Corticobasal syndrome and primary progressive aphasia as manifestations of LRRK2 gene mutations

Abstract

Background: Mutations in the LRRK2 gene are an important cause of familial and nonfamilial parkinsonism. Despite pleomorphic pathology, LRRK2 mutations are believed to manifest clinically as typical Parkinson disease (PD). However, most genetic screens have been limited to PD clinic populations.

Objective: To clinically characterize LRRK2 mutations in cases recruited from a spectrum of neurodegenerative diseases.

Methods: We screened for the common G2019S mutation and several additional previously reported LRRK2 mutations in 434 individuals. A total of 254 patients recruited from neurodegenerative disease clinics and 180 neurodegenerative disease autopsy cases from the University of Pennsylvania brain bank were evaluated.

Results: Eight cases were found to harbor a LRRK2 mutation. Among patients with a mutation, two presented with cognitive deficits leading to clinical diagnoses of corticobasal syndrome and primary progressive aphasia.

Conclusion: The clinical presentation of LRRK2-associated neurodegenerative disease may be more heterogeneous than previously assumed.

Figure. Distribution of cortical atrophy on MRI studies of Patients 1 and 2

Patient 1 is a LRRK2 G2019S heterozygote and carries a clinical diagnosis of corticobasa syndrome. Patient 2 is a LRRK2 R793M heterozygote and carries a clinical diagnosis of primary progressive aphasia/frontotemporal dementia. Areas of relative atrophy compared to control groups of healthy seniors are shown in color (statistical threshold for display p < 0.001).