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

By D. Healy, M. Falchi, S. O'sullivan, V. Bonifati, A. Durr, S. Bressman, A. Brice, J. Aasly, C. Zabetian, S. Goldwurm and 15 more. Lancet Neurology, 2008

1,476 citations recorded by the source corpus.

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.

Subfields: Neurology

View Paper: https://www.semanticscholar.org/paper/033d9b7c57ba893af89f822cc441cd0e909dd77d

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Citations in the corpus

• Past, Present, and Future of Parkinson’s Disease: A Special Essay on the 200th Anniversary of the Shaking Palsy (2017, neutral): “G2019S mutations is indistinguishable from that of Idiopathic Parkinson’s disease (iPD), although tremor is more common and leg tremor may be a useful diagnostic clue.(161) The p.”
• Parkinson's disease: from monogenic forms to genetic susceptibility factors. (2009, background): “The international LRRK2 Consortium including 21 centers from North America and Europe determined the age-specific penetrance of the LRRK2 G2019S mutation to be 28% at 59, 51% at 69 and 74% at 79 years with no effect of the sex (39).”
• Epidemiology and etiology of Parkinson’s disease: a review of the evidence (2011, result): “Compared to idiopathic PD, the disease was more benign in LRRK2 carriers [217].”
• Clinical Neurology and Epidemiology of the Major Neurodegenerative Diseases. (2018, background): “Moreover, LRRK2 mutations usually manifest as a benign tremor-predominant phenotype (asymmetric parkinsonism) and have a decreased risk for cognitive and olfactory dysfunction (Healy et al. 2008).”
• Evaluating drug targets through human loss-of-function genetic variation (2019, neutral): “The GWAS-implicated common variants were not included in the case series on which our estimate is based 63 , but G2019S does account for the majority of cases in that series.”
• Missing pieces in the Parkinson's disease puzzle (2010, background): “Among mutation carriers, disease penetrance markedly increases as a function of ag”