High prevalence of LRRK2 mutations in familial and sporadic Parkinson's disease in Portugal

Abstract

Mutations in the Leucine-Rich Repeat Kinase 2 (LRRK2) gene are the most frequent known cause of Parkinson's disease (PD), but their prevalence varies markedly between populations. Here we studied the frequency and associated phenotype of four recurrent LRRK2 mutations (R1441C, R1441G, R1441H, and G2019S) in familial and sporadic PD from a single referral center in Lisbon, Portugal. Among 138 unrelated PD probands, we identified 9 heterozygous G2019S carriers (6.52%) and 1 heterozygous R1441H carrier (0.72%). The G2019S mutation was present in 4 of the 107 sporadic (3.74%) and in 5 of the 31 familial probands (16.1%). Mutations were not found among 101 Portuguese controls. The G2019S mutation was present on a single haplotype and displayed reduced penetrance. Heterozygous parkin gene mutations were also found in 2 G2019S-positive probands, but their pathogenic role is unclear. The clinical phenotype in patients with LRRK2 mutations was indistinguishable from that of typical PD, including impaired sense of smell. The G2019S mutation is a very common genetic determinant among the Portuguese patients with PD, and the R1441H mutation is also present in this population. These data have important implications for the diagnostic work-up and genetic counseling of patients with this disease in Portugal.

LRRK2gene variation and its contribution to Parkinson disease

“…Taking only into consideration large studies (n4250 cases) in which p.Gly2019Ser mutation has been examined, this mutation presents with an overall prevalence of 1.04% ( Goldwurm et al, 2005;Kay et al, 2005;Marongiu et al, 2006;Paisán-Ruiz et al, 2008;Ross et al, 2006;Tomiyama et al, 2006;Williams-Gray et al, 2006;Zabetian et al, 2006b]. However, if we consider PD cases of Portuguese, Ashkenazi Jewish and North African Arab ancestries, its prevalence, especially in familial cases, is much higher, being 16.1%, 20%, and 42%, respectively [Bras et al, 2005;Ferreira et al, 2007;Ishihara et al, 2006;Lesage et al, 2005;Ozelius et al, 2006]; contrarily, it was absent in a large, Belgian PD cohort analyzed . Taken together, ethnicity has a significant influence on p.Gly2019Ser frequency.…”

Olfactory dysfunction in LRRK2 G2019S mutation carriers

“…[2][3][4] The range and severity of nonmotor features associated with LRRK2 mutations is also not well-defined. Several studies suggest that olfactory disturbance is a feature of LRRK2 PD 3,[5][6][7][8] but the degree of the impairment is debated. Finally, it is uncertain whether carriers who have not yet developed PD have abnormal olfaction, 6,7 and whether this may be an endophenotype or trait of carrying the mutated LRRK2 gene.…”

“…16 -18 However, the association with olfaction in LRRK2 PD is less clear: olfaction has been reported as normal, 19 not as significantly affected, or as consistently impaired as in idiopathic PD. 3,[5][6][7][8] Olfactory loss may precede clinical PD by at least 4 years, 20 and thus may be a marker of developing PD. Reports of olfaction in LRRK2 mutation carriers without PD, a group that is at increased risk of developing PD, are both limited and conflicting.…”

Analysis of Leucine-rich repeat kinase 2 (LRRK2) and Parkinson protein 2 (parkin, PARK2) genes mutations in Slovak Parkinson disease patients

“…Frequencies ranged from the no cases to 35.7% in sporadic and 42% in familial North-African Arab patients (Brás et al 2005;Lesage et al 2005Lesage et al , 2006Lesage et al , 2008Clark et al 2006;Deng et al 2006;Gaig et al 2006;Goldwurm et al 2006;Infante et al 2006;Ozelius et al 2006;Marongiu et al 2006;Mata et al 2006Mata et al , 2009bCivitelli et al 2007;Cossu et al 2007;Ferreira et al 2007;González-Fernández et al 2007;Ishihara et al 2007;Orr-Urtreger et al 2007;Perez-Pastene et al 2007;Squillaro et al 2007;Hulihan et al 2008;Munhoz et al 2008;Pimentel et al 2008;Correia Guedes et al 2009;De Rosa et al 2009;Floris et al 2009;Gorostidi et al 2009). …”