Objective: The aim of this study was to investigate the presence of LRRK2 p.L1795F variant in PD patients from Central Europe.

Background: Pathogenic variants in LRRK2 are one of the most common high-risk genetic factors for Parkinson’s disease (PD). Recently, the lesser-known LRRK2 p.L1795F variant was proposed as a strong genetic risk factor for PD [1], with a functional effect via stimulating the LRRK2 kinase activity [2]. However, further families are currently lacking in the literature.

Method: A multicentre early-onset and familial PD cohort from 9 movement disorder centres across Central Europe within the CEGEMOD consortium [3] was screened for rare LRRK2 variants using whole exome sequencing data (n=219).

Results: We identified 3 PD cases with heterozygous LRRK2 p.L1795F variant and 1 PD case was additionally identified through standard genetic testing. All 4 patients were from a region close to Slovak-Hungarian borders. The age of onset was 25, 45, 55 and 69 respectively and 3 cases had positive family history with several family members affected [Figure 1]. All 4 cases were characterized as akinetic-rigid PD subtype, with their disease onset as unilateral bradykinesia and rigidity, responsive to levodopa treatment. None of them developed any kind of tremor over the years. Postural instability later developed in all 4 cases (100%), with freezing being present in 2 cases (50%). All 4 cases were characterized by early onset of severe dyskinesia and motor fluctuations, with 2 receiving LCIG therapy and 2 implanted with STN DBS; all these cases showed unsatisfactory effect on motor fluctuations .

Conclusion: Our data suggest that the p.L1795F may represent the most common currently known pathogenic LRRK2 variant in Central Europe (AF = 0.0091) compared to more studied p.G2019S (AF = 0.00164), which is lower than in North-West Europe as reported previously [4]. Together with the ongoing clinical trials for LRRK2 inhibitors, this finding emphasizes the urgent need for more ethnic diversity in PD genetic research.

This study was funded by the Slovak Grant and Development Agency under contracts APVV-22-0279 and by the Slovak Scientific Grant Agency under contract VEGA 1/0712/22.

Pedigrees of LRRK2 L1795F PD patients

References: [1] Pitz V, Makarious M, Bandrés-Ciga S, Iwaki H, Singleton A, Nalls M, Heilbron K, Blauwendraat C.Analysis of rare Parkinson's disease variants in millions of people. Res Sq [Preprint]. 2023 Apr 10:rs.3.rs-2743857. doi: 10.21203/rs.3.rs-2743857/v1. PMID: 37090536; PMCID: PMC10120789.
[2] Kalogeropulou AF, Purlyte E, Tonelli F, Lange SM, Wightman M, Prescott AR, Padmanabhan S, Sammler E, Alessi DR. Impact of 100 LRRK2 variants linked to Parkinson’s disease on kinase activity and microtubule binding. Biochem J. 2022 Sep 16;479(17):1759-1783. doi: 10.1042/BCJ20220161. PMID: 35950872; PMCID: PMC9472821.
[3] Ostrozovicova M, Dusek P, Grofik M, Han V, Holly P, Jech R, Klivenyi P, Kovacs N, Kulcsarova K, Kurca E, Lackova A, Magocova V, Necpal J, Pinter D, Ruzicka E, Serranova T, Smilowska K, Straka I, Svorenova T, Tamas G, Valkovic P, Zarubova K, Houlden H, Rizig M, Skorvanek M. Central European Group on Genetics of Movement Disorders. Eur J Neurol. 2023 Dec 7. doi: 10.1111/ene.16165. PMID: 38059386.
[4] Skorvanek M, Rizig M, Athanasiou-Fragkouli A, Necpal J, Straka I, Tamas G, Kurca E, Mosejova A, Han V, Lorincova T, Ostrozovicova M, Liesenerova S, Levicka P, Fajcikova L, Minar M, Valkovic P, Mákos O, Kelemen A, Grofik M, Cibulka M, Jama F, Houlden H; members of the CEGEMOD study group. LRRK2 mutations in Parkinson's disease patients from Central Europe: A case control study. Parkinsonism Relat Disord. 2021 Feb;83:110-112. doi: 10.1016/j.parkreldis.2020.12.021. PMID: 33561776.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/frequency-of-lrrk2-p-l1795f-variant-in-parkinsons-disease-patients-from-central-europe-within-the-cegemod-consortium/