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

J Parkinsons Dis. 2018;8(1):93-100. doi: 10.3233/JPD-171237.


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.

Keywords: Alpha-synuclein; LRRK2; genetic risk factor; glial cytoplasmic inclusions; leucine-rich repeat kinase 2; multiple system atrophy; mutation; neuronal cytoplasmic inclusions; olivopontocerebellar degeneration; p.Ile1371Val.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Brain / pathology
  • Brain Chemistry
  • Female
  • Humans
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / genetics*
  • Middle Aged
  • Multiple System Atrophy / genetics*
  • Multiple System Atrophy / pathology
  • Mutation, Missense*
  • Neuroglia / chemistry
  • Neuroglia / ultrastructure
  • Neurons / chemistry
  • Neurons / ultrastructure
  • Pedigree
  • Point Mutation*
  • Sequence Analysis, DNA
  • alpha-Synuclein / genetics
  • tau Proteins / genetics


  • MAPT protein, human
  • alpha-Synuclein
  • tau Proteins
  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2