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LRRK2 (PARK8; encoding the protein Lrrk2/dardarin)

The leucine-rich repeat kinase 2 gene (LRRK2), located on chromosome 12 (12q12), encodes the protein dardarin. This contains both GTPase and kinase domains, as well as two protein-protein interaction domains (leucine-rich and WD40 repeats) [45]. In 2004, mutations in this gene were associated with the development of PD in several kindreds [46, 47]. Since then, pathogenic LRRK2 substitutions have become recognized as one of the most important causes of both familial and sporadic forms of PD [48-50].

While the majority of patients with LRRK2-linked disease present with a phenotype that is clinically indistinguishable from typical PD, there are several case reports of patients who present with clinically and neuropathologically atypical forms of the disease [47]. Two members of family A (one of the families in which mutations in LRRK2 were first described as being associated with PD) [47] presented with dementia in the absence of parkinsonian symptoms and carried the p.Y1699C amino acid change [51]. A novel mutation (p.L1165P) was also found in a PD patient who developed severe neuropsychological symptoms and dementia [52], although in this instance the pathogenicity of the mutation has not been proven. In 2012, Meeus et al. [53] screened the major AD and PD genes in a cohort of DLB and PD-D cases from Belgium. They identified a female PD-D patient with an onset of parkinsonism at 70 years and progressive cognitive decline that led to dementia with important functional impairment [Mini-Mental State Examination (MMSE) score 14/30 at age 86] who carried the p.R1441C LRRK2 mutation.

The most common LRRK2 mutation in White populations is the p.G2019S variant, which affects a key residue in the kinase domain of this large and complex protein. This variant appears to underlie disease in about 1% of patients with sporadic PD and 4% of patients with hereditary PD, and its frequency varies greatly with geographical or ethnic origin, being highest in the Middle East and higher in southern than in northern Europe [54].

Overall, the prevalence of cognitive dysfunction and dementia among LRRK2 p.G2019S patients is low [54-56]. Four studies assessing cognitive dysfunction in LRRK2 p.G2019S PD cases in different populations have found no significant differences between p.G2019S carriers and non-carriers [57-60]. However, a larger study performed in a worldwide series showed a significantly lower prevalence of cognitive impairment in LRRK2-related PD than in idiopathic PD: only 23% of patients with LRRK2 p.G2019S were found to have evidence of cognitive impairment (MMSE score <24) compared with 70% of patients with idiopathic PD [54]. This finding clearly argues against the speculation that genetic variability at the LRRK2 locus could underlie both AD and PD, given the previous association of the chromosome 12q12 locus with late-onset AD [61].

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