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Phenotypic bases of NOTCH2NLC GGC expansion positive neuronal intranuclear inclusion disease in a Southeast Asian cohort.
Clin Genet. 2020 09; 98(3):274-281.CG

Abstract

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.

Authors+Show Affiliations

Department of Neurology, National Neuroscience Institute, Tan Tock Seng Hospital, Singapore.Department of Neurology, National Neuroscience Institute, Tan Tock Seng Hospital, Singapore.Department of Neuroradiology, National Neuroscience institute, Singapore.Department of Neurology, National Neuroscience Institute, Tan Tock Seng Hospital, Singapore.Department of Clinical and Translational Research, Singapore General Hospital, Singapore.Department of Clinical and Translational Research, Singapore General Hospital, Singapore.SingHealth Duke-NUS Institute of Precision Medicine, Singapore. Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore.SingHealth Duke-NUS Institute of Precision Medicine, Singapore.Human Genetics, Genome Institute of Singapore, A*STAR, Singapore. Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.Department of Pathology, Tan Tock Seng Hospital, Singapore.Department of Neurology, National Neuroscience Institute, Tan Tock Seng Hospital, Singapore.Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.Department of Neuroradiology, National Neuroscience institute, Singapore.Department of Neurology, National Neuroscience Institute, Singapore General Hospital, Singapore.Neuroscience and Behavioural Disorders, Duke NUS Medical School, Singapore. Department of Neurology, National Neuroscience Institute, Singapore General Hospital, Singapore.Department of Neuroradiology, National Neuroscience institute, Singapore.Department of Neurology, National Neuroscience Institute, Tan Tock Seng Hospital, Singapore. Neuroscience and Behavioural Disorders, Duke NUS Medical School, Singapore.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32602554

Citation

Chen, Zhiyong, et al. "Phenotypic Bases of NOTCH2NLC GGC Expansion Positive Neuronal Intranuclear Inclusion Disease in a Southeast Asian Cohort." Clinical Genetics, vol. 98, no. 3, 2020, pp. 274-281.
Chen Z, Xu Z, Cheng Q, et al. Phenotypic bases of NOTCH2NLC GGC expansion positive neuronal intranuclear inclusion disease in a Southeast Asian cohort. Clin Genet. 2020;98(3):274-281.
Chen, Z., Xu, Z., Cheng, Q., Tan, Y. J., Ong, H. L., Zhao, Y., Lim, W. K., Teo, J. X., Foo, J. N., Lee, H. Y., Tan, J. M. M., Hang, L., Yu, W. Y., Ting, S. K. S., Tan, E. K., Lim, T. C. C., & Ng, A. S. L. (2020). Phenotypic bases of NOTCH2NLC GGC expansion positive neuronal intranuclear inclusion disease in a Southeast Asian cohort. Clinical Genetics, 98(3), 274-281. https://doi.org/10.1111/cge.13802
Chen Z, et al. Phenotypic Bases of NOTCH2NLC GGC Expansion Positive Neuronal Intranuclear Inclusion Disease in a Southeast Asian Cohort. Clin Genet. 2020;98(3):274-281. PubMed PMID: 32602554.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Phenotypic bases of NOTCH2NLC GGC expansion positive neuronal intranuclear inclusion disease in a Southeast Asian cohort. AU - Chen,Zhiyong, AU - Xu,Zheyu, AU - Cheng,Qianhui, AU - Tan,Yi Jayne, AU - Ong,Helen L, AU - Zhao,Yi, AU - Lim,Weng Khong, AU - Teo,Jing Xian, AU - Foo,Jia Nee, AU - Lee,Hwei Yee, AU - Tan,Jeanne M M, AU - Hang,Liting, AU - Yu,Wai-Yung, AU - Ting,Simon K S, AU - Tan,Eng-King, AU - Lim,Tchoyoson C C, AU - Ng,Adeline S L, Y1 - 2020/07/26/ PY - 2020/05/05/received PY - 2020/06/08/revised PY - 2020/06/25/accepted PY - 2020/7/1/pubmed PY - 2021/7/13/medline PY - 2020/7/1/entrez KW - GGC repeat expansion KW - NOTCH2NLC KW - diffusion-weighted imaging KW - neurofilament light KW - neuronal intranuclear inclusion disease SP - 274 EP - 281 JF - Clinical genetics JO - Clin Genet VL - 98 IS - 3 N2 - 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. SN - 1399-0004 UR - https://www.unboundmedicine.com/medline/citation/32602554/Phenotypic_bases_of_NOTCH2NLC_GGC_expansion_positive_neuronal_intranuclear_inclusion_disease_in_a_Southeast_Asian_cohort_ L2 - https://doi.org/10.1111/cge.13802 DB - PRIME DP - Unbound Medicine ER -