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- LRRK2 G2019S impact on Parkinson disease; clinical phenotype and treatment in Tunisian patients
- Guedi ALI BARREH, Ikram SGHAIER, Youssef ABIDA, Alya GHARBI, Amina NASRI, Saloua MRABET, Amira SOUISSI, Mouna BEN DJEBARA, Sameh TRABELSI, Imen KACEM, Amina GARGOURI-BERRACHI, Riadh GOUIDER
- Received December 30, 2023 Accepted April 19, 2024 Published online April 23, 2024
- DOI: https://doi.org/10.14802/jmd.23276 [Accepted]
- 207 View
- 14 Download
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Abstract
PDF - Background
LRRK2-G2019S is the most frequent mutation in North African Parkinson's disease (PD) patients.Data on its impact on disease progression and treatment response remains elusive.Therefore, we aimed to explore the clinical features,treatments,and complications through the disease course of PD Tunisian patients according to their LRRK2-G2019S profile.
Methods
Longitudinal retrospective study conducted in the department of Neurology,Razi University Hospital.We included clinically diagnosed PD patients according to the MDS criteria and reviewed their medical records for clinical,treatment, and neuropsychological assessments.LRRK2-G2019S mutation was screened among all cases using Sanger sequencing.The correlation of LRRK2-G2019S and the clinical PD features was then evaluated.
Results
We included 393 PD patients with 41.5% of cases were mutated for LRRK2-G2019S. Those with mutation exhibited an earlier age of onset(p=0.017),and female-PD cases had a higher mutation frequency (p=0.008).Mutation carriers displayed distinct clinical features,with a higher frequency of postural instability gait difficulty (PIGD)forms(adjusted-p<0.001).Throughout the disease progression,carriers showed a faster annual progression in UPDRS-III scores (adjusted-p=0.009) and a significantly higher Levodopa Equivalent Dosevalues in later stages(1060.81 vs. 877.83 for 6-8 years).Motor complications such as dyskinesia (adjusted-p<0.001) and motor fluctuations(31.9% vs. 25.7%,adjusted-p<0.001) were more prevalent in carriers,particularly in later stages.LRRK2-G2019S carriers also exhibited a lower prevalence of non-motor symptoms including cognitive disordersfor episodic memory(adjusted-p<0.001),attention(adjusted-p<0.001),and dysexecutive disorders (adjusted-p=0.039),as well asneuropsychiatric symptoms and dysautonomic signs.
Conclusion
This study demonstrated the variability of clinical profile among Tunisian PD cases explained by the incomplete penetrance of LRRK2-G2019S that increases with age.Further studies with biomarker and disease progression data are necessary to improve PD management.
- Leucine-Rich Repeat Kinase 2-Linked Parkinson’s Disease: Clinical and Molecular Findings
- Udhaya Kumari, Eng-King Tan
- J Mov Disord. 2010;3(2):25-31.
- DOI: https://doi.org/10.14802/jmd.10008
- 14,947 View
- 104 Download
- 3 Crossref
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Abstract
PDF
Mutations in Leucine-rich repeat kinase 2 (LRRK2) gene are the most common cause of sporadic and familial late onset Parkinson’s disease (PD). The G2019S common mutation has been identified about 1% of sporadic cases and 4–7% of familial cases. Over 50 variants have since been identified in LRRK2, and at least 7 of these are confirmed to be pathogenic. In addition to pathogenic mutations, several common polymorphisms in the LRRK2 gene (G2385R and R1628P) have been identified that may explain up to 10% of sporadic PD in Asian populations. LRRK2 is a large complex multidomain protein with 2,527-amino-acid and the molecular weight is 286 kDa. LRRK2 multidomain protein consists of a catalytic core domain, kinase domain and a number of putative protein-protein interaction domains. LRRK2 mutations found in PD families, including the G2019S and I2020T mutations show increased intrinsic kinase activity, when assessed with myelin basic protein as substrate. The modification of LRRK2 GTPase and kinase activity affecting residues in the ROC, COR and mitogen-activated protein kinase kinase kinases domains is believed to lead to neuronal cell death, but the pathways involved remain unclear. A number of
in vivo models inC. elegans, D. melanogaster and mice have been developed to study the patho/physiological function of LRRK2. Based on current literature, a toxic gain of function in LRRK2 kinase activity is a possible pathophysiologic mechanism and thus inhibition of kinase activity in experimental models offers a potential therapeutic strategy for LRRK2-linked PD.-
Citations
Citations to this article as recorded by
- Structural Insights and Development of LRRK2 Inhibitors for Parkinson’s Disease in the Last Decade
Gunjan Thakur, Vikas Kumar, Keun Woo Lee, Chungkil Won
Genes.2022; 13(8): 1426. CrossRef - Sequential screening nominates the Parkinson's disease associated kinase LRRK2 as a regulator of Clathrin-mediated endocytosis
George R. Heaton, Natalie Landeck, Adamantios Mamais, Mike A. Nalls, Jonathon Nixon-Abell, Ravindran Kumaran, Alexandra Beilina, Laura Pellegrini, Yan Li, Kirsten Harvey, Mark R. Cookson
Neurobiology of Disease.2020; 141: 104948. CrossRef - Target Engagement in Lead Generation
Timothy B. Durham, Maria-Jesus Blanco
Bioorganic & Medicinal Chemistry Letters.2015;[Epub] CrossRef
- Structural Insights and Development of LRRK2 Inhibitors for Parkinson’s Disease in the Last Decade
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