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

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      BackgroundMutations 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?MethodsResearchers 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.FindingsSix 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.InterpretationMutations 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.FundingUK 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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      Parkinsonism: onset, progression and mortality.

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        Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism.

        Parkinson's disease is a common neurodegenerative disease with complex clinical features. Autosomal recessive juvenile parkinsonism (AR-JP) maps to the long arm of chromosome 6 (6q25.2-q27) and is linked strongly to the markers D6S305 and D6S253; the former is deleted in one Japanese AR-JP patient. By positional cloning within this microdeletion, we have now isolated a complementary DNA done of 2,960 base pairs with a 1,395-base-pair open reading frame, encoding a protein of 465 amino acids with moderate similarity to ubiquitin at the amino terminus and a RING-finger motif at the carboxy terminus. The gene spans more than 500 kilobases and has 12 exons, five of which (exons 3-7) are deleted in the patient. Four other AR-JP patients from three unrelated families have a deletion affecting exon 4 alone. A 4.5-kilobase transcript that is expressed in many human tissues but is abundant in the brain, including the substantia nigra, is shorter in brain tissue from one of the groups of exon-4-deleted patients. Mutations in the newly identified gene appear to be responsible for the pathogenesis of AR-JP, and we have therefore named the protein product 'Parkin'.
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          Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology.

          We have previously linked families with autosomal-dominant, late-onset parkinsonism to chromosome 12p11.2-q13.1 (PARK8). By high-resolution recombination mapping and candidate gene sequencing in 46 families, we have found six disease-segregating mutations (five missense and one putative splice site mutation) in a gene encoding a large, multifunctional protein, LRRK2 (leucine-rich repeat kinase 2). It belongs to the ROCO protein family and includes a protein kinase domain of the MAPKKK class and several other major functional domains. Within affected carriers of families A and D, six post mortem diagnoses reveal brainstem dopaminergic degeneration accompanied by strikingly diverse pathologies. These include abnormalities consistent with Lewy body Parkinson's disease, diffuse Lewy body disease, nigral degeneration without distinctive histopathology, and progressive supranuclear palsy-like pathology. Clinical diagnoses of Parkinsonism with dementia or amyotrophy or both, with their associated pathologies, are also noted. Hence, LRRK2 may be central to the pathogenesis of several major neurodegenerative disorders associated with parkinsonism.
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            Author and article information

            Affiliations
            [a ]Department of Clinical Neurosciences, Institute of Neurology, University College London, London, UK
            [b ]Genomic Medicine, Imperial College, London and Twin Research and Genetic Epidemiology Unit, St. Thomas Campus, Kings College London, UK
            [c ]Reta Lila Weston Institute for Neurological Studies, University of London, UK
            [d ]Department of Clinical Genetics, Erasmus MC, Rotterdam, Netherlands
            [e ]Institut National de la Santé et de la Recherche Médicale U679, Neurologie et Thérapeutique Expérimentale, Hôpital de la Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris
            [f ]Fédération de Neurologie, Centre Hospitalier Universitaire Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris
            [g ]Département de Génétique, Cytogénétique et Embryologie, Hôpital de la Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris
            [h ]Beth Israel Medical Centre, Department of Neurology, NY and the Albert Einstein College of Medicine, Department of Neurology, Bronx, NY, USA
            [i ]Department of Neurology, St Olav's Hospital and Department of Neuroscience, NTNU, 7006 Trondheim, Norway
            [j ]Geriatric Research Education and Clinical Centre, Veterans Affairs Puget Sound Health Care System, and Department of Neurology, University of Washington, Seattle, WA, USA
            [k ]Parkinson Institute, Istituti Clinici di Perfezionamento, Milan, Italy
            [l ]Neurological Clinic Research Unit, Institute of Molecular Medicine, Lisbon School of Medicine, Portugal
            [m ]Neurology Service, Institut Clinic Maltias del Sistema Nervios, Hospital Clinic Universitari, University of Barcelona, Spain
            [n ]Division of Genetic Disorders, Wadsworth Centre, New York State Department of Health, Albany, NY, USA
            [o ]Department of Neurology, University of Luebeck, Luebeck, Germany
            [p ]Faculty of Medicine (Neurosciences), Monash University, Melbourne, Australia
            [q ]University of Toronto, Toronto, Canada
            [r ]Department of Neurology, Mayo Clinic Jacksonville, Florida, USA
            [s ]Service of Neurology, University Hospital “Marques de Valdecilla”, (CIBERNED), Santander, Spain
            [t ]Department of Neurology, Mater Misericordiae University Hospital, and the Conway Institute of Biomolecular and Biomedical Research, Dublin, Ireland
            [u ]Sobell Department of Motor Neuroscience and Movement Disorders, Institute of Neurology, Queen Square, London, UK
            [v ]Department of Molecular Pathogenesis, Institute of Neurology, Queen Square, London, UK
            [w ]Department of Neurodegenerative Diseases, Hertie-Institut for Clinical Brain Research, University of Tuebingen, Germany
            Author notes
            [* ]Correspondence to: Daniel G Healy, Department of Clinical Neurosciences, Institute of Neurology, University College London, London WC1N 3BG, UK danhealy@ 123456doctors.org.uk
            Contributors
            Journal
            Lancet Neurol
            Lancet Neurol
            Lancet Neurology
            Lancet Pub. Group
            1474-4422
            1474-4465
            July 2008
            July 2008
            : 7
            : 7
            : 583-590
            2832754
            18539534
            LANEUR70117
            10.1016/S1474-4422(08)70117-0
            © 2008 Elsevier Ltd. All rights reserved.

            This document may be redistributed and reused, subject to certain conditions.

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