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%).
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).
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 clinical picture of all patients with the LRRK2-G2019S mutation was typical for levodopa-responsive parkinsonism and age of disease onset varied widely (from 39 to 71 years).
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.
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.
Mutations in five causative genes combined [alpha-Synuclein (SNCA), Parkin, PTEN-induced kinase 1 (PINK1), DJ-1, Leucine-rich repeat kinase 2 (LRRK2)] account for 2-3% of all cases with classical parkinsonism, often clinically indistinguishable from idiopathic Parkinson's disease.
Twelve- to sixteen-month-old (G2019S) LRRK2 transgenic mice prepared by us displayed progressive degeneration of substantia nigra pars compacta (SNpc) dopaminergic neurons and parkinsonism phenotypes of motor dysfunction.
Our findings in a representative series of index cases from families with ADPD emphasize the important contribution of LRRK2G2019S and GBA (L444P and N370S) mutations to parkinsonism in Brazilian families.