Objective: We describe a rare case of atypical parkinsonism associated with leucine-rich repeat kinase 2 (LRRK2) gene mutation presenting with clinical features suggestive of multiple system atrophy (MSA).

Background: Mutations in the LRRK2 gene are a well-established cause of autosomal dominant Parkinson’s disease (PD) with a phenotype resembling idiopathic PD. However, atypical presentations, including cases with clinical features of MSA, have been rarely reported. Given the distinct neuropathology of PD and MSA, the occurrence of MSA-like syndromes in LRRK2 mutation carriers points to the importance of evaluating for any disease entity within the spectrum of parkinsonism in such genetic mutations.

Method: We report a case of a 67-year-old female with a confirmed LRRK2 mutation who developed rapidly progressive parkinsonism with early autonomic dysfunction and poor levodopa response supportive of MSA. The patient’s symptoms progressively worsened over four years leading to walker dependence. MRI brain revealed bilateral striatal T2 hyperintensities with symmetric T1 and GRE hypointensities, while FDG PET imaging showed bilateral caudate and putamen hypometabolism suggestive of parkinsonism. FDOPA was abnormal with absent tracer activity in bilateral putamina and decreased activity in the right caudate nucleus.

Results: Our patient exhibited an MSA-P phenotype characterized by autonomic failure and a lack of sustained levodopa response. A review of the literature identified a limited number of cases (up to 4) where LRRK2 mutations were associated with confirmed or probable MSA, either clinically or pathologically. Most reported cases in the literature demonstrated a more aggressive disease course than typical LRRK2-PD, with a rapid progression and variable levodopa responsiveness.

Conclusion: This case adds evidence that LRRK2 mutations can manifest with atypical parkinsonism in particular MSA-like syndromes. While rare, clinicians should remain open to variable LRRK2 phenotypes, mostly in patients with early autonomic dysfunction and poor response to dopamine therapy. Further research is needed to clarify the underlying mechanisms linking LRRK2 mutations to MSA-like pathology and whether additional genetic or environmental factors contribute to this atypical presentation. Establishing necessity of genetic testing in atypical parkinsonism remains a key area for future exploration.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/atypical-parkinsonism-with-lrrk2-mutation-presenting-as-multiple-system-atrophy/