Nineteenth annual symposia on etiology, pathogenesis, and treatment of Parkinson's disease and other movement disorders

Abstract

Background: Recent studies of referral-based samples indicate that a single mutation (G2019S) in exon 41 of the LRRK2 gene accounts for an unexpectedly large proportion of both familial and sporadic cases of Parkinson's disease (PD). If these data are representative of PD in the general population, then genetic testing for LRRK2 mutations might be useful in clinical settings. Methods: We resequenced exons 31, 35, and 41 of the LRRK2 gene in 371 PD patients consecutively recruited through five movement disorder clinics, and in 281 controls. Results: We found mutations in 6 (1.6%) PD patients, including two heterozygous for new putative pathogenic variants (R1441H, IVS31ϩ3A3 G). None of these mutations were observed in the control group. R1441H replaces a highly conserved amino acid, whereas IVS31ϩ3A3 G is predicted to disrupt splicing. We also found evidence of substantially reduced penetrance in a family with a previously reported pathogenic mutation (R1441C). Conclusions: Our findings in a clinic-based PD sample suggest that LRRK2 mutations are sufficiently common to justify testing in neurological practice. More data are needed, however, on the spectrum, frequency, and penetrance of pathogenic variants in the gene before such testing is implemented. We investigated the frequency of seven mutations in the gene that codes for leucine-rich repeat protein kinase 2 (LRRK2) in a large community-based population of 400 unrelated Parkinson's disease (PD) patients and 453 age-and gender-matched control subjects. The frequency of heterozygosity for the most common LRRK2 mutation, a glycine-to-serine amino acid substitution at codon 2019 (Gly2019Ser, G2019S), was 6 of 399 cases (1.5%, only one of whom had a positive family history), compared to 1 of Published online in Wiley InterScience (www.interscience.wiley. com). DOI: 10.1002/mds.20664 Movement Disorders Vol. 20, No. 9, 2005, pp. 1235-1249 © 2005 Movement Disorder Society 453 controls (0.6%). The risk of parkinsonism was increased sevenfold among subjects with the G2019S mutation (odds ratio 6.9; 95% CI 0.8 -318.1; P ϭ 0.06). Another LRRK2 mutation (2378GϾT, R793M) was present in three control subjects and no cases. No other LRRK2 mutations were found. The frequency of G2019S heterozygotes was higher among cases who reported one or more first-degree family members affected with PD (2.3%; 1/43) than among cases without familial PD (1.4%; 5/356). The clinical features of parkinsonism in cases with G2019S mutations were largely typical of idiopathic Parkinson's disease, but one or more unusual features were observed in almost all cases. The wide range of age of onset (57-90 years) among cases with the G2019S mutation, and its occurrence in an 82-year-old unaffected control subject, suggests that other modifying genes or environmental factors influence the penetrance of this LRRK2 mutation. Mutations in six genes (SNCA, PRKN, PINK1, DJ-1, MAPT,and UCH-L1) have been identified in familial parkinsonism in the last 8 years. The PARK8 locus on chromosome 12p11.2-q13.1 was...