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

Vollstedt EJ 1 , Schaake S 1 , Lohmann K 1 , Padmanabhan S 2 , Brice A 3 , Lesage S 4 Show all authors , Tesson C 4 , Vidailhet M 3 , Wurster I 5 , Hentati F 6 , Mirelman A 7 , Giladi N 8 , Marder K 9 , Waters C 10 , Fahn S 10 , Kasten M 11 , Brüggemann N 12 , Borsche M 12 , Foroud T 13 , Tolosa E 14 , Garrido A 14 , Annesi G 15 , Gagliardi M 15 , Bozi M 16 , Stefanis L 17 , Ferreira JJ 18 , Correia Guedes L 19 , Avenali M 20 , Petrucci S 21 , Clark L 22 , Fedotova EY 23 , Abramycheva NY 23 , Alvarez V 24 , Menéndez-González M 25 , Jesús Maestre S 26 , Gómez-Garre P 26 , Mir P 26 , Belin AC 27 , Ran C 27 , Lin CH 28 , Kuo MC 28 , Crosiers D 29 , Wszolek ZK 30 , Ross OA 31 , Jankovic J 32 , Nishioka K 33 , Funayama M 34 , Clarimon J 35 , Williams-Gray CH 36 , Camacho M 36 , Cornejo-Olivas M 37 , Torres-Ramirez L 38 , Wu YR 39 , Lee-Chen GJ 40 , Morgadinho A 41 , Pulkes T 42 , Termsarasab P 42 , Berg D 43 , Kuhlenbäumer G 43 , Kühn AA 44 , Borngräber F 44 , de Michele G 45 , De Rosa A 45 , Zimprich A 46 , Puschmann A 47 , Mellick GD 48 , Dorszewska J 49 , Carr J 50 , Ferese R 51 , Gambardella S 51 , Chase B 52 , Markopoulou K 53 , Satake W 54 , Toda T 55 , Rossi M 54 , Merello M 56 , Lynch T 57 , Olszewska DA 57 , Lim SY 58 , Ahmad-Annuar A 59 , Tan AH 58 , Al-Mubarak B 60 , Hanagasi H 61 , Koziorowski D 62 , Ertan S 63 , Genç G 64 , de Carvalho Aguiar P 65 , Barkhuizen M 66 , Pimentel MMG 67 , Saunders-Pullman R 68 , van de Warrenburg B 69 , Bressman S 70 , Toft M 71 , Appel-Cresswell S 72 , Lang AE 73 , Skorvanek M 74 , Boon AJW 75 , Krüger R 76 , Sammler EM 77 , Tumas V 78 , Zhang BR 79 , Garraux G 80 , Chung SJ 81 , Kim YJ 82 , Winkelmann J 83 , Sue CM 84 , Tan EK 85 , Damásio J 86 , Klivényi P 87 , Kostic VS 88 , Arkadir D 89 , Martikainen M 90 , Borges V 91 , Hertz JM 92 , Brighina L 93 , Spitz M 94 , Suchowersky O 95 , Riess O 96 , Das P 97 , Mollenhauer B 98 , Gatto EM 99 , Petersen MS 100 , Hattori N 34 , Wu RM 28 , Illarioshkin SN 23 , Valente EM 101 , Aasly JO 102 , Aasly A 103 , Alcalay RN 10 , Thaler A 104 , Farrer MJ 105 , Brockmann K 5 , Corvol JC 106 , Klein C 1 , MJFF Global Genetic Parkinson's Disease Study Group

Affiliations 

  • 1 Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
  • 2 Research Programs, The Michael J. Fox Foundation for Parkinson's Research, New York, New York, USA
  • 3 Department of Neurology, Sorbonne University, Paris Brain Institute - ICM, Inserm, CNRS, Assistance Publique Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Paris, France
  • 4 Sorbonne University, Paris Brain Institute - ICM, Inserm, CNRS, Paris, France
  • 5 Department of Neurodegenerative Diseases, University of Tuebingen, Tuebingen, Baden Wuerttemberg, Germany, Hertie Institute for Clinical Brain Research and German Centre for Neurodegenerative Diseases, Tuebingen, Germany
  • 6 Mongi Ben Hmida National Institute of Neurology, Tunis, Tunisia
  • 7 Laboratory of Early Markers of Neurodegeneration, Neurological Institute, Tel-Aviv Medical Center, Tel-Aviv, Israel; Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel; Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv, Israel
  • 8 Neurological Institute, Tel-Aviv Medical Center, Tel-Aviv, Israel; Sackler School of Medicine, Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv, Israel
  • 9 Department of Neurology, Taub Institute for Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York, USA
  • 10 Department of Neurology, Columbia University, New York, New York, USA
  • 11 Department of Psychiatry and Psychotherapy and Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
  • 12 Department of Neurology and Institute of Neurogenetics, University of Lübeck, Lübeck, Germany
  • 13 Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, USA
  • 14 Parkinson Disease and Movement Disorders Unit, Neurology Service, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona (UB), Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED:CB06/05/0018-ISCIII), Barcelona, Spain
  • 15 Institute of Biomedical Research and Innovation, National Research Council, Cosenza, Italy
  • 16 Parkinson's and Movement Disorders Unit, 2nd Department of Neurology of the University of Athens, Attikon Hospital, Haidari, Athens, Greece; Psychiatry Hospital of Attica "Dafni," Neurology Department, Haidari, Athens, Greece
  • 17 First Department of Neurology, Medical School of the National and Kapodistrian University of Athens, Eginition Hospital, Athens, Greece
  • 18 Laboratory of Clinical Pharmacology and Therapeutics, University of Lisbon, Lisbon, Portugal; Instituto de Medicina Molecular João Lobo Antunes, Faculty of Medicine, University of Lisbon, Lisbon, Portugal
  • 19 Department of Neuroscience and Mental Health, Neurology Department, Hospital de Santa Maria, CHULN, Lisbon, Portugal; Instituto de Medicina Molecular João Lobo Antunes, Faculty of Medicine, University of Lisbon, Lisbon, Portugal
  • 20 Neurorehabilitation Unit, IRCCS Mondino Foundation, Pavia, Italy; Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy
  • 21 Department of Clinical and Molecular Medicine, Sapienza University of Rome, Rome, Italy; Sant' Andrea University Hospital, Rome, Italy
  • 22 Department of Pathology and Cell Biology, Vagelos College of Physicians & Surgeons, Columbia University Irving Medical Center, New York, New York, USA; Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University Irving Medical Center, New York, New York, USA; Laboratory of Personalized Genomic Medicine, Vagelos College of Physicians & Surgeons, Columbia University Irving Medical Center, New York, New York, USA
  • 23 Department of Neurogenetics, Research Center of Neurology, Moscow, Russia
  • 24 Laboratório de Genética, Hospital Universitario Central de Asturias, Oviedo, Asturias, Spain, Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
  • 25 Servicio Neurología, Hospital Universitario Central de Asturias, Oviedo, Spain; Instituto de Investigación; Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Oviedo, Spain
  • 26 Unidad de Trastornos del Movimiento, Servicio de Neurología y Neurofisiología Clínica, Instituto de Biomedicina de Sevilla, Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
  • 27 Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
  • 28 Department of Neurology, National Taiwan University Hospital, Taipei, Taiwan; Department of Neurology, National Taiwan University College of Medicine, Taipei, Taiwan
  • 29 Department of Neurology, Antwerp University Hospital, Edegem, Belgium; Born Bunge Institute, Department of Neurology, University of Antwerp, Wilrijk, Belgium; Center for Molecular Neurology, VIB, Wilrijk, Belgium
  • 30 Department of Neurology, Mayo Clinic, Jacksonville, Florida, USA
  • 31 Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA
  • 32 Parkinson's Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, Texas, USA
  • 33 Department of Neurology, Juntendo University School of Medicine, Bunkyo, Tokyo, Japan
  • 34 Research Institute for Diseases of Old Age, Graduate School of Medicine, Juntendo University, Bunkyo, Tokyo, Japan
  • 35 Department of Neurology, Biomedical Research Institute IIB-Sant Pau, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
  • 36 Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
  • 37 Neurogenetics Research Center, Instituto Nacional de Ciencias Neurologicas, Lima, Peru; Center for Global Health, Universidad Peruana Cayetano Heredia, Lima, Peru
  • 38 Movement Disorders Unit, Instituto Nacional de Ciencias Neurologicas, Lima, Peru
  • 39 Department of Neurology, Chang Gung University, Chang Gung Memorial Hospital, Linkou Medical Center, Taoyuan, Taiwan
  • 40 Department of Life Science, National Taiwan Normal University, Taipei, Taiwan
  • 41 Movement Disorders Clinic, Department of Neurology, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
  • 42 Division of Neurology, Department of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
  • 43 Department of Neurology, Christian-Albrechts-Universität, Kiel, Germany
  • 44 Movement Disorder and Neuromodulation Unit, Charité, Universitätsmedizin Berlin, Department of Neurology, Berlin, Germany
  • 45 Department of Neurosciences and Reproductive and Odontostomatological Sciences, Federico II University, Naples, Italy
  • 46 Department of Neurology, Medical University, Vienna, Austria
  • 47 Department of Neurology, Clinical Sciences, Lund University, Lund, Sweden; Department of Neurology, Skåne University, Lund, Sweden
  • 48 Griffith Institute for Drug Discovery (GRIDD), School of Environment and Science, Griffith University, Brisbane, Queensland, Australia
  • 49 Laboratory of Neurobiology, Department of Neurology, Poznan University of Medical Sciences, Poznan, Poland
  • 50 Division of Neurology, Department of Medicine, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa
  • 51 IRCCS Neuromed, Localita' Camerelle, Pozzilli, Isernia, Italy; Department of Biomolecular Sciences, University of Urbino "Carlo Bo", Urbino, Italy
  • 52 Department of Neurology, NorthShore University HealthSystem, Evanston, Illinois, USA
  • 53 Department of Neurology, NorthShore University HealthSystem, Evanston Illinois and Department of Neurology, University of Chicago, Chicago, Illinois, USA
  • 54 Sección Movimientos Anormales, Departamento de Neurociencias, Fleni, Buenos Aires, Argentina; Argentine National Scientific and Technological Research Council (CONICET), Buenos Aires, Argentina
  • 55 Department of Neurology, The University of Tokyo, Tokyo, Japan
  • 56 Sección Movimientos Anormales, Departamento de Neurociencias, Fleni, Buenos Aires, Argentina; Argentine National Scientific and Technological Research Council (CONICET), Argentina; Pontificia Universidad Católica Argentina (UCA), Buenos Aires, Argentina
  • 57 Department of Neurology, The Dublin Neurological Institute at the Mater Misericordiae University Hospital, Dublin, Ireland; School of Medicine and Medical Sciences, University College Dublin, Dublin, Ireland
  • 58 Division of Neurology and the Mah Pooi Soo & Tan Chin Nam Centre for Parkinson's & Related Disorders, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 59 Department of Biomedical Science, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 60 Behavioural Genetics Unit, Department of Genetics, Research Centre, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
  • 61 Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey
  • 62 Department of Neurology, Medical University in Warsaw, Warsaw, Poland
  • 63 Department of Neurology, School of Medicine, Koç University, Istanbul, Turkey
  • 64 Department of Neurology, University of Health Sciences, Şişli Hamidiye Etfal Training and Research Hospital, İstanbul, Turkey
  • 65 Hospital Israelita Albert Einstein, São Paulo, Brazil; Department of Neurology and Neurosurgery, Universidade Federal de São Paulo, São Paulo, Brazil
  • 66 DST/NWU Preclinical Drug Development Platform, North-West University, Potchefstroom, North-West, South Africa
  • 67 Department of Genetics, Institute of Biology Roberto Alcantara Gomes, State University of Rio de Janeiro, Rio de Janeiro, Brazil
  • 68 Department of Neurology, Icahn School of Medicine at Mount Sinai, New York, New York, USA
  • 69 Department of Neurology, Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Centre, Nijmegen, The Netherlands
  • 70 Department of Neurology, Beth Israel Medical Center, New York, New York, USA; Department of Neurology at Albert Einstein College of Medicine, New York, New York, USA
  • 71 Department of Neurology, Oslo University Hospital, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway
  • 72 Pacific Parkinson's Research Centre, Division of Neurology, Department of Medicine, Vancouver, British Columbia, Canada
  • 73 Edmond J. Safra Program in Parkinson's Disease, Division of Neurology, Department of Medicine, University of Toronto, Toronto Western Hospital, Toronto, Ontario, Canada
  • 74 Department of Neurology, Pavol Jozef Šafárik University in Košice, Košice, Slovakia; Department of Neurology, University Hospital L. Pasteur, Kosice, Slovakia
  • 75 Department of Clinical Genetics, Erasmus MC University Medical Center Rotterdam, Rotterdam, The Netherlands
  • 76 Luxembourg Centre for Systems Biomedicine (LCSB), University of Luxembourg, Esch-sur-Alzette, Luxembourg; Transversal Translational Medicine, Luxembourg Institute of Health (LIH), Strassen, Luxembourg; Parkinson Research Clinic, Centre Hospitalier de Luxembourg (CHL), Luxembourg, Luxembourg
  • 77 Neurology Department, Ninewells Hospital and Medical School, Dundee, United Kingdom; MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, UK
  • 78 Behavioral and Movement Disorders Section, Ribeirão Preto Medical School, University of São Paulo, Brazil
  • 79 Department of Neurology, Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China
  • 80 Department of Neurology, Centre Hospitalier Universitaire (CHU) de Liège, Liège, Belgium; MoVeRe Group, GIGA-CRC In Vivo Imaging, University of Liege, Liège, Belgium
  • 81 Medical Genetic Center, Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
  • 82 Department of Neurology, Yonsei University College of Medicine, Seoul, South Korea; Department of Neurology, Yongin Severance Hospital, Yonsei University Health System, Yongin, South Korea
  • 83 Institute of Neurogenomics, Helmholtz Zentrum Muenchen, Neuherberg, Germany; Neurogenetics, Technische Universitaet Muenchen, Munich, Germany; Institute of Human Genetics, Klinikum rechts der Isar der TUM, Munich, Germany; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany
  • 84 Department of Neurogenetics, Kolling Institute, University of Sydney, Sydney, New South Wales, Australia; Department of Neurology, Royal North Shore Hospital, St Leonards, New South Wales, Australia
  • 85 Department of Neurology, National Neuroscience Institute, Duke NUS Medical School, Singapore General Hospital, Singapore, Singapore
  • 86 Department of Neurology, Hospital de Santo António - Centro Hospitalar Universitário do Porto, Porto, Portugal; UnIGENe, Instituto de Biologia Molecular e Celular (IBMC), Instituto de Investigação e Inovação em Saúde (i3S), Universidade do Porto, Portugal
  • 87 Department of Neurology, University of Szeged, Szeged, Hungary
  • 88 Department for Neurodegeneration, Clinic for Neurology CCS, Belgrade, Serbia
  • 89 Department of Neurology, Hadassah Medical Center and the Hebrew University, Jerusalem, Israel
  • 90 Neurocenter, Turku University Hospital, Turku, Finland; Clinical Neurosciences, Faculty of Medicine, University of Turku, Turku, Finland
  • 91 Department of Neurology and Neurosurgery, Universidade Federal de São Paulo, São Paulo, Brazil
  • 92 Department of Clinical Genetics, Odense University Hospital, Odense C, Denmark
  • 93 Department of Neurology, Milan Center for Neuroscience, University of Milano-Bicocca/San Gerardo Hospital, Monza, Italy
  • 94 Neurology Service, State University of Rio de Janeiro, Rio de Janeiro, Brazil
  • 95 Department of Medicine, Medical Genetics and Pediatrics, University of Alberta, Edmonton, Alberta, Canada
  • 96 Institute of Medical Genetics and Applied Genomics, University of Tuebingen, Tuebingen, Germany
  • 97 Centre for Genetic Disorders, Institute of Science, Banaras Hindu University, Varanasi, Uttar Pradesh, India
  • 98 Movement Disorder Paracelsus-Elena-Klinik, Kassel, Germany; Department of Neurology, University Medical Center Göttingen, Göttingen, Germany
  • 99 Movement Disorders, Department of Neurology, Instituto de Neurosciencias Buenos Aires, Buenos Aires, Argentina
  • 100 Centre of Health Science, University of the Faroe Islands, Tórshavn, Faroe Islands; Department of Occupational Medicine and Public Health, The Faroese Hospital System, Tórshavn, Faroe Islands
  • 101 Neurogenetics Research Centre, IRCCS Mondino Foundation, Pavia; Department of Molecular Medicine, University of Pavia, Pavia, Italy
  • 102 Department of Neurology, St. Olavs Hospital, Trondheim, Norway
  • 103 Department of Neuromedicine and Movement Science, Norwegian University of Science and Technology, Trondheim, Norway
  • 104 Movement Disorders, Neurological Institute, Tel-Aviv Medical Center, Tel-Aviv, Israel; Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv, Israel; Sackler School of Medicine, Tel-Aviv University, Tel-Aviv, Israel
  • 105 Fixel Institute, Department of Neurology, University of Florida, Gainesville, Florida, USA
  • 106 Sorbonne University, Paris Brain Institute - ICM, Inserm, CNRS, Assistance Publique Hôpitaux de Paris, Pitié-Salpêtrière Hospital, Department of Neurology, Paris, France
Mov Disord, 2023 Feb;38(2):286-303.
PMID: 36692014 DOI: 10.1002/mds.29288

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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