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

Area of Science:

• Neurogenetics
• Neurodegenerative Diseases
• Pathology

Background:

• Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are a common cause of Lewy body Parkinson's disease (PD).
• LRRK2 mutations can also manifest as other neurodegenerative conditions, including multiple system atrophy (MSA) and progressive supranuclear palsy (PSP).
• The underlying mechanisms for this pathological pleomorphism remain unclear.

Observation:

• This study investigated a case with a rare LRRK2, p.Ile1371Val variant and pathologically confirmed MSA.
• Neuropathological evaluation revealed greater involvement of the olivopontocerebellar system compared to the striatonigral system.
• Genetic sequencing of 188 neurodegenerative disease-associated genes was performed on 26 brain samples.

Findings:

• A known LRRK2, p.Ile1371Val genetic variant was identified in a patient with clinically diagnosed and pathologically proven MSA.
• This variant was previously reported in a postmortem case of Lewy body PD.
• Another LRRK2 variant, p.Ile2020Thr, has also been associated with MSA neuropathology.

Implications:

• Genetic variants within the LRRK2 gene can present with clinical and neuropathological features of MSA.
• Further research is crucial to elucidate the mechanisms driving diverse neurodegenerative trajectories in neuronal and glial cells.
• Understanding LRRK2's role in different neurodegenerative diseases can inform diagnostic and therapeutic strategies.