Objective: Leucine-rich repeat kinase 2 (LRRK2) mutations are the most common cause of Parkinson disease (PD). Several dominantly inherited pathogenic substitutions have been identified in different domains of the Lrrk2 protein. Herein, we characterize the clinical and genetic features associated with Lrrk2 p.R1441C.
Methods: We identified 33 affected and 15 unaffected LRRK2 c.4321C>T (p.R1441C) mutation carriers through an international consortium originating from three continents. The age-specific cumulative incidence of PD was calculated by Kaplan-Meier analysis.
Results: The clinical presentation of Lrrk2 p.R1441C carriers was similar to sporadic PD and Lrrk2 p.G2019S parkinsonism. The mean age at onset for parkinsonism was 60 years, range 30-79 years; fewer than 20% of the patients had symptoms before the age 50 years, while by 75 years >90% of them had developed symptoms. Haplotype analysis suggests four independent founders for the p.R1441C mutation.
Conclusions: The distribution in age at onset and clinical features in Lrrk2 p.R1441C patients are similar to idiopathic and Lrrk2 p.G2019S parkinsonism. Several independent founders of the p.R1441C substitution suggest this site is prone to recurrent mutagenesis.