TY - JOUR
T1 - LRRK2 p.Ile1371Val mutation in a case with neuropathologically confirmed multi-system atrophy
AU - Lee, Kelsey
AU - Nguyen, Khanh Dung
AU - Sun, Chao
AU - Liu, Mei
AU - Zafar, Faria
AU - Saetern, Jimmy
AU - Flierl, Adrian
AU - Tetrud, James W.
AU - Langston, J. William
AU - Dickson, Dennis
AU - Schule, Birgitt
N1 - Publisher Copyright:
© 2018 - IOS Press and the Authors. All Rights Reserved.
PY - 2018
Y1 - 2018
N2 - 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.
AB - 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.
KW - Alpha-synuclein
KW - Genetic risk factor
KW - Glial cytoplasmic inclusions
KW - LRRK2
KW - Leucine-rich repeat kinase 2
KW - Multiple system atrophy
KW - Mutation
KW - Neuronal cytoplasmic inclusions
KW - Olivopontocerebellar degeneration
KW - P.Ile1371Val
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U2 - 10.3233/JPD-171237
DO - 10.3233/JPD-171237
M3 - Article
C2 - 29480226
AN - SCOPUS:85043581610
SN - 1877-7171
VL - 8
SP - 93
EP - 100
JO - Journal of Parkinson's disease
JF - Journal of Parkinson's disease
IS - 1
ER -