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Fulltext Clinical Phenotype of LRRK2 R1441C in 2 Chinese Sisters

Lim SY, Lim JL, Ahmad-Annuar A, Lohmann K, Tan AH, Lim KB, et al.

Neurodegener Dis, 2020;20(1):39-45.
PMID: 32580205 DOI: 10.1159/000508131

Pathogenic and risk variants in the LRRK2 gene are among the main genetic contributors to Parkinson's disease (PD) worldwide, and LRRK2-targeted therapies for patients with PARK-LRRK2are now entering clinical trials. However, in contrast to the LRRK2 G2019S mutation commonly found in Caucasians, North-African Arabs, and Ashkenazi Jews, relatively little is known about other causative LRRK2 mutations, and data on genotype-phenotype correlations are largely lacking. This report is from an ongoing multicentre study in which next-generation sequencing-based PD gene panel testing has so far been conducted on 499 PD patients of various ethnicities from Malaysia. We describe 2 sisters of Chinese ancestry with PD who carry the R1441C mutation in LRRK2 (which in Asians has been reported in only 2 Chinese patients previously), and highlight interesting clinical observations made over a decade of close follow-up. We further explored the feasibility of using a brief, expert-administered rating scale (the Clinical Impression of Severity Index; CISI-PD) to capture data on global disease severity in a large (n = 820) unselected cohort of PD patients, including severely disabled individuals typically excluded from research studies. All patients in this study were managed and evaluated by the same PD neurologist, and these data were used to make broad comparisons between the monogenic PD cases versus the overall "real world" PD cohort. This report contributes to the scarce literature on R1441C PARK-LRRK2, offering insights into natural history and epidemiological aspects, and provides support for the application of a simple and reliable clinical tool that can improve the inclusion of under-represented patient groups in PD research.

Matched MeSH terms: Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics*
Fulltext Association of LRRK2 Haplotype With Age at Onset in Parkinson Disease

Xiao B, Deng X, Ng EY, Allen JC, Lim SY, Ahmad-Annuar A, et al.

JAMA Neurol, 2018 01 01;75(1):127-128.
PMID: 29131875 DOI: 10.1001/jamaneurol.2017.3363
Matched MeSH terms: Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics*
Fulltext Unravelling the genetic links between Parkinson's disease and lung cancer

Leong YQ, Koh RY, Chye SM, Ng KY

Biol Chem, 2023 May 25;404(6):551-567.
PMID: 36634094 DOI: 10.1515/hsz-2022-0228

Increase evidence from epidemiological studies have shown an inverse association between Parkinson's disease (PD) and lung cancer. PD and lung cancer are both geriatric diseases, where these two diseases are sharing some common genetic determinants. Several PD-associated genes including alpha synuclein (SNCA), PTEN-induced kinase 1 (PINK1), parkin, parkinsonism associated deglycase (DJ-1), leucine-rich repeat kinase 2 (LRRK2), F-box protein 7 (FBXO7) and ubiquitin C-terminal hydrolase L1 (UCHL1) were reported to have altered expressions in lung cancer patients. This indicates that certain PD-associated genes might be important in conferring anticancer effects. This review aims to depict the physiological functions of these genes, and discuss the putative roles of these PD-associated genes in lung cancer. The understanding of the roles of these genes in the lung cancer progression might be important in the identification of new treatment targets for lung cancer. Gene therapy that aims to alter the expressions of these genes could be developed for future anticancer therapy. As a result, studying the roles of these genes in lung cancer may also help to understand their involvements as well as their roles in the pathogenesis of PD.

Matched MeSH terms: Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics
Fulltext LRRK2 N551K and R1398H variants are protective in Malays and Chinese in Malaysia: A case-control association study for Parkinson's disease

Gopalai AA, Lim JL, Li HH, Zhao Y, Lim TT, Eow GB, et al.

Mol Genet Genomic Med, 2019 Nov;7(11):e604.
PMID: 31487119 DOI: 10.1002/mgg3.604

BACKGROUND: The LRRK2 gene is associated with Parkinson's disease (PD) as a number of mutations within the gene have been shown to be susceptibility factors. Studies on various global populations have determined that mutations such as G2019S, G2385R, and R1628P in LRRK2 increase the risk of developing PD while the N551K-R1398H haplotype is associated with conferring protection against developing PD. Here we report a study looking at the N551K and R1398H variants for the first time in the Malaysian population.
METHODS: Cases (523) which conformed to the United Kingdom PD Brain Bank Criteria for PD were recruited through trained neurologists and age- and ethnically matched controls (491) were individuals free of any neurological disorder. The N551K and R1398H mutations were genotyped using the Taqman SNP genotyping assay.
RESULTS: A significant protective association for N551K was found in those of Malay ancestry, with a protective trend seen for R1398H. A meta-analysis of Chinese individuals in this cohort with other published cohorts of Chinese ancestry indicated a significant protective role for N551K and R1398H.
CONCLUSION: This study reports that the N551K-R1398H haplotype is also relevant to the Malaysian population, with a significant protective effect found in those of Malay and Chinese ancestries.

Matched MeSH terms: Leucine-Rich Repeat Serine-Threonine Protein Kinase-2/genetics*
Lack of association between the LRRK2 A419V variant and Asian Parkinson's disease

Gopalai AA, Lim SY, Aziz ZA, Lim SK, Tan LP, Chong YB, et al.

Ann Acad Med Singap, 2013 May;42(5):237-40.
PMID: 23771111

INTRODUCTION: The G2385R and R1628P LRRK2 gene variants have been associated with an increased risk of Parkinson's disease (PD) in the Asian population. Recently, a new LRRK2 gene variant, A419V, was reported to be a third risk variant for PD in Asian patients. Our objective was to investigate this finding in our cohort of Asian subjects.
MATERIALS AND METHODS: Eight hundred and twenty-eight subjects (404 PD patients, and 424 age and gender-matched control subjects without neurological disorders) were recruited. Genotyping was done by Taqman® allelic discrimination assay on an Applied Biosystems 7500 Fast Real-Time PCR machine.
RESULTS: The heterozygous A419V genotype was found in only 1 patient with PD, compared to 3 in the control group (0.4% vs 1.3%), giving an odds ratio of 0.35 (95% confidence interval (CI), 0.01 to 3.79; P = 0.624).
CONCLUSION: A419V is not an important LRRK2 risk variant in our Asian cohort of patients with PD. Our data are further supported by a literature review which showed that 4 out of 6 published studies reported a negative association of this variant in PD.

Matched MeSH terms: Leucine-Rich Repeat Serine-Threonine Protein Kinase-2