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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. 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

5. 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

6. 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

7. 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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8. 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

9. 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

10. 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

12. 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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14. 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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15. 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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16. 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

17. 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

19. 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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20. 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

21. 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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22. 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

23. 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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25. 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

26. 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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27. 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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28. A panel study on patients with dominant cerebellar ataxia highlights the frequency of channelopathies.

Author

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, and Sznajer, Yves

Subjects
CEREBELLAR ataxia, GENOTYPES, POLYGLUTAMINE, MOVEMENT disorders, DISEASE duration, PROGNOSIS, AGE factors in disease, CALCIUM, DEGENERATION (Pathology), GENES, LONGITUDINAL method, PROTEOLYTIC enzymes, PHENOTYPES
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 were found among a single gene group, comparing 23 patients with CACNA1A expansions (spinocerebellar ataxia 6) to 22 patients with CACNA1A point mutations, which had lower average age at onset (25.2 versus 47.3 years) with longer disease duration (18.7 versus 10.9), but lower severity indexes (0.39 versus 0.44), indicating slower progression of the disease. In conclusion, we identified relevant genetic variations in up to 15% of cases after exclusion of polyglutamine expansion spinocerebellar ataxias, and confirmed CACNA1A and SPG7 as major ataxia genes. We could delineate firm genotype-phenotype correlations that are important for genetic counselling and of possible prognostic value. [ABSTRACT FROM AUTHOR]

Published
2017
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29. ELOVL5 Mutations Cause Spinocerebellar Ataxia 38

Author

Di Gregorio, Eleonora, primary, Borroni, Barbara, additional, Giorgio, Elisa, additional, Lacerenza, Daniela, additional, Ferrero, Marta, additional, Lo Buono, Nicola, additional, Ragusa, Neftj, additional, Mancini, Cecilia, additional, Gaussen, Marion, additional, Calcia, Alessandro, additional, Mitro, Nico, additional, Hoxha, Eriola, additional, Mura, Isabella, additional, Coviello, Domenico A., additional, Moon, Young-Ah, additional, Tesson, Christelle, additional, Vaula, Giovanna, additional, Couarch, Philippe, additional, Orsi, Laura, additional, Duregon, Eleonora, additional, Papotti, Mauro Giulio, additional, Deleuze, Jean-François, additional, Imbert, Jean, additional, Costanzi, Chiara, additional, Padovani, Alessandro, additional, Giunti, Paola, additional, Maillet-Vioud, Marcel, additional, Durr, Alexandra, additional, Brice, Alexis, additional, Tempia, Filippo, additional, Funaro, Ada, additional, Boccone, Loredana, additional, Caruso, Donatella, additional, Stevanin, Giovanni, additional, and Brusco, Alfredo, additional

Published
2014
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30. Alteration of Fatty-Acid-Metabolizing Enzymes Affects Mitochondrial Form and Function in Hereditary Spastic Paraplegia

Author

Tesson, Christelle, primary, Nawara, Magdalena, additional, Salih, Mustafa A.M., additional, Rossignol, Rodrigue, additional, Zaki, Maha S., additional, Al Balwi, Mohammed, additional, Schule, Rebecca, additional, Mignot, Cyril, additional, Obre, Emilie, additional, Bouhouche, Ahmed, additional, Santorelli, Filippo M., additional, Durand, Christelle M., additional, Oteyza, Andrés Caballero, additional, El-Hachimi, Khalid H., additional, Al Drees, Abdulmajeed, additional, Bouslam, Naima, additional, Lamari, Foudil, additional, Elmalik, Salah A., additional, Kabiraj, Mohammad M., additional, Seidahmed, Mohammed Z., additional, Esteves, Typhaine, additional, Gaussen, Marion, additional, Monin, Marie-Lorraine, additional, Gyapay, Gabor, additional, Lechner, Doris, additional, Gonzalez, Michael, additional, Depienne, Christel, additional, Mochel, Fanny, additional, Lavie, Julie, additional, Schols, Ludger, additional, Lacombe, Didier, additional, Yahyaoui, Mohamed, additional, Al Abdulkareem, Ibrahim, additional, Zuchner, Stephan, additional, Yamashita, Atsushi, additional, Benomar, Ali, additional, Goizet, Cyril, additional, Durr, Alexandra, additional, Gleeson, Joseph G., additional, Darios, Frederic, additional, Brice, Alexis, additional, and Stevanin, Giovanni, additional

Published
2012
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31. Delving into the complexity of hereditary spastic paraplegias: how unexpected phenotypes and inheritance modes are revolutionizing their nosology

Author

Tesson, Christelle, Koht, Jeanette, Stevanin, Giovanni, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-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)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Department of neurology, Drammen Hospital, Service de Génétique Cytogénétique et Embryologie [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), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Administateur, HAL Sorbonne Université

Subjects
Paraplegia, Review Paper, [SDV.GEN]Life Sciences [q-bio]/Genetics, Genetic Loci, Genetic Diseases, Inborn, Genetics, Humans, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Genetics(clinical), [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.GEN] Life Sciences [q-bio]/Genetics, Lipid Metabolism, Cytoskeleton
Abstract

Hereditary spastic paraplegias (HSP) are rare neurodegenerative diseases sharing the degeneration of the corticospinal tracts as the main pathological characteristic. They are considered one of the most heterogeneous neurological disorders. All modes of inheritance have been described for the 84 different loci and 67 known causative genes implicated up to now. Recent advances in molecular genetics have revealed clinico-genetic heterogeneity of these disorders including their clinical and genetic overlap with other diseases of the nervous system. The systematic analysis of a large set of genes, including exome sequencing, is unmasking unusual phenotypes or inheritance modes associated with mutations in HSP genes and related genes involved in various neurological diseases. A new nosology may emerge after integration and understanding of these new data to replace the current classification. Collectively, functions of the known genes implicate the disturbance of intracellular membrane dynamics and trafficking as the consequence of alterations of cytoskeletal dynamics, lipid metabolism and organelle structures, which represent in fact a relatively small number of cellular processes that could help to find common curative approaches, which are still lacking. Electronic supplementary material The online version of this article (doi:10.1007/s00439-015-1536-7) contains supplementary material, which is available to authorized users.

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32. Correction: Clinical, neuropathological, and genetic characterization of STUB1variants 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 Maldergem, Lionel, van Broeckhoven, Christine, Coutelier, Marie, Tesson, Christelle, Stevanin, Giovanni, Duyckaerts, Charles, Brice, Alexis, Durr, Alexandra, Durr, Alexandra, Stevanin, Giovanni, Brice, Alexis, Darios, Frédéric, Forlani, Sylvie, Site, Pitié-Salpêtrière, Banneau, Guillaume, Cazeneuve, Cécile, Charles, Perrine, Duyckaerts, Charles, Fontaine, Bertrand, Azulay, Jean-Philippe, Boesfplug-Tanguy, Odile, Goizet, Cyril, Hannequin, Didier, Hazan, Jamilé, Burgo, Andrea, Verny, Christophe, Koenig, Michel, Labauge, Pierre, Marelli, Cecilia, N’guyen, Karine, Rodriguez, Diana, Belarbi, Soraya, Hamri, Abdelmadjid, Tazir, Meriem, Boesch, Sylvia, Pandolfo, Massimo, Laura, Jardim, Guergueltcheva, Velina, Tournev, Ivalo, Pedraza Linarès, Olga Lucia, Nielsen, Jørgen E., Svenstrup, Kirsten, Zaki, Maha, Bauer, Peter, Schöls, Lüdger, Schüle, Rebecca, Lossos, Alexander, Bassi, Maria-Teresa, Basso, Manuela, Bertini, Enrico, Brusco, Alfredo, Casali, Carlo, Casari, Giorgio, Criscuolo, Chiara, Filla, Alessandro, Orsi, Laura, Santorelli, Filippo M., Valente, Enza Maria, Vavla, Marinela, Vazza, Giovanni, Megarbane, André, Benomar, Ali, Kremer, Berry, Van Roon-Mom, Willeke, Roxburgh, Richard, Erichsen, Anne Kjersti, Tallaksen, Chantal, Alonso, Isabel, Coutinho, Paula, Loureiro, José Léal, Sequeiros, Jorge, Salih, Mustapha, Kostic, Vladimir S, Rouco Axpe, Idoia, Elsayed, Liena, Paucar, Martin Arce, Roumani, Samir, Bing-Wen, Soong, Reid, Evan, Suran, Nethisinghe, Warner, Thomas, and Wood, Nicholas

Abstract

A Correction to this paper has been published: https://doi.org/10.1038/s41436-020-01064-y

Published
2021
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33. SUMOylation by SUMO2 is implicated in the degradation of misfolded ataxin-7 via RNF4 in SCA7 models

Author

Marinello, Martina, Werner, Andreas, Giannone, Mariagiovanna, Tahiri, Khadija, Alves, Sandro, Tesson, Christelle, den Dunnen, Wilfred, Seeler, Jacob-S., Brice, Alexis, and Sittler, Annie

Abstract

Perturbation of protein homeostasis and aggregation of misfolded proteins is a major cause of many human diseases. A hallmark of the neurodegenerative disease spinocerebellar ataxia type 7 (SCA7) is the intranuclear accumulation of mutant, misfolded ataxin-7 (polyQ-ATXN7). Here, we show that endogenous ATXN7 is modified by SUMO proteins, thus also suggesting a physiological role for this modification under conditions of proteotoxic stress caused by the accumulation of polyQ-ATXN7. Co-immunoprecipitation experiments, immunofluorescence microscopy and proximity ligation assays confirmed the colocalization and interaction of polyQ-ATXN7 with SUMO2 in cells. Moreover, upon inhibition of the proteasome, both endogenous SUMO2/3 and the RNF4 ubiquitin ligase surround large polyQ-ATXN7 intranuclear inclusions. Overexpression of RNF4 and/or SUMO2 significantly decreased levels of polyQ-ATXN7 and, upon proteasomal inhibition, led to a marked increase in the polyubiquitination of polyQ-ATXN7. This provides a mechanism for the clearance of polyQ-ATXN7 from affected cells that involves the recruitment of RNF4 by SUMO2/3-modified polyQ-ATXN7, thus leading to its ubiquitination and proteasomal degradation. In a SCA7 knock-in mouse model, we similarly observed colocalization of SUMO2/3 with polyQ-ATXN7 inclusions in the cerebellum and retina. Furthermore, we detected accumulation of SUMO2/3 high-molecular-mass species in the cerebellum of SCA7 knock-in mice, compared with their wild-type littermates, and changes in SUMO-related transcripts. Immunohistochemical analysis showed the accumulation of SUMO proteins and RNF4 in the cerebellum of SCA7 patients. Taken together, our results show that the SUMO pathway contributes to the clearance of aggregated ATXN7 and suggest that its deregulation might be associated with SCA7 disease progression.

Published
2019
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34. PLA2G6-associated late-onset parkinsonism in a Sudanese family.

Author

Bakhit Y, Tesson C, Ibrahim MO, Eltom K, Eltazi I, Elsayed LEO, Lesage S, Seidi O, Corvol JC, and Wüllner U

Subjects
Adult, Humans, Middle Aged, Genetic Testing, Group VI Phospholipases A2 genetics, Mutation, Dystonia genetics, Dystonic Disorders genetics, Parkinsonian Disorders genetics
Abstract

Introduction: 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., Material and Methods: 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., Result: 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&#95;003560:c.2070&#95;2072del (p.Val691del) and a missense variant NM&#95;003560:c.956C>T (p.Thr319Met). Both variants were classified as pathogenic., Conclusion: 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., (© 2023 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Published
2023
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35. Genetic and Phenotypic Basis of Autosomal Dominant Parkinson's Disease in a Large Multi-Center Cohort.

Author

Lesage S, Houot M, Mangone G, Tesson C, Bertrand H, Forlani S, Anheim M, Brefel-Courbon C, Broussolle E, Thobois S, Damier P, Durif F, Roze E, Tison F, Grabli D, Ory-Magne F, Degos B, Viallet F, Cormier-Dequaire F, Ouvrard-Hernandez AM, Vidailhet M, Lohmann E, Singleton A, Corvol JC, and Brice A

Abstract

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 1,805 index cases (592 with autosomal dominant inheritance and 1,213 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 = 0.001). PD patients with LRRK2 variants were more likely to have higher rates of late-onset PD (>50 years; OR 1.5, 95% CI [1.0-2.1], 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., (Copyright © 2020 Lesage, Houot, Mangone, Tesson, Bertrand, Forlani, Anheim, Brefel-Courbon, Broussolle, Thobois, Damier, Durif, Roze, Tison, Grabli, Ory-Magne, Degos, Viallet, Cormier-Dequaire, Ouvrard-Hernandez, Vidailhet, Lohmann, Singleton, Corvol and Brice.)

Published
2020
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36. A panel study on patients with dominant cerebellar ataxia highlights the frequency of channelopathies.

Author

Coutelier M, Coarelli G, Monin ML, Konop J, Davoine CS, Tesson C, Valter R, Anheim M, Behin A, Castelnovo G, Charles P, David A, Ewenczyk C, Fradin M, Goizet C, Hannequin D, Labauge P, Riant F, Sarda P, Sznajer Y, Tison F, Ullmann U, Van Maldergem L, Mochel F, Brice A, Stevanin G, and Durr A

Subjects
ATPases Associated with Diverse Cellular Activities, Adolescent, Adult, Age of Onset, Aged, Aged, 80 and over, Child, Child, Preschool, Cohort Studies, Female, Genes, Dominant, Genotype, Humans, Male, Middle Aged, Phenotype, Young Adult, Calcium Channels genetics, Cerebellar Ataxia genetics, Cerebellar Ataxia physiopathology, Channelopathies genetics, Channelopathies physiopathology, Metalloendopeptidases genetics
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 were found among a single gene group, comparing 23 patients with CACNA1A expansions (spinocerebellar ataxia 6) to 22 patients with CACNA1A point mutations, which had lower average age at onset (25.2 versus 47.3 years) with longer disease duration (18.7 versus 10.9), but lower severity indexes (0.39 versus 0.44), indicating slower progression of the disease. In conclusion, we identified relevant genetic variations in up to 15% of cases after exclusion of polyglutamine expansion spinocerebellar ataxias, and confirmed CACNA1A and SPG7 as major ataxia genes. We could delineate firm genotype-phenotype correlations that are important for genetic counselling and of possible prognostic value., (© The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Published
2017
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37. Interferon β induces clearance of mutant ataxin 7 and improves locomotion in SCA7 knock-in mice.

Author

Chort A, Alves S, Marinello M, Dufresnois B, Dornbierer JG, Tesson C, Latouche M, Baker DP, Barkats M, El Hachimi KH, Ruberg M, Janer A, Stevanin G, Brice A, and Sittler A

Subjects
Adult, Aged, Animals, Ataxin-7, Cells, Cultured, Child, Gene Knock-In Techniques, Humans, Mice, Mice, Inbred C57BL, Mice, Transgenic, Nerve Tissue Proteins metabolism, Rats, Rats, Wistar, Spinocerebellar Ataxias drug therapy, Interferon-beta therapeutic use, Motor Activity genetics, Mutation genetics, Nerve Tissue Proteins genetics, Spinocerebellar Ataxias genetics, Spinocerebellar Ataxias physiopathology
Abstract

We showed previously, in a cell model of spinocerebellar ataxia 7, that interferon beta induces the expression of PML protein and the formation of PML protein nuclear bodies that degrade mutant ataxin 7, suggesting that the cytokine, used to treat multiple sclerosis, might have therapeutic value in spinocerebellar ataxia 7. We now show that interferon beta also induces PML-dependent clearance of ataxin 7 in a preclinical model, SCA7(266Q/5Q) knock-in mice, and improves motor function. Interestingly, the presence of mutant ataxin 7 in the mice induces itself the expression of endogenous interferon beta and its receptor. Immunohistological studies in brains from two patients with spinocerebellar ataxia 7 confirmed that these modifications are also caused by the disease in humans. Interferon beta, administered intraperitoneally three times a week in the knock-in mice, was internalized with its receptor in Purkinje and other cells and translocated to the nucleus. The treatment induced PML protein expression and the formation of PML protein nuclear bodies and decreased mutant ataxin 7 in neuronal intranuclear inclusions, the hallmark of the disease. No reactive gliosis or other signs of toxicity were observed in the brain or internal organs. The performance of the SCA7(266Q/5Q) knock-in mice was significantly improved on two behavioural tests sensitive to cerebellar function: the Locotronic® Test of locomotor function and the Beam Walking Test of balance, motor coordination and fine movements, which are affected in patients with spinocerebellar ataxia 7. In addition to motor dysfunction, SCA7(266Q/5Q) mice present abnormalities in the retina as in patients: ataxin 7-positive neuronal intranuclear inclusions that were reduced by interferon beta treatment. Finally, since neuronal death does not occur in the cerebellum of SCA7(266Q/5Q) mice, we showed in primary cell cultures expressing mutant ataxin 7 that interferon beta treatment improves Purkinje cell survival.

Published
2013
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