Objective: To report on the clinical, pathological, and genetic findings of four cases of levodopa-responsive parkinsonism with long survival and tauopathy.

Background: The most common form of parkinsonism (PS) is Lewy body disease (PD). The second most common degenerative cause of PS is progressive supranuclear palsy (PSP), where abnormally phosphorylated tau inclusions characterize the pathology. A relatively uncommon tauopathy with features of PS is corticobasal degeneration (CBD). Prognosis in PSP and CBD is less favorable than PD. We report four cases of dopa-responsive PS tauopathy with unusually long survival.

Method: Saskatchewan Movement Disorder Program (SMDP) has operated uninterrupted since 1968. Patients are seen on a first-come, first-served basis. Videos are made on all consenting individuals. Autopsy studies are offered to patients to establish a definitive diagnosis. Canadian-certified neuropathologists performed pathology studies at no cost to the family.

Results: Four patients (3 males, 1 female) with clinical diagnosis of Parkinsonism are included. Median onset age was 28 years (range: 13-53 years) and median survival after onset was 52 years (range: 25-61 years). Genetic and pathological findings varied among the cases. One patient with a heterozygous LRRK2 Gly2019Ser mutation showed substantia nigra degeneration tau inclusions involving multiple brain regions, including the brainstem, cerebellum, cerebral isocortex, white matter, and limbic lobe. Another case with a homozygous DNAJC12 p.K63* mutation exhibited mild tauopathy predominantly in the brainstem and deep gray structures. A third patient with a Parkin gene mutation displayed mild tauopathy with tau inclusions in the midbrain, hippocampal formation, and cingulate gyrus. The fourth case, without genetic study, had pathology consistent with PS-neurofibrillary tangles. Notably, all cases were levodopa-responsive. Tau distribution patterns in these cases differed from typical PSP and CBD, suggesting a distinct form of tauopathy-associated parkinsonism.

Conclusion: We show another mostly genetic form of tauopathy associated parkinsonism, distinct from PSP and CBD. These findings suggest that there are several different metabolic pathways for tau inclusion formation with widely varying outcomes. Further studies are needed to determine the pathophysiology of tau protein formation.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/dopa-responsive-parkinsonism-secondary-to-tauopathy-clinical-pathological-and-genetic-study/