LRRK2 G2019S impact on Parkinson disease; clinical phenotype and treatment in Tunisian patients.

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.