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

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Summary

          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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          Most cited references25

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          Association between early-onset Parkinson's disease and mutations in the parkin gene.

          Mutations in the parkin gene have recently been identified in patients with early-onset Parkinson's disease, but the frequency of the mutations and the associated phenotype have not been assessed in a large series of patients. We studied 73 families in which at least one of the affected family members was affected at or before the age of 45 years and had parents who were not affected, as well as 100 patients with isolated Parkinson's disease that began at or before the age of 45 years. All subjects were screened for mutations in the parkin gene with use of a semiquantitative polymerase-chain-reaction assay that simultaneously amplified several exons. We sequenced the coding exons in a subgroup of patients. We also compared the clinical features of patients with parkin mutations and those without mutations. Among the families with early-onset Parkinson's disease, 36 (49 percent) had parkin mutations. The age at onset ranged from 7 to 58 years. Among the patients with isolated Parkinson's disease, mutations were detected in 10 of 13 patients (77 percent) with an age at onset of 20 years or younger, but in only 2 of 64 patients (3 percent) with an age at onset of more than 30 years. The mean (+/-SD) age at onset in the patients with parkin mutations was younger than that in those without mutations (32+/-11 vs. 42+/-11 years, P<0.001), and they were more likely to have symmetric involvement and dystonia at onset, to have hyperreflexia at onset or later, to have a good response to levodopa therapy, and to have levodopa-induced dyskinesias during treatment. Nineteen different rearrangements of exons (deletions and multiplications) and 16 different point mutations were detected. Mutations in the parkin gene are a major cause of early-onset autosomal recessive familial Parkinson's disease and isolated juvenile-onset Parkinson's disease (at or before the age of 20 years). Accurate diagnosis of these cases cannot be based only on the clinical manifestations of the disease.
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            LRRK2 G2019S as a cause of Parkinson's disease in Ashkenazi Jews.

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              A common LRRK2 mutation in idiopathic Parkinson's disease.

              Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene have been shown to cause autosomal dominant Parkinson's disease. Few mutations in this gene have been identified. We investigated the frequency of a common heterozygous mutation, 2877510 g-->A, which produces a glycine to serine aminoacid substitution at codon 2019 (Gly2019 ser), in idiopathic Parkinson's disease. We assessed 482 patients with the disorder, of whom 263 had pathologically confirmed disease, by direct sequencing for mutations in exon 41 of LRRK2. The mutation was present in eight (1.6%) patients. We have shown that a common single Mendelian mutation is implicated in sporadic Parkinson's disease. We suggest that testing for this mutation will be important in the management and genetic counselling of patients with Parkinson's disease.
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                Author and article information

                Contributors
                Journal
                Lancet Neurol
                Lancet Neurol
                Lancet Neurology
                Lancet Pub. Group
                1474-4422
                1474-4465
                July 2008
                July 2008
                : 7
                : 7
                : 583-590
                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
                Article
                LANEUR70117
                10.1016/S1474-4422(08)70117-0
                2832754
                18539534
                1caba37e-0378-40ed-a433-dc667e7aa98c
                © 2008 Elsevier Ltd. All rights reserved.

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

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