Several pathogenic mutations in the leucine-rich repeat kinase 2 (LRRK2; PARK8) gene recently have been identified in familial and sporadic parkinsonism.
These data suggest that parkinsonism caused by mutations in LRRK2 is likely to represent the commonest locus for autosomal dominant Parkinson's disease with a phenotype, pathology and in vivo imaging similar to idiopathic, late-onset Parkinson's disease.
Understanding the molecular function of the LRRK2 protein and its associated pathways might elucidate the switch between Lewy body pathology and neurofibrillary tangles, and holds promise for prospective therapeutics that might slow or halt progression of many forms of parkinsonism.
The third patient was characterized by parkinsonism without Lewy bodies but demonstrated dystrophic neurites in the substantia nigra intensely stained for Lrrk2.
Moreover, mutations in LRRK2 known to cause parkinsonism are associated not only with dopaminergic neuronal degeneration, but also with the accumulation of synuclein, tau, neither, or both proteins.
Therefore, the LRRK2 mutation has a relatively high frequency in the AJ population, is not fully penetrant for parkinsonism in the elderly, and does not appear to be commonly associated with late-onset dementia.
However we can not rule out other genetic variation at the LRRK2 locus may play a role in parkinsonian disorders with amyotrophic lateral sclerosis and may be considered candidates for genetic screening.
We have identified Family SK where Lrrk2G2019S segregates with slowly progressive parkinsonism and the affected proband has tau-immunopositive neurofibrillary tangle pathology.