Clinical Features and Classification of Neuronal Intranuclear Inclusion Disease

Hongfei Tai; An Wang; Yumei Zhang; Shaocheng Liu; Yunzhu Pan; Kai Li; Guixian Zhao; Mengwen Wang; Guode Wu; Songtao Niu; Hua Pan; Bin Chen; Wei Li; Xingao Wang; Gehong Dong; Wei Li; Ying Zhang; Sheng Guo; Xiaoyun Liu; Mingxia Li; Hui Liang; Ming Huang; Wei'an Chen; Zaiqiang Zhang; China NIID Collaboration Alliance

doi:10.1212/NXG.0000000000200057

Clinical Features and Classification of Neuronal Intranuclear Inclusion Disease

Neurol Genet. 2023 Feb 28;9(2):e200057. doi: 10.1212/NXG.0000000000200057. eCollection 2023 Apr.

Authors

Hongfei Tai¹, An Wang¹, Yumei Zhang¹, Shaocheng Liu¹, Yunzhu Pan¹, Kai Li¹, Guixian Zhao¹, Mengwen Wang¹, Guode Wu¹, Songtao Niu¹, Hua Pan¹, Bin Chen¹, Wei Li¹, Xingao Wang¹, Gehong Dong¹, Wei Li¹, Ying Zhang¹, Sheng Guo¹, Xiaoyun Liu¹, Mingxia Li¹, Hui Liang¹, Ming Huang¹, Wei'an Chen¹, Zaiqiang Zhang¹; China NIID Collaboration Alliance

Affiliation

¹ Department of Neurology (H.T., A.W., S.L., Y.P., S.N., H.P., B.C., X.W., Z.Z.), Beijing Tiantan Hospital, Capital Medical University; China National Clinical Research Center for Neurological Diseases (H.T., A.W., Yumei Zhang, S.L., Y.P., S.N., H.P., B.C., X.W., G.D., Z.Z.), Beijing; Monogenic Disease Research Center for Neurological Disorders (Yumei Zhang), Beijing Tiantan Hospital, Capital Medical University; Department of Neurology (K.L.), Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences; Department of Neurology (G.Z.), Huashan Hospital, Shanghai Medical College, Fudan University; Department of Neurology (M.W.), The First Affiliated Hospital of Fujian Medical University, Fujian Medical University, Fuzhou; Department of Neurology (G.W.), Lanzhou University Second Hospital; Department of Pathology (G.D.), Beijing Tiantan Hospital, Capital Medical University; Department of Neurology (W.L.), Army Medical Center of People's Liberation Army, Chongqing; Department of Neurology (Ying Zhang), The First People's Hospital of Shangqiu; Department of Neurology (S.G.), The First Affiliated Hospital of Xinxiang Medical University; Department of Neurology (X.L.), Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan; Department of Neurology (M.L.), The First People's Hospital of Huaihua City; Department of Neurology (H.L.), The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou; Department of Neurology (M.H.), Hubei Provincial Hospital of Integrated Chinese & Western Medicine, Wuhan; and Department of Neurology (W.C.), First Affiliated Hospital of Wenzhou Medical University, China.

Abstract

Background and objectives: Neuronal intranuclear inclusion body disease (NIID) is a neurodegenerative disease with highly heterogeneous clinical manifestations. The present study aimed to characterize clinical features and propose a classification system based on a large cohort of NIID in China.

Methods: The Chinese NIID registry was launched from 2017, and participants' demographics and clinical features were recorded. Brain MRI, skin pathologies, and the number of GGC repeat expansions in the 5' untranslated region of the NOTCH2NLC gene were evaluated in all patients.

Results: In total, 223 patients (64.6% female) were recruited; the mean (SD) onset age was 56.7 (10.3) years. The most common manifestations were cognitive impairment (78.5%) and autonomic dysfunction (70.9%), followed by episodic symptoms (51.1%), movement disorders (50.7%), and muscle weakness (25.6%). Imaging markers included hyperintensity signals along the corticomedullary junction on diffusion-weighted imaging (96.6%), white matter lesions (98.1%), paravermis (55.0%), and focal cortical lesions (10.1%). The median size of the expanded GGC repeats in these patients was 115 (range, 70-525), with 2 patients carrying >300 GGC repeats. A larger number of GGC repeats was associated with younger age at onset (r = -0.329, p < 0.0001). According to the proposed clinical classification based on the most prominent manifestations, the patients were designated into 5 distinct types: cognitive impairment-dominant type (34.1%, n = 76), episodic neurogenic event-dominant type (32.3%, n = 72), movement disorder-dominant type (17.5%, n = 39), autonomic dysfunction-dominant type (8.5%, n = 19), and neuromuscular disease-dominant type (7.6%, n = 17). Notably, 32.3% of the episodic neurogenic event-dominant type of NIID has characteristic focal cortical lesions on brain MRI presenting localized cortical edema or atrophy. The mean onset age of the neuromuscular disease-dominant type was 47.2 (17.6) years, younger than the other types (p < 0.001). There was no significant difference in the sizes of GGC repeats among the patients in the 5 types (p = 0.547, Kruskal-Wallis test).

Discussion: This observational study of NIID establishes an overall picture of the disease regarding clinical, imaging, and genetic characteristics. The proposed clinical classification of NIID based on the most prominent manifestation divides patients into 5 types.