Phenotypic bases of NOTCH2NLC GGC expansion positive neuronal intranuclear inclusion disease in a Southeast Asian cohort

• Main Authors: Chen, Zhiyong, Xu, Zheyu, Cheng, Qianhui, Tan, Jayne Yi, Ong, Helen L., Zhao, Yi, Lim, Weng Khong, Teo, Jing Xian, Foo, Jia Nee, Lee, Hwei Yee, Tan, Jeanne M. M., Hang, Liting, Yu, Wai-Yung, Ting, Simon K. S., Tan, Eng-King, Lim, Tchoyoson C. C., Ng, Adeline S. L.
• Other Authors: Lee Kong Chian School of Medicine (LKCMedicine)
• Format: Article
• Language: English
• Published: 2021
• Subjects: Science::Medicine; Diffusion-weighted Imaging; GGC Repeat Expansion
• Online Access: https://hdl.handle.net/10356/152268
• Institution: Nanyang Technological University

Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disorder associated with GGC repeats of >60 to 500 copies in the 5'-untranslated region of NOTCH2NLC. The clinical and genetic characterization of NIID outside of East Asia remains unknown. We identified twelve patients who underwent genetic testing using long-read sequencing or repeat primed polymerase chain reaction. All were positive for a GGC repeat expansion; the median repeat length was 107 (range 92-138). Ten were Chinese and two of Malay ethnicity. Age at onset ranged from 50 to 69 years. Eight (66.7%) patients had dementia, while four (33.3%) patients were oligosymptomatic, without typical NIID symptoms of dementia, Parkinsonism, or muscle weakness. GGA interruptions within the GGC expansion were present in four patients; the number of GGA interruptions was highest (6.71%) in the patient with the earliest age at onset (50 years). Median plasma neurofilament light level was 47.3 pg/mL in seven patients (range 26-380 pg/mL). The highest level (380 pg/mL) was found in one patient who experienced an encephalitic episode. Overall, we describe a cohort of genetically confirmed NIID patients from Southeast Asia and provide further information that the presence of GGA interruptions within GGC repeat expansions may serve as a potential genetic modifier in NIID.