Статья

Phenotype, genotype, and worldwide genetic penetrance of LRRK2-associated Parkinson's disease: a case-control study

Daniel G. HealyDepartment of Clinical Neurosciences, Institute of Neurology, University College London, London, UK. [email protected]Mario FalchiGenomic Medicine, Imperial College, London and Twin Research and Genetic Epidemiology Unit, St. Thomas Campus, Kings College London, UKSean S. O’SullivanReta Lila Weston Institute for Neurological Studies, University of London, UKVincenzo BonifatiDepartment of Clinical Genetics, Erasmus MC, Rotterdam, NetherlandsAlexandra DurrDépartement de Génétique, Cytogénétique et Embryologie, Hôpital de la Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, ParisSusan BressmanBeth Israel Medical Centre, Department of Neurology, NY and the Albert Einstein College of Medicine, Department of Neurology, Bronx, NY, USAAlexis BriceFédération de Neurologie, Centre Hospitalier Universitaire Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, ParisJan AaslyDepartment of Neurology, St Olav's Hospital and Department of Neuroscience, NTNU, 7006 Trondheim, NorwayCyrus P. ZabetianGeriatric Research Education and Clinical Centre, Veterans Affairs Puget Sound Health Care System, and Department of Neurology, University of Washington, Seattle, WA, USAStefano GoldwurmParkinson Institute, Istituti Clinici di Perfezionamento, Milan, ItalyJoaquim J. FerreiraNeurological Clinic Research Unit, Institute of Molecular Medicine, Lisbon School of Medicine, PortugalEduardo TolosaNeurology Service, Institut Clinic Maltias del Sistema Nervios, Hospital Clinic Universitari, University of Barcelona, SpainDenise M. KayDivision of Genetic Disorders, Wadsworth Centre, New York State Department of Health, Albany, NY, USAChristine KleinDepartment of Neurology, University of Luebeck, Luebeck, GermanyDavid R. WilliamsFaculty of Medicine (Neurosciences), Monash University, Melbourne, AustraliaConnie MarrasUniversity of Toronto, Toronto, CanadaAnthony E. LangUniversity of Toronto, Toronto, CanadaZbigniew K. WszołekDepartment of Neurology, Mayo Clinic Jacksonville, Florida, USAJosé BercianoService of Neurology, University Hospital "Marques de Valdecilla", (CIBERNED), Santander, SpainAnthony H.V. SchapiraDepartment of Clinical Neurosciences, Institute of Neurology, University College London, London, UKTimothy LynchDepartment of Neurology, Mater Misericordiae University Hospital, and the Conway Institute of Biomolecular and Biomedical Research, Dublin, IrelandKailash P. BhatiaSobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, Queen Square, London, UKThomas GasserDepartment of Neurodegenerative Diseases, Hertie-Institut for Clinical Brain Research, University of Tuebingen, GermanyAndrew J. LeesDepartment of Clinical Neurosciences, Institute of Neurology, University College London, London, UKNicholas WoodDepartment of Molecular Pathogenesis, Institute of Neurology, Queen Square, London, UK

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Аннотация

BACKGROUND: Mutations in LRRK2, the gene that encodes leucine-rich repeat kinase 2, are a cause of Parkinson's disease (PD). The International LRRK2 Consortium was established to answer three key clinical questions: can LRRK2-associated PD be distinguished from idiopathic PD; which mutations in LRRK2 are pathogenic; and what is the age-specific cumulative risk of PD for individuals who inherit or are at risk of inheriting a deleterious mutation in LRRK2? METHODS: Researchers from 21 centres across the world collaborated on this study. The frequency of the common LRRK2 Gly2019Ser mutation was estimated on the basis of data from 24 populations worldwide, and the penetrance of the mutation was defined in 1045 people with mutations in LRRK2 from 133 families. The LRRK2 phenotype was defined on the basis of 59 motor and non-motor symptoms in 356 patients with LRRK2-associated PD and compared with the symptoms of 543 patients with pathologically proven idiopathic PD. FINDINGS: Six mutations met the consortium's criteria for being proven pathogenic. The frequency of the common LRRK2 Gly2019Ser mutation was 1% of patients with sporadic PD and 4% of patients with hereditary PD; the frequency was highest in the middle east and higher in southern Europe than in northern Europe. The risk of PD for a person who inherits the LRRK2 Gly2019Ser mutation was 28% at age 59 years, 51% at 69 years, and 74% at 79 years. The motor symptoms (eg, disease severity, rate of progression, occurrence of falls, and dyskinesia) and non-motor symptoms (eg, cognition and olfaction) of LRRK2-associated PD were more benign than those of idiopathic PD. INTERPRETATION: Mutations in LRRK2 are a clinically relevant cause of PD that merit testing in patients with hereditary PD and in subgroups of patients with PD. However, this knowledge should be applied with caution in the diagnosis and counselling of patients. FUNDING: UK Medical Research Council; UK Parkinson's Disease Society; UK Brain Research Trust; Internationaal Parkinson Fonds; Volkswagen Foundation; National Institutes of Health: National Institute of Neurological Disorders and Stroke and National Institute of Aging; Udall Parkinson's Disease Centre of Excellence; Pacific Alzheimer Research Foundation Centre; Italian Telethon Foundation; Fondazione Grigioni per il Morbo di Parkinson; Michael J Fox Foundation for Parkinson's Research; Safra Global Genetics Consortium; US Department of Veterans Affairs; French Agence Nationale de la Recherche.

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Идентификаторы

DOI: 10.1016/s1474-4422(08)70117-0

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