Clinical,radiological,myopathological Features,and NOTCH2NLC Gene Of Adult-onset Neuronal Intranuclear Inclusion Disease

Objetctives:The adult-onset Neuronal intranuclear inclusion disease(adult-onset NIID)is a rare neurodegenerative disorder pathologically characterized by the extensive loss of neurons and the presence of eosinophilic hyaline intranuclear inclusions in the central and peripheral nervous cells,and also in multiple other organs.We summarised a group of patients with skin biopsy and genetic diagnosis in our research center,retrospectively analyzing the characteristics of NIID imaging and clinical,and summarized the clinical characteristics.Materials and Methods:12 patients with adult-onset NIID diagnosed in the Department of Neurology,First Affiliated Hospital of Nanchang University from Octorber 2017 to December2019 were included in this study.A retrospective analysis of 12 cases of NIIID was performed.Skin histopathologic biopsies were performed in 12 patients,In addition to observing pathological changes,the expression and distribution of p62 and ubiquitin in cells were observed by immunostaining.Repeat-primed PCR was conducted to confirm the genetic variations in patients with NIID and controls.Results:1 、6 cases of man and 6 cases of woman fulfilling the clinical features of neuronal intranuclear inclusion disease including with a ratio of 1:1.There were 3families and 9 sporadic.The age is from 57 to 73 years old were included in this study,with average age of 66.0±4.7 years old.The onset ages were ranged from 47 to 60 years old,with average onset age of 57.3±6.5 years old.The time of onset to treatment was from 1 to 10 years,with 50% of patients Consult physician in 5years.The most common initial symptom in the 12 patients was episodic encephalopathy(3/12,25.00%).Other symptoms included cognitive dysfunction(2/12,16.67%),tremor(2/12,16.67%),headache(2/12,16.67%),voting(2/12,16.67%)and baldder dysfunction(1/12,8.33%).The most common symptom in the 12 patients was slowly progressive cognitive dysfunction(9/12,75.00%),episodic encephalopathy(6/12,50.00%),baldder dysfunction(6/12,50.00%),limb weakness(6/12,50.00%),limb sensory disturbance(5/12,41.67%),tremor(3/12,25.00%),ataxia(3/12,25.00%)and miosis(2/12,16.67%).2、11 of 12 patients had head MRI showing extensively curve-like high signals along the corticomedullary junction on DWI and showing a broadly symmetrical white matter high signal on T2 WI and Flair.3 patients had high signals on the corpus callosum and one on the cerebral cortex with enhanced.3、11 of 12 patients were identified with eosinophilic intranuclear inclusions in the nucleus of fibroblasts,fat cells and ductal epithelial cells of sweat glands on H&E staining through skin biopsy,with inclusion bodies formed by ubiquitin and p62 protein with immunohistochemical and immunofluorescent examination.Electron microscopy revealed that intranuclear inclusion represented a pile of round-halo filament materials without a limiting membrane in the center of the nucleus.A patient simultaneously presented with lots of abnormal nuclei filled with metachromatic substance in the ductal epithelial cells of sweat glands and adipocyte,which were immunopositive to p62.Electron microscopy revealed round-halo intranuclear inclusions in the center of the nucleus.4、DNA was available from 12 patients.RP-PCR was used to verify the genic mutation in the above 12 patients.Conclusions:1、Episodic encephalopathy has a great value to recongnize according our research,and we need to extend the rang of it.It is likely include such as episodic headache,episodic vomiting,episodic fever and so on.Those symptoms may be a clinical manifestation of NIID.We should not be limited to such a limited category of episodic encephalopathy and lead to clinical diagnosis bias.2、The diagnostic value of the streamer sign for NIID is overemphasized at present.There is not every patient of NIID has a streamer sign based on literature or our research.It is easy to escape diagnosis and diagnosis bias when we diagonse the disease only rely on this change.In addition,ther are some features of cranial MRI of some NIID patients such as symmetrical white matter lesions,DWI high signal of the corpus callosum,and edema and enhancement of the posterior cortex.3、Skin biopsy is still the most convenient pathological diagnosis method for NIID.P62 immunohistochemical staining is a simple and sensitive method,which can replace electron microscopy in a certain sense.4、The GGC repeats expansion in the 5’-untranslated region(5′UTR)of the NOTCH2 NLC gene was identified associated with NIID.