Penetrance in Parkinson’s Disease Related to the LRRK2 R1441G Mutation in the Basque Country (Spain) Javier Ruiz-Martı ´nez, 1,2 * Ana Gorostidi, 3 Berta Iban ˜ez, 4 Ainhoa Alzualde, 3 David Otaegui, 3 Fermin Moreno, 1 Adolfo Lo ´pez de Munain, 1 Alberto Bergareche, 5 Juan Carlos Go ´mez-Esteban, 6 and Jose ´ F. Martı ´ Masso ´ 1 1 Servicio de Neurologı´a, Hospital Donostia, San Sebastia´n, Gipuzkoa, Spain 2 Centro Investigacio´n Biome´dica en Red Para Enfermedades Neurodegenerativas (CIBERNED). Instituto de Salud Carlos III, Madrid, Spain 3 Laboratorio de Neurogene´tica, Hospital Donostia, San Sebastia´n, Gipuzkoa, Spain 4 Fundacio´n Vasca de Innovacio´n e Investigacio´n Sanitarias (BIOEF), Sondika, Bizkaia, Spain 5 Servicio de Neurologı´a, Hospital del Bidasoa, Iru´n, Gipuzkoa, Spain 6 Servicio de Neurologı´a, Hospital de Cruces, Barakaldo, Bizkaia, Spain Abstract: The LRRK2 R1441G mutation was first identified in Basque families and it is responsible for 46% of familial Parkinson’s disease (PD) and for 2.5% of sporadic PD in the PD population of Basque ascent. The aim of this study was to determine LRRK2 R1441G penetrance in PD in the Basque Country (Spain) to help in a more accurate genetic counsel- ing. A total of 59 sibships containing 244 individuals, with a total of 40 PD-affected relatives, were studied. Genetic test- ing for the R1441G mutation in the LRRK2 gene was per- formed in 133 individuals and was positive in 51% of them. Lifetime penetrance of R1441G mutations turned out to be 12.5% at 65 years to 83.4% at 80 years. No gender differen- ces were found in penetrance. Ó 2010 Movement Disorder Society Key words: LRRK2; penetrance; Parkinson’s disease; R1441G The PARK8 locus was originally mapped in 2002 in the Japanese Sagamihara family 1 and mutations in this locus in the LRRK2 gene that encodes a protein called Dardarin were discovered in 2004. 2,3 Parkinson’s dis- ease (PD) associated with LRRK2 mutations is cur- rently the most common known genetic cause of auto- somal dominant Parkinson’s disease. These cases have a late onset and a typical clinical picture of idiopathic PD. The most frequent LRRK2 mutation, G2019S, originated from a common founder 4 and it has been observed throughout the world. 4–6 G2019S accounts for 5% of familial parkinsonism and for 0.5%–2% of sporadic PD in Caucasians. 7 In some populations, such as Ashkenazi Jews 8 or North African Arabs, 9 it accounts for 29% and 37% of patients with familial PD, respectively. Age-dependent penetrance studies of G2019S have reported different results. Lesage et al. 9 reported a 33% penetrance at age 50, which increased to 100% at age 75, whereas Kacher- gus et al. 4 reported a 17% penetrance at age 50, increasing to 85% at age 70. More recent studies have reported a lower lifetime penetrance and a decreased age-dependent penetrance ranging from 15% at age 60 and 32% at age 80. 10 Last year, Healy et al. 11 esti- mated the risk of PD in LRRK2 G2019S carriers from 28% at 59 years to 74% at 79 years. These variations in reported penetrance could be explained by the presence of differences in study design and also by differences in the approach to include the role of genetic or environmental suscepti- bility modifiers. The LRRK2 R1441G mutation was first identified in four families from the Basque Coun- Potential conflict of interest: The authors declare that they have no conflicts of interest that relate to the research covered in the article. *Correspondence to: Dr. Javier Ruiz-Martı ´nez, Department of Neurology, Hospital Donostia. Paseo Dr. Beguiristain s/n, 20014 Donostia – San Sebastia ´n, Gipuzkoa (Spain) E-mail: javier.ruizmartinez@osakidetza.net Received 4 December 2009; Revised 14 January 2010; Accepted 6 May 2010 Published online 18 August 2010 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/mds.23278 2340 Movement Disorders Vol. 25, No. 14, 2010, pp. 2340–2345 Ó 2010 Movement Disorder Society