Parkinson's disease (PD) has been linked to genetic mutations, particularly within the LRRK2 gene. The G2019S mutation, the most common variant, is a primary cause of autosomal-dominant PD. While carrying an LRRK2 pathogenic mutation increases the risk of developing PD, the likelihood of disease onset (penetrance) is influenced by factors such as age and ethnicity. This suggests a complex interplay between genetic predisposition and environmental or lifestyle factors in the development of Parkinson's disease.
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This article is sharing the most recent research report of Pr Hicham Elotmani (Department of Neurology Casablanca, Morocco ) about ''An overview of the worldwide distribution
of LRRK2 mutations in Parkinson’s disease''.
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1. Genetic landscape of LRRK2-related Parkinson’s disease
• Parkinson’s disease (PD) is associated with mutations in the LRRK2 gene, with the G2019S mutation being the most prevalent and a major cause of autosomal-dominant PD.
• Penetrance of LRRK2 pathogenic variants is influenced by age and ethnic background.
2. Phenotype & therapeutic approaches
• Clinical features of LRRK2-PD are generally similar to idiopathic PD, with some distinctions, such as higher rates of depression and better olfactory function.
• LRRK2 mutation carriers tend to have a slower disease progression and are more prone to experience dyskinesias.
• Deep brain stimulation is particularly effective for G2019S mutation carriers.
• The upregulation of LRRK2 kinase activity in the G2019S mutation suggests the potential of kinase inhibitors as a therapeutic option.
3. Worldwide distribution of LRRK2 mutations
• The G2019S mutation is most prevalent in north African countries, particularly Tunisia, Morocco and Algeria. The Ashkenazi–Jewish population in Israel also shows a relatively higher prevalence of the G2019S mutation.
• Prevalence of G2019S mutation decreases as one moves away from northwest Africa, creating a geographical gradient.
• Other regions like north America, south America, Asia, Russia and Australia report lower prevalence rates of themG2019S mutation.
• Other pathogenic LRRK2 mutations exhibit varying prevalence rates globally, with some regions showing very low occurrences or being entirely absent.
4. Founder effect of G2019S mutation
• The founder effect is observed in the concentration of the G2019S mutation in northwest Africa, suggesting a shared common ancestor with the Berber ethnicity at least 5000 years ago.
• This mutation is not commonly found in Asian populations, except for unique variations like R1628P and G2385R in southeast Asia.
5. Age of onset in LRRK2 mutations
• The age of onset for individuals with LRRK2 mutations, like G2019S, closely mirrors the general age of onset for PD patients in the studies we examined.
• Our finding highlights the potential influence of participant selection biases favoring younger individuals in PD research and underscores the importance of addressing these biases in future studies.
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