A series of 106 patients with isolated or familial Parkinsonism underwent clinical evaluation and genetic testing for the LRRK2G2019S mutation which was identified in 34/106 patients (32%).
Our report adds evidence that patients with LRRK2 monogenetic Parkinsonism are well suited candidates for DBS treatment and may indicate a potential genetic predictor for positive long-term effect of STN-DBS treatment.
All patients carrying the LRRK2G2019S exhibited typical levodopa-responsive parkinsonism, and severe levodopa-induced dyskinesia was observed in the patient carrying the LRRK2 and parkin mutations.
Using Cox proportional hazard models to evaluate the risk of parkinsonism among family members of PD subjects, having a daughter with PD compared with a son was associated with increased risk of parkinsonism in the parent (HR 2.59, p=0.014) as was having a child with a LRRK2G2019S mutation (HR 3.19, p=0.003).
To review the molecular genetics and functional biology of leucine-rich repeat kinase 2 (LRRK2) in parkinsonism and to summarize the opportunities and challenges to develop interventions for Parkinson disease (PD) based on this genetic insight.
In conclusion we show that the interaction of Lrrk1-Lrrk2 can form protein dimers and this interaction may influence the age of symptomatic manifestation in Lrrk2-parkinsonism patients.
The third patient was characterized by parkinsonism without Lewy bodies but demonstrated dystrophic neurites in the substantia nigra intensely stained for Lrrk2.
Several pathogenic mutations in the leucine-rich repeat kinase 2 (LRRK2; PARK8) gene recently have been identified in familial and sporadic parkinsonism.
LRRK2p.S1761R carriers developed levodopa-responsive asymmetrical parkinsonism, with variable age at onset (range: 37-72 years) suggesting age-dependent penetrance.
The mutation is located within the Roc domain of the protein and enhances GTP-binding and kinase activity, further implicating these activities as the mechanisms that underlie LRRK2-linked parkinsonism.
We aim to characterize these compensatory mechanisms and early disease-related changes by quantifying movement-related cerebral function in subjects at significantly increased risk of developing Parkinson's disease, namely carriers of a leucine-rich repeat kinase 2-G2019S mutation associated with dominantly inherited parkinsonism.
The present study also establishes that G2019S mutation leads to a reduction in lysosomal pH and increased expression of the lysosomal ATPase ATP13A2, a gene linked to a parkinsonian syndrome (Kufor-Rakeb syndrome), in brain samples from mouse and human LRRK2G2019S carriers.