p.L1795F LRRK2 variant is a common cause of Parkinson's disease in Central Europe

Abstract

Pathogenic variants in LRRK2 are one of the most common genetic risk factors for Parkinson's disease (PD). Recently, the lesser-known p.L1795F variant was proposed as a strong genetic risk factor for PD, however, further families are currently lacking in literature. A multicentre young onset and familial PD cohort (n = 220) from 9 movement disorder centres across Central Europe within the CEGEMOD consortium was screened for rare LRRK2 variants using whole exome sequencing data. We identified 4 PD cases with heterozygous p.L1795F variant. All 4 cases were characterised by akinetic-rigid PD phenotype with early onset of severe motor fluctuations, 2 receiving LCIG therapy and 2 implanted with STN DBS; all 4 cases showed unsatisfactory effect of advanced therapies on motor fluctuations. Our data also suggest that p.L1795F may represent the most common currently known pathogenic LRRK2 variant in Central Europe compared to the more studied p.G2019S, being present in 1.81% of PD cases within the Central European cohort and 3.23% of familial PD cases. Together with the ongoing clinical trials for LRRK2 inhibitors, this finding emphasises the urgent need for more ethnic diversity in PD genetic research.

Keywords: Genetics; L1795F; LRRK2; Mutation; Parkinson’s disease; Risk factor.

Figure 1

Schematic representation of the LRRK2 gene with highlighted PD-associated pathogenic mutations including the proposed p.L1795F variant.

Figure 2

Pedigrees of LRRK2 p.L1795F positive PD patients. AAO: age at onset; y = years; CP = cerebral palsy;

Figure 3