Prevalence of NOTCH2NLC and FMR1 Repeat Expansions in Atypical Parkinsonism Compared to Asymptomatic Elderly Individuals

• Published in: Movement disorders
• Main Authors: Chen, Pin‐Shiuan, Liu, Yi‐Ling, Chiang, Pu‐Tien, Tsai, Hsin‐Hsi, Lee, Ming‐Jen, Chang, Yang‐Yee, Lan, Min‐Yu, Wu, Yih‐Ru, Hsiao, Ing‐Tsung, Li, Cheng‐Hsuan, Fan, Sung‐Pin, Tai, Chun‐Hwei, Chiang, Han‐Lin, Chen, Chun‐Yu, Lee, Tsung‐Lin, Chang, Koping, Lu, Chin‐Song, Chang, Hsiu‐Chen, Ke, Yi‐Syuan, Feng, Yen‐Chen Anne, Hsu, Jacob Shujui, Lin, Chin‐Hsien
• Format: Journal Article
• Language: English
• Published: United States 15.07.2025
• Subjects: neuronal intranuclear inclusion body disease; multiple system atrophy; repeat expansion; fragile X‐associated tremor/ataxia syndrome; progressive supranuclear palsy
• ISSN: 0885-3185; 1531-8257
• DOI: 10.1002/mds.30290

Repeat expansions in NOTCH2NLC and FMR1 share clinical features, including parkinsonism and ataxia, resembling atypical parkinsonian syndromes. We analyzed these expansions in atypical parkinsonism patients without corticomedullary junction hyperintensity on diffusion-weighted imaging, comparing them to asymptomatic elderly individuals. We analyzed two cohorts: (1) 252 patients with atypical parkinsonism, including 165 with multiple system atrophy (MSA), 58 with progressive supranuclear palsy (PSP), and 29 with corticobasal syndrome, analyzed by repeat-primed polymerase chain reaction; and (2) 341 asymptomatic individuals over 60 from Taiwan Biobank, analyzed via whole-genome sequencing. We identified NOTCH2NLC expansions (≥60 repeats) in six patients (2.38%) with atypical parkinsonism (MSA: 4, PSP: 2; range: 102-124) and two asymptomatic individuals (0.58%, range: 63-225). Although more frequent in atypical parkinsonism (P = 0.07), the difference was not significant. FMR1 expansions were rare in both groups. NOTCH2NLC expansions may mimic PSP and MSA in early stages, warranting careful genetic evaluation. © 2025 International Parkinson and Movement Disorder Society.