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. 2025 Feb 17;11(1):30.
doi: 10.1038/s41531-025-00881-9.

Updated MDSGene review on the clinical and genetic spectrum of LRRK2 variants in Parkinson´s disease

Clara Krüger  1 , Shen-Yang Lim  2   3 , Alissa Buhrmann  1 , Fenja L Fahrig  1 , Carolin Gabbert  1 , Natascha Bahr  1 , Harutyun Madoev  1 , Connie Marras  4 , Christine Klein  1 , Katja Lohmann  5
Affiliations

Updated MDSGene review on the clinical and genetic spectrum of LRRK2 variants in Parkinson´s disease

Clara Krüger et al. NPJ Parkinsons Dis. .

Abstract

Pathogenic variants in the LRRK2 gene are one of the most commonly identifiable monogenic causes of Parkinson´s disease (PD, PARK-LRRK2). This systematic MDSGene literature review comprehensively summarizes published demographic, clinical, and genetic findings related to LRRK2 variants ( https://www.mdsgene.org/ ). Data on 4660 individuals with 283 different variants were curated. The median age at onset in the PD patients with available information was 56 years, notably, with approximately one-third having PD onset <50 years. Tremor was the most frequently reported initial symptom and more common than reported in other dominantly inherited forms of PD. Of the 211 potentially PD-causing variants, 25 were classified as pathogenic or likely pathogenic, and the remaining 186 (88.2%) were variants of uncertain significance. p.G2019S was the most frequently reported pathogenic variant, followed by p.R1441G and p.R1441C. This systematic review represents the most extensive database on PARK-LRRK2 to date and provides a vital resource to improve precision medicine.

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Conflict of interest statement

Competing interests: The authors declare no competing interests. C.M. has received honoraria from the Parkinson’s Foundation. C.K. serves as a medical advisor to Centogene and Takeda and previously to Retromer Therapeutics and has received Speakers’ honoraria from Desitin and Bial. K.L. is an Associate Editor at npj Parkinson’s Disease. K.L. was not involved in the journal’s review of, or decisions related to, this manuscript.

Figures

Fig. 1
Fig. 1. Flowchart of the literature search.
The number of included and excluded articles at the different steps is indicated.
Fig. 2
Fig. 2. Mutation screening methods.
Frequencies of the mutation screening methods in the included patients.
Fig. 3
Fig. 3. Results of the pathogenicity scoring.
Comparison of the ACMG-based pathogenicity scoring of all LRRK2 variants from VarSome, Franklin, manual ACMG pathogenicity scoring, and the final pathogenicity scoring.
Fig. 4
Fig. 4. Potentially pathogenic variants in LRRK2.
Schematic representation of the LRRK2 gene (A) and protein (B) with the localization of the included variants. The position of the variants is indicated by arrows, and the predicted pathogenicity is provided by color (red, pathogenic; black, likely pathogenic; blue, variants of uncertain significance (VUS). Protein domains in B are color-coded.
Fig. 5
Fig. 5. Other clinical features in the included patients.
A The age at onset (AAO) distribution is shown in 10-year bands on the x-axis. The percentage of patients is displayed on the y-axis. The graph shows the distribution for all included PD patients (blue), for the patients with VUS only (gray), for the patients with the p.G2019S variant (black), and for patients with (likely) pathogenic variants (red). B Box plots for the AAO in years in the four groups, depicting medians and interquartile ranges. Outlier points are also displayed and are defined as data points that lie outside 1.5 times the interquartile range (IQR) from the lower or upper quartile boundary. C Initial signs and symptoms in the included patients with pathogenic or likely pathogenic variants. D Levodopa response quantifications in the included PD patients with pathogenic or likely pathogenic variants. The x-axis shows the six divisions of the levodopa response quantifications and the y-axis the number of patients.
Fig. 6
Fig. 6. Signs and symptoms in the included patients at last examination.
Cardinal clinical signs and symptoms in the included PARK-LRRK2 patients with pathogenic or likely pathogenic variants.
See this image and copyright information in PMC

References

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