesson, Christelle, Elhassan, Ali A., Ahmed, Mohamed Anwer, Alebeed, Mohamed A., Elrasheed, Salma M., Omar, Mawia A., Abubaker, Rayan, Eltom, Khalid, Shaheen, Mutaz T., Ibrahim, Yousuf A., Almak, Murad E., Ali, Hiba A., Abugrain, Ahmed A., Almahal, Mohamed A., MohamedSharif, Abubaker A., Tahir, Mohamed Y., Malik, Sawazen M., Abdelrahman, Hazim Eldirdiri, Khidir, Reem J., Mohamed, Malaz T., Abdalla, Abdelmohaymin, Elsayed, Liena E. O., Lesage, Suzanne, Corvol, Jean-Christophe, Seidi, Osheik, Wüllner, Ullrich, Bakhit, Yousuf, Ibrahim, Mohamed O., Tesson, Christelle, Elhassan, Ali A., Ahmed, Mohamed Anwer, Alebeed, Mohamed A., Elrasheed, Salma M., Omar, Mawia A., Abubaker, Rayan, Eltom, Khalid, Shaheen, Mutaz T., Ibrahim, Yousuf A., Almak, Murad E., Ali, Hiba A., Abugrain, Ahmed A., Almahal, Mohamed A., MohamedSharif, Abubaker A., Tahir, Mohamed Y., Malik, Sawazen M., Abdelrahman, Hazim Eldirdiri, Khidir, Reem J., Mohamed, Malaz T., Abdalla, Abdelmohaymin, Elsayed, Liena E. O., Lesage, Suzanne, Corvol, Jean-Christophe, Seidi, Osheik, and Wüllner, Ullrich

Abstract

PINK1 is the second most predominant gene associated with autosomal recessive Parkinson's disease. Homo-zygous mutations in this gene are associated with an early onset of symptoms. Bradykinesia, tremors, and rigidity are common features, while dystonia, motor fluctuation, and non-motor symptoms occur in a lower percentage of cases and usually respond well to levodopa. We investigated 14 individuals with parkinsonism and eleven symptom-free siblings from three consanguineous Sudanese families, two of them multigenerational, using a custom gene panel screening 34 genes, 27 risk variants, and 8 candidate genes associated with parkinsonism. We found a known pathogenic nonsense PINK1 variant (NM_032409.3:c.1366C>T; p.(Gln456*)), a novel pathogenic single base duplication (NM_032409.3:c.1597dup; p.(Gln533Profs*29)), and another novel pathogenic insertion (NM_032409.3:c.1448_1449ins[1429_1443; TTGAG]; p.(Arg483Serfs*7)). All variants were homozygous and co -segregated in all affected family members. We also identified intrafamilial and interfamilial phenotypic het-erogeneity associated with PINK1 mutations in these Sudanese cases, possibly reflecting the nature of the Sudanese population that has a large effective population size, which suggests a higher possibility of novel findings in monogenic and polygenic diseases in Sudan.

Published
2023
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15. Embracing Monogenic Parkinson's Disease:The MJFF Global Genetic PD Cohort

Author

Vollstedt, Eva Juliane, Schaake, Susen, Lohmann, Katja, Padmanabhan, Shalini, Brice, Alexis, Lesage, Suzanne, Tesson, Christelle, Vidailhet, Marie, Wurster, Isabel, Hentati, Faycel, Mirelman, Anat, Giladi, Nir, Marder, Karen, Waters, Cheryl, Fahn, Stanley, Kasten, Meike, Brüggemann, Norbert, Borsche, Max, Foroud, Tatiana, Tolosa, Eduardo, Garrido, Alicia, Annesi, Grazia, Gagliardi, Monica, Bozi, Maria, Stefanis, Leonidas, Ferreira, Joaquim J., Correia Guedes, Leonor, Avenali, Micol, Petrucci, Simona, Clark, Lorraine, Fedotova, Ekaterina Y., Abramycheva, Natalya Y., Alvarez, Victoria, Menéndez-González, Manuel, Jesús Maestre, Silvia, Gómez-Garre, Pilar, Mir, Pablo, Belin, Andrea Carmine, Ran, Caroline, Lin, Chin Hsien, Kuo, Ming Che, Crosiers, David, Wszolek, Zbigniew K., Ross, Owen A., Boon, Agnita J.W., Riess, Olaf, Bonifati, Vincenzo, Kievit, Anneke A., Vollstedt, Eva Juliane, Schaake, Susen, Lohmann, Katja, Padmanabhan, Shalini, Brice, Alexis, Lesage, Suzanne, Tesson, Christelle, Vidailhet, Marie, Wurster, Isabel, Hentati, Faycel, Mirelman, Anat, Giladi, Nir, Marder, Karen, Waters, Cheryl, Fahn, Stanley, Kasten, Meike, Brüggemann, Norbert, Borsche, Max, Foroud, Tatiana, Tolosa, Eduardo, Garrido, Alicia, Annesi, Grazia, Gagliardi, Monica, Bozi, Maria, Stefanis, Leonidas, Ferreira, Joaquim J., Correia Guedes, Leonor, Avenali, Micol, Petrucci, Simona, Clark, Lorraine, Fedotova, Ekaterina Y., Abramycheva, Natalya Y., Alvarez, Victoria, Menéndez-González, Manuel, Jesús Maestre, Silvia, Gómez-Garre, Pilar, Mir, Pablo, Belin, Andrea Carmine, Ran, Caroline, Lin, Chin Hsien, Kuo, Ming Che, Crosiers, David, Wszolek, Zbigniew K., Ross, Owen A., Boon, Agnita J.W., Riess, Olaf, Bonifati, Vincenzo, and Kievit, Anneke A.

Abstract

Background: As gene-targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial-ready cohorts is limited. Objective: The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD-linked variants; (2) provide harmonized and quality-controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD. Methods: We conducted a worldwide, systematic online survey to collect individual-level data on individuals with PD-linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ-1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype–phenotype relationships were analyzed. Results: We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals, 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35, 429 PRKN, 75 PINK1, 13 DJ-1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34%) were indicated as not previously published. Conclusions: Within the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD-linked variants; (2) provide harmonized and quality-controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view towa

Published
2023

16. Embracing Monogenic Parkinson's Disease: The MJFF Global Genetic PD Cohort

Author

Michael J. Fox Foundation for Parkinson's Research, Vollstedt, Eva-Juliane, Schaake, Susen, Lohmann, Katja, Padmanabhan, Shalini, Brice, Alexis, Lesage, Suzanne, Tesson, Christelle, Vidailhet, Marie, Wurster, Isabel, Hentati, Faycel, Mirelman, Anat, Giladi, Nir, Marder, Karen, Waters, Cheryl, Fahn, Stanley, Kasten, Meike, Brüggemann, Norbert, Borsche, Max, Foroud, Tatiana, Tolosa, Eduardo, Garrido, Alicia, Annesi, Grazia, Gagliardi, Monica, Bozi, Maria, Stefanis, Leonidas, Ferreira, Joaquim, Correia Guedes, Leonor, Avenali, Micol, Petrucci, Simona, Clark, Lorraine, Fedotova, Ekaterina Y., Abramycheva, Natalya Y., Alvarez, Victoria, Menéndez-González, Manuel, Jesús Maestre, Silvia, Gómez-Garre, Pilar, Mir, Pablo, Belin, Andrea Carmine, Ran, Caroline, Lin, Chin-Hsien, Kuo, Ming-Che, Crosiers, David, Wszolek, Zbigniew K., Ross, Owen A., Jankovic, Joseph, Nishioka, Kenya, Funayama, Manabu, Clarimon, Jordi, Williams-Gray, Caroline H., Camacho, Marta, Cornejo-Olivas, Mario, Torres-Ramírez, Luis, Wu, Yih-Ru, Lee-Chen, Guey-Jen, Morgadinho, Ana, Pulkes, Teeratorn, Termsarasab, Pichet, Berg, Daniela, Kuhlenbäumer, Gregor, Kühn, Andrea A., Borngräber, Friederike, Michele, Giuseppe de, Rosa, Anna De, Zimprich, Alexander, Puschmann, Andreas, Mellick, George D., Dorszewska, Jolanta, Carr, Jonathan, Ferese, Rosangela, Gambardella, Stefano, Chase, Bruce, Markopoulou, Katerina, Satake, Wataru, Toda, Tatsushi, Rossi, Malco, Merello, Marcelo, Lynch, Timothy, Olszewska, Diana A., Lim, Shen-Yang, Ahmad-Annuar, Azlina, Tan, Ai Huey, Al-Mubarak, Bashayer, Hanagasi, Hasmet, Koziorowski, Dariusz, Ertan, Sibel, Genç, Gençer, Aguiar, Patricia de Carvalho, Barkhuizen, Melinda, Pimentel, Marcia M. G., Saunders-Pullman, Rachel, Warrenburg, Bart van de, Bressman, Susan, Toft, Mathias, Appel-Cresswell, Silke, Lang, Anthony E., Skorvanek, Matej, Boon, Agnita J. W., Krüger, Rejko, Sammler, Esther M., Tumas, Vitor, Zhang, Bao-Rong, Garraux, Gaetan, Chung, Sun Ju, Kim, Yun Joong, Winkelmann, Juliane, Sue, Carolyn M., Tan, Eng-King, Damásio, Joana, Klivényi, Péter, Kostic, Vladimir S., Arkadir, David, Martikainen, Mika, Borges, Vanderci, Hertz, Jens Michael, Brighina, Laura, Spitz, Mariana, Suchowersky, Oksana, Riess, Olaf, Das, Parimal, Mollenhauer, Brit, Gatto, Emilia M., Petersen, Maria Skaalum, Hattori, Nobutaka, Wu, Ruey-Meei, Illarioshkin, Sergey N., Valente, Enza Maria, Aasly, Jan O., Aasly, Anna, Alcalay, Roy N., Thaler, Avner, Farrer, Matthew J., Brockmann, Kathrin, Corvol, Jean-Christophe, Klein, Christine, on behalf of the MJFF Global Genetic Parkinson's Disease Study Group, Michael J. Fox Foundation for Parkinson's Research, Vollstedt, Eva-Juliane, Schaake, Susen, Lohmann, Katja, Padmanabhan, Shalini, Brice, Alexis, Lesage, Suzanne, Tesson, Christelle, Vidailhet, Marie, Wurster, Isabel, Hentati, Faycel, Mirelman, Anat, Giladi, Nir, Marder, Karen, Waters, Cheryl, Fahn, Stanley, Kasten, Meike, Brüggemann, Norbert, Borsche, Max, Foroud, Tatiana, Tolosa, Eduardo, Garrido, Alicia, Annesi, Grazia, Gagliardi, Monica, Bozi, Maria, Stefanis, Leonidas, Ferreira, Joaquim, Correia Guedes, Leonor, Avenali, Micol, Petrucci, Simona, Clark, Lorraine, Fedotova, Ekaterina Y., Abramycheva, Natalya Y., Alvarez, Victoria, Menéndez-González, Manuel, Jesús Maestre, Silvia, Gómez-Garre, Pilar, Mir, Pablo, Belin, Andrea Carmine, Ran, Caroline, Lin, Chin-Hsien, Kuo, Ming-Che, Crosiers, David, Wszolek, Zbigniew K., Ross, Owen A., Jankovic, Joseph, Nishioka, Kenya, Funayama, Manabu, Clarimon, Jordi, Williams-Gray, Caroline H., Camacho, Marta, Cornejo-Olivas, Mario, Torres-Ramírez, Luis, Wu, Yih-Ru, Lee-Chen, Guey-Jen, Morgadinho, Ana, Pulkes, Teeratorn, Termsarasab, Pichet, Berg, Daniela, Kuhlenbäumer, Gregor, Kühn, Andrea A., Borngräber, Friederike, Michele, Giuseppe de, Rosa, Anna De, Zimprich, Alexander, Puschmann, Andreas, Mellick, George D., Dorszewska, Jolanta, Carr, Jonathan, Ferese, Rosangela, Gambardella, Stefano, Chase, Bruce, Markopoulou, Katerina, Satake, Wataru, Toda, Tatsushi, Rossi, Malco, Merello, Marcelo, Lynch, Timothy, Olszewska, Diana A., Lim, Shen-Yang, Ahmad-Annuar, Azlina, Tan, Ai Huey, Al-Mubarak, Bashayer, Hanagasi, Hasmet, Koziorowski, Dariusz, Ertan, Sibel, Genç, Gençer, Aguiar, Patricia de Carvalho, Barkhuizen, Melinda, Pimentel, Marcia M. G., Saunders-Pullman, Rachel, Warrenburg, Bart van de, Bressman, Susan, Toft, Mathias, Appel-Cresswell, Silke, Lang, Anthony E., Skorvanek, Matej, Boon, Agnita J. W., Krüger, Rejko, Sammler, Esther M., Tumas, Vitor, Zhang, Bao-Rong, Garraux, Gaetan, Chung, Sun Ju, Kim, Yun Joong, Winkelmann, Juliane, Sue, Carolyn M., Tan, Eng-King, Damásio, Joana, Klivényi, Péter, Kostic, Vladimir S., Arkadir, David, Martikainen, Mika, Borges, Vanderci, Hertz, Jens Michael, Brighina, Laura, Spitz, Mariana, Suchowersky, Oksana, Riess, Olaf, Das, Parimal, Mollenhauer, Brit, Gatto, Emilia M., Petersen, Maria Skaalum, Hattori, Nobutaka, Wu, Ruey-Meei, Illarioshkin, Sergey N., Valente, Enza Maria, Aasly, Jan O., Aasly, Anna, Alcalay, Roy N., Thaler, Avner, Farrer, Matthew J., Brockmann, Kathrin, Corvol, Jean-Christophe, Klein, Christine, and on behalf of the MJFF Global Genetic Parkinson's Disease Study Group

Abstract

[Background] As gene-targeted therapies are increasingly being developed for Parkinson's disease (PD), identifying and characterizing carriers of specific genetic pathogenic variants is imperative. Only a small fraction of the estimated number of subjects with monogenic PD worldwide are currently represented in the literature and availability of clinical data and clinical trial-ready cohorts is limited., [Objective] The objectives are to (1) establish an international cohort of affected and unaffected individuals with PD-linked variants; (2) provide harmonized and quality-controlled clinical characterization data for each included individual; and (3) further promote collaboration of researchers in the field of monogenic PD., [Methods] We conducted a worldwide, systematic online survey to collect individual-level data on individuals with PD-linked variants in SNCA, LRRK2, VPS35, PRKN, PINK1, DJ-1, as well as selected pathogenic and risk variants in GBA and corresponding demographic, clinical, and genetic data. All registered cases underwent thorough quality checks, and pathogenicity scoring of the variants and genotype–phenotype relationships were analyzed., [Results] We collected 3888 variant carriers for our analyses, reported by 92 centers (42 countries) worldwide. Of the included individuals, 3185 had a diagnosis of PD (ie, 1306 LRRK2, 115 SNCA, 23 VPS35, 429 PRKN, 75 PINK1, 13 DJ-1, and 1224 GBA) and 703 were unaffected (ie, 328 LRRK2, 32 SNCA, 3 VPS35, 1 PRKN, 1 PINK1, and 338 GBA). In total, we identified 269 different pathogenic variants; 1322 individuals in our cohort (34%) were indicated as not previously published., [Conclusions] Within the MJFF Global Genetic PD Study Group, we (1) established the largest international cohort of affected and unaffected individuals carrying PD-linked variants; (2) provide harmonized and quality-controlled clinical and genetic data for each included individual; (3) promote collaboration in the field of genetic PD with a view toward clinical and genetic stratification of patients for gene-targeted clinical trials. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Published
2023

17. PLA2G6-associated late-onset parkinsonism in a Sudanese family

Author

Bakhit, Yousuf, Tesson, Christelle, Group, Sudanese Parkinson's Disease Study, Ibrahim, Mohamed O, Eltom, Khalid, Eltazi, Isra, Elsayed, Liena E O, Lesage, Suzanne, Seidi, Osheik, Corvol, Jean-Christophe, and Wüllner, Ullrich

Subjects
Adult, genetics [Dystonic Disorders], Group VI Phospholipases A2, PLA2G6 protein, human, genetics [Parkinsonian Disorders], Mutation, Humans, genetics [Group VI Phospholipases A2], ddc:610, Genetic Testing, Middle Aged, genetics [Dystonia]
Abstract

The phospholipase A2 group VI gene (PLA2G6) encodes an enzyme that catalyzes the hydrolytic release of fatty acids from phospholipids. Four neurological disorders with infantile, juvenile, or early adult-onset are associated with PLA2G6 genetic alterations, namely infantile neuroaxonal dystrophy (INAD), atypical neuroaxonal dystrophy (ANAD), dystonia-parkinsonism (DP), and autosomal recessive early-onset parkinsonism (AREP). Few studies in Africa reported PLA2G6-associated disorders and none with parkinsonism of late adult onset.The patients were clinically assessed following UK Brain Bank diagnostic criteria and International Parkinson and Movement Disorder Society's Unified Parkinson's Disease Rating Scale (MDS-UPDRS). Brain MRI without contrast was performed. Genetic testing was done using a custom-made Twist panel, screening 34 known genes, 27 risk factors, and 8 candidate genes associated with parkinsonism. Filtered variants were PCR-amplified and validated using Sanger sequencing and also tested in additional family members to study their segregation.Two siblings born to consanguineous parents developed parkinsonism at the age of 58 and 60 years, respectively. MRI showed an enlarged right hippocampus in patient 2, but no overt abnormalities indicative of INAD or iron deposits. We found two heterozygous variants in PLA2G6, an in-frame deletion NM_003560:c.2070_2072del (p.Val691del) and a missense variant NM_003560:c.956C>T (p.Thr319Met). Both variants were classified as pathogenic.This is the first case in which PLA2G6 is associated with late-onset parkinsonism. Functional analysis is needed to confirm the dual effect of both variants on the structure and function of iPLA2β.

Published
2023

18. 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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19. Confirmation of RAB32 Ser71Arg Involvement in Parkinson's Disease.

Author

Cogan, Guillaume, Tesson, Christelle, Brefel‐Courbon, Christine, Lanore, Aymeric, Kodjovi, Gatepe Cedoine, Welment, Lisa, Clot, Fabienne, Lesage, Suzanne, and Brice, Alexis

Subjects
*PARKINSON'S disease, *MOVEMENT disorders, *MAGNETIC resonance imaging, *SLEEP disorders, *GENETICS
Abstract

This letter discusses the confirmation of the involvement of the RAB32 Ser71Arg variant in Parkinson's disease (PD). The RAB32 gene is one of several genes associated with PD, and this variant has been found in multiple families and unrelated individuals with PD. The variant does not affect the interaction between RAB32 and LRRK2, another protein associated with PD, but it does enhance LRRK2 kinase activation, suggesting its pathogenicity. The variant has been found in individuals from different geographical origins, indicating a common ancestor. The authors also report a case of a patient with the RAB32 Ser71Arg variant in France, confirming its presence in European individuals with PD. The frequency of the variant in European PD cases is 0.1%, but it represents 0.7% of European cases with a family history of PD. The phenotype of individuals with the variant is similar to typical PD, although the response to treatment with levodopa is not as good as previously reported. The authors suggest that the inclusion of the RAB32 Ser71Arg variant in diagnostic strategies is necessary for its identification and for providing genetic counseling to PD patients. [Extracted from the article]

Published
2024
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20. CYP2U1 activity is altered by missense mutations in hereditary spastic paraplegia 56

Author

Durand, Christelle M., Dhers, Laura, Tesson, Christelle, Tessa, Alessandra, Fouillen, Laetitia, Jacqueré, Stéphanie, Raymond, Laure, Coupry, Isabelle, Benard, Giovanni, Darios, Frédéric, El‐ Hachimi, Khalid H., Astrea, Guja, Rivier, François, Banneau, Guillaume, Pujol, Claire, Lacombe, Didier, Durr, Alexandra, Babin, Patrick J., Santorelli, Filippo M., Pietrancosta, Nicolas, Boucher, Jean‐Luc, Mansuy, Daniel, Stevanin, Giovanni, and Goizet, Cyril

Published
2018
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21. Detection of ATXN2 Expansions in an Exome Dataset: An Underdiagnosed Cause of Parkinsonism.

Author

Casse, Fanny, Courtin, Thomas, Tesson, Christelle, Ferrien, Mélanie, Noël, Sandrine, Fauret‐Amsellem, Anne‐Laure, Gareau, Thomas, Guegan, Justine, Anheim, Mathieu, Mariani, Louise‐Laure, Le Forestier, Nadine, Tranchant, Christine, Corvol, Jean‐Christophe, Lesage, Suzanne, and Brice, Alexis

Subjects
PARKINSON'S disease, PARKINSONIAN disorders, SPINOCEREBELLAR ataxia, POLYMERASE chain reaction
Abstract

Background: CAG‐repeat expansions in Ataxin 2 (ATXN2) are known to cause spinocerebellar ataxia type 2 (SCA2), but CAA interrupted expansions may also result in autosomal dominant Parkinson's disease (AD PD). However, because of technical limitations, such expansions are not explored in whole exome sequencing (WES) data. Objectives: To identify ATXN2 expansions using WES data from PD cases. Methods: We explored WES data from a cohort of 477 index cases with PD using ExpansionHunter (Illumina DRAGEN Bio‐IT Platform, San Diego, CA). Putative expansions were confirmed by combining polymerase chain reaction and fragment length analysis followed by sub‐cloning and sequencing methods. Results: Using ExpansionHunter, we identified three patients from two families with AD PD carrying either ATXN2 22/39 or 22/37 repeats, both interrupted by four CAA repeats. Conclusion: These findings demonstrate the usefulness of WES to detect pathogenic CAG repeat expansions, which were found in 1.7% of AD PD in the ATXN2 gene in our exome dataset. [ABSTRACT FROM AUTHOR]

Published
2023
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25. Correction: Clinical, neuropathological, and genetic characterization of STUB1 variants in cerebellar ataxias: a frequent cause of predominant cognitive impairment

Author

Roux, Thomas, primary, Barbier, Mathieu, additional, Papin, Mélanie, additional, Davoine, Claire-Sophie, additional, Sayah, Sabrina, additional, Coarelli, Giulia, additional, Charles, Perrine, additional, Marelli, Cecilia, additional, Parodi, Livia, additional, Tranchant, Christine, additional, Goizet, Cyril, additional, Klebe, Stephan, additional, Lohmann, Ebba, additional, Van Maldergem, Lionel, additional, van Broeckhoven, Christine, additional, Coutelier, Marie, additional, Tesson, Christelle, additional, Stevanin, Giovanni, additional, Duyckaerts, Charles, additional, Brice, Alexis, additional, Durr, Alexandra, additional, Darios, Frédéric, additional, Forlani, Sylvie, additional, Site, Pitié-Salpêtrière, additional, Banneau, Guillaume, additional, Cazeneuve, Cécile, additional, Fontaine, Bertrand, additional, Azulay, Jean-Philippe, additional, Boesfplug-Tanguy, Odile, additional, Hannequin, Didier, additional, Hazan, Jamilé, additional, Burgo, Andrea, additional, Verny, Christophe, additional, Koenig, Michel, additional, Labauge, Pierre, additional, N’guyen, Karine, additional, Rodriguez, Diana, additional, Belarbi, Soraya, additional, Hamri, Abdelmadjid, additional, Tazir, Meriem, additional, Boesch, Sylvia, additional, Pandolfo, Massimo, additional, Laura, Jardim, additional, Guergueltcheva, Velina, additional, Tournev, Ivalo, additional, Pedraza Linarès, Olga Lucia, additional, Nielsen, Jørgen E., additional, Svenstrup, Kirsten, additional, Zaki, Maha, additional, Bauer, Peter, additional, Schöls, Lüdger, additional, Schüle, Rebecca, additional, Lossos, Alexander, additional, Bassi, Maria-Teresa, additional, Basso, Manuela, additional, Bertini, Enrico, additional, Brusco, Alfredo, additional, Casali, Carlo, additional, Casari, Giorgio, additional, Criscuolo, Chiara, additional, Filla, Alessandro, additional, Orsi, Laura, additional, Santorelli, Filippo M., additional, Valente, Enza Maria, additional, Vavla, Marinela, additional, Vazza, Giovanni, additional, Megarbane, André, additional, Benomar, Ali, additional, Kremer, Berry, additional, Van Roon-Mom, Willeke, additional, Roxburgh, Richard, additional, Erichsen, Anne Kjersti, additional, Tallaksen, Chantal, additional, Alonso, Isabel, additional, Coutinho, Paula, additional, Loureiro, José Léal, additional, Sequeiros, Jorge, additional, Salih, Mustapha, additional, Kostic, Vladimir S, additional, Rouco Axpe, Idoia, additional, Elsayed, Liena, additional, Paucar, Martin Arce, additional, Roumani, Samir, additional, Bing-Wen, Soong, additional, Reid, Evan, additional, Suran, Nethisinghe, additional, Warner, Thomas, additional, and Wood, Nicholas, additional

Published
2021
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26. Spinocerebellar ataxia type 36 exists in diverse populations and can be caused by a short hexanucleotide GGCCTG repeat expansion

Author

Obayashi, Masato, Stevanin, Giovanni, Synofzik, Matthis, Monin, Marie-Lorraine, Duyckaerts, Charles, Sato, Nozomu, Streichenberger, Nathalie, Vighetto, Alain, Desestret, Virginie, Tesson, Christelle, Wichmann, H-Erich, Illig, Thomas, Huttenlocher, Johanna, Kita, Yasushi, Izumi, Yuishin, Mizusawa, Hidehiro, Schöls, Ludger, Klopstock, Thomas, Brice, Alexis, Ishikawa, Kinya, and Dürr, Alexandra

Published
2015
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27. Clinical Variability of SYNJ1-Associated Early-Onset Parkinsonism

Author

Lesage, Suzanne, primary, Mangone, Graziella, additional, Tesson, Christelle, additional, Bertrand, Hélène, additional, Benmahdjoub, Mustapha, additional, Kesraoui, Selma, additional, Arezki, Mohamed, additional, Singleton, Andrew, additional, Corvol, Jean-Christophe, additional, and Brice, Alexis, additional

Published
2021
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28. Genetic and phenotypic basis of autosomal dominant Parkinson's disease in a large multi-center cohort

Author

Lesage, Suzanne, Houot, Marion, Mangone, Graziella, Tesson, Christelle, Bertrand, Hélène, Forlani, Sylvie, Anheim, Mathieu, Brefel-Courbon, Christine, Broussolle, Emmanuel, Thobois, Stephane, Damier, Philippe, Durif, Franck, Roze, Emmanuel, Tison, François, Grabli, David, Ory-Magne, Fabienne, Degos, Bertrand, Viallet, François, Cormier-Dequaire, Florence, Ouvrard-Hernandez, Anne-Marie, Vidailhet, Marie, Lohmann, Ebba, Singleton, Andrew, Corvol, Jean-Christophe, Brice, Alexis, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)

Subjects
[SCCO]Cognitive science, Genotype-Phenotype correlations, [SCCO.NEUR]Cognitive science/Neuroscience, Autosomal dominant inheritance, Parkinson’s disease, G2019S, LRRK2, SNCA, MESH: Parkinson’s disease, SNCA, VPS35, VPS35
Abstract

International audience; LRRK2, SNCA and VPS35 are unequivocally associated with autosomal dominant Parkinson’s disease (PD). We evaluated the prevalence of LRRK2, SNCA and VPS35 mutations and associated clinical features in a large French multi-center cohort of PD patients. Demographic and clinical data were collected for 1805 index cases (592 with autosomal dominant inheritance and 1213 isolated cases) since 1990. All probands were screened with TaqMan assays for LRRK2 Gly2019Ser. In the absence of this mutation, the coding sequences of the three genes were analyzed by Sanger sequencing and/or next-generation sequencing. The data for the three genes were analyzed according to age at onset, family history, ethnic origin and clinical features. We identified 160 index cases (8.9%) with known pathogenic variants: 138 with pathogenic LRRK2 variants (7.6%), including 136 with the Gly2019Ser mutation, 19 with SNCA point mutations or genomic rearrangements (1.1%), and three with the VPS35 Asp620Asn mutation (0.16%). Mutation frequencies were higher in familial than isolated cases, consistent with autosomal dominant inheritance (12.0% vs. 7.3%; OR 1.7, 95% CI [1.2-2.4], p = 0.003). PD patients with LRRK2 variants were more likely to have higher rates of late-onset PD (> 50 years; OR 1.5, 95% CI [1.0-2.2], p = 0.03), whereas those with SNCA mutations tended to have earlier age at onset disease (≤ 50 years, p = 0.06). The clinical features of LRRK2 carriers and those without any pathogenic variants in known PD-associated genes were similar. The likelihood of detecting disease-causing mutations was higher in cases compatible with autosomal dominant inheritance.

Published
2020

29. Characterization of recessive Parkinson's disease in a large multicenter study

Author

Lesage, Suzanne, Lunati, Ariane, Houot, Marion, Romdhan, Sawssan, Clot, Fabienne, Tesson, Christelle, Mangone, Graziella, Le Toullec, Benjamin, Courtin, Thomas, Larcher, Kathy, Benmahdjoub, Mustapha, Arezki, Mohammed, Bouhouche, Ahmed, Anheim, Mathieu, Roze, Emmanuel, Viallet, François, Tison, François, Broussolle, Emmanuel, Emre, Murat, Hanagasi, Hasmet, Bilgic, Basar, Tazir, Meriem, Djebara, Mouna, Gouider, Riadh, Tranchant, Christine, Vidailhet, Marie, Le Guern, Eric, Corti, Olga, Mhiri, Chokri, Lohmann, Ebba, Singleton, Andrew, Corvol, Jean-Christophe, Brice, Alexis, 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), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Mohammed V de Rabat [Agdal] (UM5), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Laboratoire Parole et Langage (LPL), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Institut des sciences cognitives Marc Jeannerod - Centre de neuroscience cognitive - UMR5229 (ISC-MJ), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Istanbul University, and National Institutes of Health [Bethesda] (NIH)

Subjects
[SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], genotype-phenotype correlations, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, PINK1, [SCCO.NEUR]Cognitive science/Neuroscience, Parkinson’s disease, PRKN, autosomal recessive inheritance
Abstract

International audience; Studies of the phenotype and population distribution of rare genetic forms of parkinsonism are required, now that gene‐targeting approaches for Parkinson disease have reached the clinical trial stage. We evaluated the frequencies of PRKN, PINK1, and DJ‐1 mutations in a cohort of 1,587 cases. Mutations were found in 14.1% of patients; 27.6% were familial and 8% were isolated. PRKN was the gene most frequently mutated in Caucasians, whereas PINK1 mutations predominated in Arab‐Berber individuals. Patients with PRKN mutations had an earlier age at onset, and less asymmetry, levodopa‐induced motor complications, dysautonomia, and dementia than those without mutations

Published
2020

30. Clinical, neuropathological, and genetic characterization of STUB1 variants in cerebellar ataxias:a frequent cause of predominant cognitive impairment

Author

Roux, Thomas, Barbier, Mathieu, Papin, Mélanie, Davoine, Claire Sophie, Sayah, Sabrina, Coarelli, Giulia, Charles, Perrine, Marelli, Cecilia, Parodi, Livia, Tranchant, Christine, Goizet, Cyril, Klebe, Stephan, Lohmann, Ebba, Van Maldergen, Lionel, van Broeckhoven, Christine, Coutelier, Marie, Tesson, Christelle, Stevanin, Giovanni, Duyckaerts, Charles, Brice, Alexis, Durr, Alexandra, Darios, Frédéric, Forlani, Sylvie, Site, Pitié Salpêtrière, Banneau, Guillaume, Cazeneuve, Cécile, Fontaine, Bertrand, Azulay, Jean Philippe, Boesfplug-Tanguy, Odile, Hannequin, Didier, Hazan, Jamilé, Burgo, Andrea, Verny, Christophe, Koenig, Michel, Labauge, Pierre, N’guyen, Karine, Rodriguez, Diana, Belarbi, Soraya, Hamri, Abdelmadjid, Tazir, Meriem, Boesch, Sylvia, Nielsen, Jørgen E., Svenstrup, Kirsten, Roux, Thomas, Barbier, Mathieu, Papin, Mélanie, Davoine, Claire Sophie, Sayah, Sabrina, Coarelli, Giulia, Charles, Perrine, Marelli, Cecilia, Parodi, Livia, Tranchant, Christine, Goizet, Cyril, Klebe, Stephan, Lohmann, Ebba, Van Maldergen, Lionel, van Broeckhoven, Christine, Coutelier, Marie, Tesson, Christelle, Stevanin, Giovanni, Duyckaerts, Charles, Brice, Alexis, Durr, Alexandra, Darios, Frédéric, Forlani, Sylvie, Site, Pitié Salpêtrière, Banneau, Guillaume, Cazeneuve, Cécile, Fontaine, Bertrand, Azulay, Jean Philippe, Boesfplug-Tanguy, Odile, Hannequin, Didier, Hazan, Jamilé, Burgo, Andrea, Verny, Christophe, Koenig, Michel, Labauge, Pierre, N’guyen, Karine, Rodriguez, Diana, Belarbi, Soraya, Hamri, Abdelmadjid, Tazir, Meriem, Boesch, Sylvia, Nielsen, Jørgen E., and Svenstrup, Kirsten

Abstract

Purpose: Pathogenic variants in STUB1 were initially described in autosomal recessive spinocerebellar ataxia type 16 and dominant cerebellar ataxia with cerebellar cognitive dysfunction (SCA48). Methods: We analyzed a large series of 440 index cerebellar ataxia cases, mostly with dominant inheritance. Results: STUB1 variants were detected in 50 patients. Age at onset and severity were remarkably variable. Cognitive impairment, predominantly frontal syndrome, was observed in 54% of STUB1 variant carriers, including five families with Huntington or frontotemporal dementia disease–like phenotypes associated with ataxia, while no STUB1 variant was found in 115 patients with frontotemporal dementia. We report neuropathological findings of a STUB1 heterozygous patient, showing massive loss of Purkinje cells in the vermis and major loss in the cerebellar hemispheres without atrophy of the pons, hippocampus, or cerebral cortex. This screening of STUB1 variants revealed new features: (1) the majority of patients were women (70%) and (2) “second hits” in AFG3L2, PRKCG, and TBP were detected in three families suggesting synergic effects. Conclusion: Our results reveal an unexpectedly frequent (7%) implication of STUB1 among dominantly inherited cerebellar ataxias, and suggest that the penetrance of STUB1 variants could be modulated by other factors, including sex and variants in other ataxia-related genes.

Published
2020

31. Clinical, neuropathological, and genetic characterization of STUB1 variants in cerebellar ataxias: a frequent cause of predominant cognitive impairment

Author

Roux, Thomas, primary, Barbier, Mathieu, additional, Papin, Mélanie, additional, Davoine, Claire-Sophie, additional, Sayah, Sabrina, additional, Coarelli, Giulia, additional, Charles, Perrine, additional, Marelli, Cecilia, additional, Parodi, Livia, additional, Tranchant, Christine, additional, Goizet, Cyril, additional, Klebe, Stephan, additional, Lohmann, Ebba, additional, Van Maldergem, Lionel, additional, van Broeckhoven, Christine, additional, Coutelier, Marie, additional, Tesson, Christelle, additional, Stevanin, Giovanni, additional, Duyckaerts, Charles, additional, Brice, Alexis, additional, Durr, Alexandra, additional, Darios, Frédéric, additional, Forlani, Sylvie, additional, Site, Pitié-Salpêtrière, additional, Banneau, Guillaume, additional, Cazeneuve, Cécile, additional, Fontaine, Bertrand, additional, Azulay, Jean-Philippe, additional, Boesfplug-Tanguy, Odile, additional, Hannequin, Didier, additional, Hazan, Jamilé, additional, Burgo, Andrea, additional, Verny, Christophe, additional, Koenig, Michel, additional, Labauge, Pierre, additional, N’guyen, Karine, additional, Rodriguez, Diana, additional, Belarbi, Soraya, additional, Hamri, Abdelmadjid, additional, Tazir, Meriem, additional, Boesch, Sylvia, additional, Pandolfo, Massimo, additional, Laura, Jardim, additional, Guergueltcheva, Velina, additional, Tournev, Ivalo, additional, Pedraza Linarès, Olga Lucia, additional, Nielsen, Jørgen E., additional, Svenstrup, Kirsten, additional, Zaki, Maha, additional, Bauer, Peter, additional, Schöls, Lüdger, additional, Schüle, Rebecca, additional, Lossos, Alexander, additional, Bassi, Maria-Teresa, additional, Basso, Manuela, additional, Bertini, Enrico, additional, Brusco, Alfredo, additional, Casali, Carlo, additional, Casari, Giorgio, additional, Criscuolo, Chiara, additional, Filla, Alessandro, additional, Orsi, Laura, additional, Santorelli, Filippo M., additional, Valente, Enza Maria, additional, Vavla, Marinela, additional, Vazza, Giovanni, additional, Megarbane, André, additional, Benomar, Ali, additional, Kremer, Berry, additional, Van Roon-Mom, Willeke, additional, Roxburgh, Richard, additional, Erichsen, Anne Kjersti, additional, Tallaksen, Chantal, additional, Alonso, Isabel, additional, Coutinho, Paula, additional, Loureiro, José Léal, additional, Sequeiros, Jorge, additional, Salih, Mustapha, additional, Kostic, Vladimir S., additional, Rouco Axpe, Idoia, additional, Elsayed, Liena, additional, Paucar, Martin Arce, additional, Roumani, Samir, additional, Bing-Wen, Soong, additional, Reid, Evan, additional, Suran, Nethisinghe, additional, Warner, Thomas, additional, and Wood, Nicholas, additional

Published
2020
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33. Mutations in KCND3 cause spinocerebellar ataxia type 22

Author

Lee, Yi-Chung, Durr, Alexandra, Majczenko, Karen, Huang, Yen-Hua, Liu, Yu-Chao, Lien, Cheng-Chang, Tsai, Pei-Chien, Ichikawa, Yaeko, Goto, Jun, Monin, Marie-Lorraine, Li, Jun Z., Chung, Ming-Yi, Mundwiller, Emeline, Shakkottai, Vikram, Liu, Tze-Tze, Tesson, Christelle, Lu, Yi-Chun, Brice, Alexis, Tsuji, Shoji, Burmeister, Margit, Stevanin, Giovanni, and Soong, Bing-Wen

Published
2012
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35. CYP7B1 mutations in pure and complex forms of hereditary spastic paraplegia type 5

Author

Goizet, Cyril, Boukhris, Amir, Durr, Alexandra, Beetz, Christian, Truchetto, Jeremy, Tesson, Christelle, Tsaousidou, Maria, Forlani, Sylvie, Guyant-Maréchal, Lucie, Fontaine, Bertrand, Guimarães, João, Isidor, Bertrand, Chazouillères, Olivier, Wendum, Dominique, Grid, Djamel, Chevy, Françoise, Chinnery, Patrick F., Coutinho, Paula, Azulay, Jean-Philippe, Feki, Imed, Mochel, Fanny, Wolf, Claude, Mhiri, Chokri, Crosby, Andrew, Brice, Alexis, and Stevanin, Giovanni

Published
2009

36. LRRK2 impairs PINK1/Parkin-dependent mitophagy via its kinase activity: pathologic insights into Parkinson’s disease

Author

Bonello, Fiona, primary, Hassoun, Sidi-Mohamed, additional, Mouton-Liger, François, additional, Shin, Yea Seul, additional, Muscat, Adeline, additional, Tesson, Christelle, additional, Lesage, Suzanne, additional, Beart, Philip M, additional, Brice, Alexis, additional, Krupp, Johannes, additional, Corvol, Jean-Christophe, additional, and Corti, Olga, additional

Published
2019
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37. Genetic and Phenotypic Characterisation of Autosomal Recessive Parkinson's Disease in a Large Multicentre Cohort

Author

Lesage, Suzanne, primary, Lunati, Ariane, additional, Houot, Marion, additional, Benromdhan, Sawssan, additional, Clot, Fabienne, additional, Tesson, Christelle, additional, Mangone, Graziella, additional, Le Toullec, Benjamin, additional, Courtin, Thomas, additional, Larcher, Kathy, additional, Benmahdjoub, Mustapha, additional, Arezki, Mohammed, additional, Bouhouche, Ahmed, additional, Anheim, Mathieu, additional, Roze, Emmanuel, additional, Viallet, François, additional, Tison, François, additional, Broussolle, Emmanuel, additional, Emre, Murat, additional, Tazir, Meriem, additional, Tranchant, Christine, additional, Vidailhet, Marie, additional, Le Guern, Eric, additional, Corti, Olga, additional, Mhiri, Chokri, additional, Lohmann, Ebba, additional, Singleton, Andrew B., additional, Corvol, Jean-Christophe, additional, Brice, Alexis, additional, and Group (PDG), French Parkinson’s Disease Genetics, additional

Published
2019
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38. LRP10 in α-synucleinopathies

Author

Tesson, Christelle, primary, Brefel-Courbon, Christine, additional, Corvol, Jean-Christophe, additional, Lesage, Suzanne, additional, Brice, Alexis, additional, Agid, Yves, additional, Anheim, Mathieu, additional, Bonnet, A.-M., additional, Borg, Michel, additional, Broussolle, Emmanuel, additional, Damier, Philippe, additional, Destée, Alain, additional, Dürr, Alexandra, additional, Durif, Franck, additional, Lohmann, Ebba, additional, Martinez, Maria, additional, Pollak, Pierre, additional, Rascol, Olivier, additional, Tison, François, additional, Tranchant, Christine, additional, Vérin, Marc, additional, Viallet, François, additional, and Vidailhet, Marie, additional

Published
2018
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39. The E3 Ubiquitin Ligases TRIM17 and TRIM41 Modulate α-Synuclein Expression by Regulating ZSCAN21

Author

Lassot, Iréna, primary, Mora, Stéphan, additional, Lesage, Suzanne, additional, Zieba, Barbara A., additional, Coque, Emmanuelle, additional, Condroyer, Christel, additional, Bossowski, Jozef Piotr, additional, Mojsa, Barbara, additional, Marelli, Cecilia, additional, Soulet, Caroline, additional, Tesson, Christelle, additional, Carballo-Carbajal, Iria, additional, Laguna, Ariadna, additional, Mangone, Graziella, additional, Vila, Miquel, additional, Brice, Alexis, additional, and Desagher, Solange, additional

Published
2018
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40. The E3 Ubiquitin Ligases TRIM17 and TRIM41 Modulate α-Synuclein Expression by Regulating ZSCAN21

Author

Lassot, Irena, Mora, Stéphan, Lesage, Suzanne, Zieba, Barbara, Coque, Emmanuelle, Condroyer, Christel, Bossowski, Jozef, Mojsa, Barbara, Marelli, Cécilia, Soulet, Caroline, Tesson, Christelle, Carballo-Carbajal, Iria, Laguna, Ariadna, Mangone, Graziella, Vila, Miquel, Brice, Alexis, Desagher, Solange, Institut de Génétique Moléculaire de Montpellier (IGMM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université - Faculté de Médecine (SU FM), Sorbonne Université (SU), Centro de Investigacion Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III [Madrid] (ISC), and University of Barcelona

Subjects
Male, Transcription, Genetic, TRIM17, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Ubiquitin-Protein Ligases, Kruppel-Like Transcription Factors, Cell Line, Tripartite Motif Proteins, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Animals, Humans, transcriptional regulation, ZSCAN21, α-synuclein/SNCA, Amino Acid Sequence, Base Sequence, Ubiquitination, Nuclear Proteins, E3 ubiquitin-ligases, Pedigree, Parkinson disease, Mice, Inbred C57BL, Gene Expression Regulation, Mutation, Proteolysis, Trans-Activators, alpha-Synuclein, Female, ubiquitin-proteasome system, TRIM41, Carrier Proteins, Protein Binding
Abstract

International audience; Although accumulating data indicate that increased α-synuclein expression is crucial for Parkinson disease (PD), mechanisms regulating the transcription of its gene, SNCA, are largely unknown. Here, we describe a pathway regulating α-synuclein expression. Our data show that ZSCAN21 stimulates SNCA transcription in neuronal cells and that TRIM41 is an E3 ubiquitin ligase for ZSCAN21. In contrast, TRIM17 decreases the TRIM41-mediated degradation of ZSCAN21. Silencing of ZSCAN21 and TRIM17 consistently reduces SNCA expression, whereas TRIM41 knockdown increases it. The mRNA levels of TRIM17, ZSCAN21, and SNCA are simultaneously increased in the midbrains of mice following MPTP treatment. In addition, rare genetic variants in ZSCAN21, TRIM17, and TRIM41 genes occur in patients with familial forms of PD. Expression of variants in ZSCAN21 and TRIM41 genes results in the stabilization of the ZSCAN21 protein. Our data thus suggest that deregulation of the TRIM17/TRIM41/ZSCAN21 pathway may be involved in the pathogenesis of PD.

Published
2017

42. CYP2U1 activity is altered by missense mutations in hereditary spastic paraplegia 56

Author

Durand, Christelle M., primary, Dhers, Laura, additional, Tesson, Christelle, additional, Tessa, Alessandra, additional, Fouillen, Laetitia, additional, Jacqueré, Stéphanie, additional, Raymond, Laure, additional, Coupry, Isabelle, additional, Benard, Giovanni, additional, Darios, Frédéric, additional, El- Hachimi, Khalid H., additional, Astrea, Guja, additional, Rivier, François, additional, Banneau, Guillaume, additional, Pujol, Claire, additional, Lacombe, Didier, additional, Durr, Alexandra, additional, Babin, Patrick J., additional, Santorelli, Filippo M., additional, Pietrancosta, Nicolas, additional, Boucher, Jean-Luc, additional, Mansuy, Daniel, additional, Stevanin, Giovanni, additional, and Goizet, Cyril, additional

Published
2017
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43. Mutation Analysis of Consanguineous Moroccan Patients with Parkinson’s Disease Combining Microarray and Gene Panel

Author

Bouhouche, Ahmed, primary, Tesson, Christelle, additional, Regragui, Wafaa, additional, Rahmani, Mounia, additional, Drouet, Valérie, additional, Tibar, Houyam, additional, Souirti, Zouhayr, additional, Ben El Haj, Rafiqua, additional, Bouslam, Naima, additional, Yahyaoui, Mohamed, additional, Brice, Alexis, additional, Benomar, Ali, additional, and Lesage, Suzanne, additional

Published
2017
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44. A panel study on patients with dominant cerebellar ataxia highlights the frequency of channelopathies.

Author

UCL - SSS/DDUV - Institut de Duve, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Centre de génétique médicale UCL, Coutelier, Marie, Coarelli, Giulia, Monin, Marie-Lorraine, Konop, Juliette, Davoine, Claire-Sophie, Tesson, Christelle, Valter, Rémi, Anheim, Mathieu, Behin, Anthony, Castelnovo, Giovanni, Charles, Perrine, David, Albert, Ewenczyk, Claire, Fradin, Mélanie, Goizet, Cyril, Hannequin, Didier, Labauge, Pierre, Riant, Florence, Sarda, Pierre, Sznajer, Yves, Tison, François, Ullmann, Urielle, Van Maldergem, Lionel, Mochel, Fanny, Brice, Alexis, Stevanin, Giovanni, Durr, Alexandra, SPATAX network, UCL - SSS/DDUV - Institut de Duve, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Centre de génétique médicale UCL, Coutelier, Marie, Coarelli, Giulia, Monin, Marie-Lorraine, Konop, Juliette, Davoine, Claire-Sophie, Tesson, Christelle, Valter, Rémi, Anheim, Mathieu, Behin, Anthony, Castelnovo, Giovanni, Charles, Perrine, David, Albert, Ewenczyk, Claire, Fradin, Mélanie, Goizet, Cyril, Hannequin, Didier, Labauge, Pierre, Riant, Florence, Sarda, Pierre, Sznajer, Yves, Tison, François, Ullmann, Urielle, Van Maldergem, Lionel, Mochel, Fanny, Brice, Alexis, Stevanin, Giovanni, Durr, Alexandra, and SPATAX network

Abstract

Autosomal dominant cerebellar ataxias have a marked heterogeneous genetic background, with mutations in 34 genes identified so far. This large amount of implicated genes accounts for heterogeneous clinical presentations, making genotype-phenotype correlations a major challenge in the field. While polyglutamine ataxias, linked to CAG repeat expansions in genes such as ATXN1, ATXN2, ATXN3, ATXN7, CACNA1A and TBP, have been extensively characterized in large cohorts, there is a need for comprehensive assessment of frequency and phenotype of more 'conventional' ataxias. After exclusion of CAG/polyglutamine expansions in spinocerebellar ataxia genes in 412 index cases with dominantly inherited cerebellar ataxias, we aimed to establish the relative frequencies of mutations in other genes, with an approach combining panel sequencing and TaqMan® polymerase chain reaction assay. We found relevant genetic variants in 59 patients (14.3%). The most frequently mutated were channel genes [CACNA1A (n = 16), KCND3 (n = 4), KCNC3 (n = 2) and KCNA1 (n = 2)]. Deletions in ITPR1 (n = 11) were followed by biallelic variants in SPG7 (n = 9). Variants in AFG3L2 (n = 7) came next in frequency, and variants were rarely found in STBN2 (n = 2), ELOVL5, FGF14, STUB1 and TTBK2 (n = 1 each). Interestingly, possible risk factor variants were detected in SPG7 and POLG. Clinical comparisons showed that ataxias due to channelopathies had a significantly earlier age at onset with an average of 24.6 years, versus 40.9 years for polyglutamine expansion spinocerebellar ataxias and 37.8 years for SPG7-related forms (P = 0.001). In contrast, disease duration was significantly longer in the former (20.5 years versus 9.3 and 13.7, P=0.001), though for similar functional stages, indicating slower progression of the disease. Of interest, intellectual deficiency was more frequent in channel spinocerebellar ataxias, while cognitive impairment in adulthood was similar among the three groups. Similar differences

Published
2017

45. Analyse génétique de patients consanguins Marocains atteints de la maladie de Parkinson combinant puce à ADN et panel de gènes

Author

Regragui Wafaa, Lesage Suzanne, Tibar Houyam, A. Bouhouche, Tesson Christelle, Brice Alexis, and Rahmani Mounia

Subjects
Neurology, Neurology (clinical)
Abstract

Introduction Jusqu’a present, 14 genes ont ete signales comme etant responsables de la forme monogenique de la maladie de Parkinson (MP), representant une frequence mondiale de 5 a 10 %. Parmi eux, 10 genes ont ete associes a la forme autosomique recessive. Objectifs Determiner le profile genetique d’une cohorte de patients consanguins d’origine Marocaine atteints de MP par la combinaison des technologies des puces a ADN et de panel de genes en sequencage nouvel generation (NGS). Methodes L’ADN de 18 patients, nes d’un mariage consanguin (14 cas isoles et 4 cas familiaux), a ete examine pour des rearrangements d’exon dans le gene PRKN en utilisant la puce Cytoscan HD (Affymetrix). Celui des patients n’ayant pas de rearrangements a ete analyse par sequencage Sanger des genes candidats au niveau des regions d’homozygotie (ROH) ou par NGS par l’utilisation d’un panel contenant 22 genes associes a la MP. Resultats Nous avons trouve des deletions d’exons du gene PRKN homozygotes chez 2 patients et heterozygotes composites chez 1 patient. Deux autres patients ont montre une ROH du locus 1p36.12 et presentent des mutations ponctuelles homozygotes Q456X et L539F du gene PINK1. L’analyse des 13 patients restant par panel NGS a montre une mutation homozygote W258X du gene ATP13A2 chez 2 patients et une mutation a l’etat heterozygote affectant le cadre de lecture dans SYNJ1 chez un patient avec un debut tardif (76 ans). Discussion L’analyse clinique a montre que les patients ayant la mutation ATP13A2 developpaient une MP debutante avec un phenotype severe, alors que les patients ayant des mutations PRKN ou PINK1 presentaient une MP a debut precoce avec un phenotype relativement benin. Conclusion En identifiant des mutations pathogenes dans 45 % (8/18) de notre serie MP, nous montrons que la combinaison de l’analyse par biopuces chromosomiques et du NGS est une approche puissante pour identifier les bases genetiques de la forme recessive de MP. Informations complementaires Ce travail a ete finance par le Centre national de recherche scientifique et technique du Ministere de l’enseignement superieur, de la recherche scientifique et de la formation des cadres du Maroc.

Published
2018

46. Lack of evidence for a role of genetic variation in TMEM230 in the risk for Parkinson's disease in the Caucasian population

Author

Giri, Anamika, primary, Mok, Kin Y., additional, Jansen, Iris, additional, Sharma, Manu, additional, Tesson, Christelle, additional, Mangone, Graziella, additional, Lesage, Suzanne, additional, Bras, José M., additional, Shulman, Joshua M., additional, Sheerin, Una-Marie, additional, Díez-Fairen, Mónica, additional, Pastor, Pau, additional, Martí, María José, additional, Ezquerra, Mario, additional, Tolosa, Eduardo, additional, Correia-Guedes, Leonor, additional, Ferreira, Joaquim, additional, Amin, Najaf, additional, van Duijn, Cornelia M., additional, van Rooij, Jeroen, additional, Uitterlinden, André G., additional, Kraaij, Robert, additional, Nalls, Michael, additional, and Simón-Sánchez, Javier, additional

Published
2017
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47. Mitochondrial morphology and cellular distribution are altered in SPG31 patients and are linked to DRP1 hyperphosphorylation

Author

Lavie, Julie, primary, Serrat, Román, additional, Bellance, Nadège, additional, Courtand, Gilles, additional, Dupuy, Jean-William, additional, Tesson, Christelle, additional, Coupry, Isabelle, additional, Brice, Alexis, additional, Lacombe, Didier, additional, Durr, Alexandra, additional, Stevanin, Giovanni, additional, Darios, Fréderic, additional, Rossignol, Rodrigue, additional, Goizet, Cyril, additional, and Bénard, Giovanni, additional

Published
2016
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48. LRP10 in α-synucleinopathies

Author

Agid, Yves, Anheim, Mathieu, Bonnet, A.-M., Borg, Michel, Brefel-Courbon, Christine, Brice, Alexis, Broussolle, Emmanuel, Corvol, Jean-Christophe, Damier, Philippe, Destée, Alain, Dürr, Alexandra, Durif, Franck, Lesage, Suzanne, Lohmann, Ebba, Martinez, Maria, Pollak, Pierre, Rascol, Olivier, Tison, François, Tranchant, Christine, Vérin, Marc, Viallet, François, Vidailhet, Marie, and Tesson, Christelle

Published
2018
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49. Expanding the Spectrum of Genes Involved in Huntington Disease Using a Combined Clinical and Genetic Approach

Author

Mariani, Louise-Laure, primary, Tesson, Christelle, additional, Charles, Perrine, additional, Cazeneuve, Cécile, additional, Hahn, Valérie, additional, Youssov, Katia, additional, Freeman, Leorah, additional, Grabli, David, additional, Roze, Emmanuel, additional, Noël, Sandrine, additional, Peuvion, Jean-Noel, additional, Bachoud-Levi, Anne-Catherine, additional, Brice, Alexis, additional, Stevanin, Giovanni, additional, and Durr, Alexandra, additional

Published
2016
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50. Spinocerebellar ataxia type 36 exists in diverse populations and can be caused by a short hexanucleotide GGCCTG repeat expansion

Author

Obayashi, Masato, primary, Stevanin, Giovanni, additional, Synofzik, Matthis, additional, Monin, Marie-Lorraine, additional, Duyckaerts, Charles, additional, Sato, Nozomu, additional, Streichenberger, Nathalie, additional, Vighetto, Alain, additional, Desestret, Virginie, additional, Tesson, Christelle, additional, Wichmann, H-Erich, additional, Illig, Thomas, additional, Huttenlocher, Johanna, additional, Kita, Yasushi, additional, Izumi, Yuishin, additional, Mizusawa, Hidehiro, additional, Schöls, Ludger, additional, Klopstock, Thomas, additional, Brice, Alexis, additional, Ishikawa, Kinya, additional, and Dürr, Alexandra, additional

Published
2014
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