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.

1st Faculty of Medicine Charles University and General University Hospital Prague

2nd Faculty of Medicine Charles University and Motol University Hospital

Charles University Prague

Comenius University and University Hospital Martin

Comenius University in Bratislava Faculty of Medicine University Hospital Bratislava

Comenius University in Bratislava Faculty of Medicine University Hospital Bratislava and Centre of Experimental Medicine Slovak Academy of Sciences

Department of Neurology and Centre of Clinical Neuroscience 1st Faculty of Medicine Charles University and General University Hospital Prague Czech Republic

Faculty of Medicine P J Šafárik University

Gottfried Schatz Research Center Medical University of Graz

Jessenius Faculty of Medicine Comenius University and University Hospital Martin

Medical School University of Pecs

P J Safarik University and University Hospital of L Pasteur

P J Safarik University Kosice

Pavol Jozef Safarik University and University Hospital of L Pasteur and UCL Queen Square Institute of Neurology

Radboud University Medical Centre; Donders institute for Brain Cognition and Behaviour Department of Neurology Parkinson Centre Nijmegen Nijmegen

Royal Veterinary College

Semmelweis University

Slovakia University

UCL Queen Square Institute of Neurology

UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery

UCL Queen Square Institute of Neurology University College London Queen Square London WC1N 3BG UK

University of Pecs Medical School

University of Szeged

Zvolen Hospital

Aktualizováno

Mov Disord Clin Pract. 2025 Aug;12(8):1132-1139. doi: 10.1002/mdc3.70045. PubMed

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