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LRRK2 p.Ile1371Val Mutation in a Case with Neuropathologically Confirmed Multi-System Atrophy

2018; IOS Press; Volume: 8; Issue: 1 Linguagem: Inglês

10.3233/jpd-171237

1877-718X

Kelsey Lee, Khanh-Dung H. Nguyen, Chao Sun, Mei Liu, Faria Zafar, Jimmy Saetern, Adrian Flierl, James W. Tetrud, J. William Langston, Dennis W. Dickson, Birgitt Schüle,

Genetic Neurodegenerative Diseases

Background: Mutations in the leucine rich repeat kinase 2 ( LRRK2) gene are among the most common genetic causes of Lewy body Parkinson’s disease (PD). However, LRRK2 mutations can also lead to a variety of pathological phenotypes other than typical PD, including relatively pure nigrostriatal cell loss without alpha-synuclein-positive Lewy bodies or Lewy neurites, progressive supranuclear palsy (PSP), and multiple system atrophy (MSA). The mechanisms behind this remarkable pleomorphic pathology are currently unclear. Objective: To genetically and pathologically characterize a case with a LRRK2, p.Ile1371Val rare variant and pathologically proven MSA. Methods: From the brain donation program at the Parkinson’s Institute and Clinical Center, we selected 26 brains with family history and a with clinicopathological diagnosis of PD ( n = 20), MSA ( n = 4), or PSP ( n = 2). We performed neuropathological evaluation, including alpha-synuclein and tau immunohistochemistry and sequenced 188 genes that have been reported as causative for or associated with neurodegenerative diseases. Results: We identified a known LRRK2, p.Ile1371Val genetic variant in a case with clinically diagnosed and pathologically proven MSA. Neuropathology revealed that the olivopontocerebellar system was more affected than the striatonigral system. Conclusions: Our data suggest that genetic variants in the LRRK2 gene can present clinically and neuropathologically as MSA. One other LRRK2 genetic variant ( LRRK2, p.Ile2020Thr) has been reported with a neuropathological diagnosis of MSA. Interestingly, the LRRK2 variant ( LRRK2, p.Ile1371Val) identified here has been reported previously in a postmortem case with Lewy body PD. Future studies are critical to discover the mechanisms leading to different neurodegenerative trajectories both in neuronal and glial cell populations.