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      Urine cytological study in patients with clinicopathologically confirmed neuronal intranuclear inclusion disease

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          Abstract

          Objective

          The diagnosis of neuronal intranuclear inclusion disease (NIID) is currently based on CGG repeat expansion in the 5′UTR of the NOTCH2NLC gene, or p62-positive intranuclear inclusions in skin biopsy. The purpose of this study is to explore the value of non-invasive pathological findings in urine sediment cells from NIID patients.

          Materials and methods

          Ten patients with clinically suspected NIID were enrolled for skin biopsy and gene screening. Morning urine (500 ml) was collected from each patient, and cell sediment was obtained by centrifugation. Urine cytology, including Giemsa staining, p62 immunostaining, and electron microscopic examination, were conducted on cell sediment.

          Results

          The main clinical symptoms of 10 patients included episodic disturbance of consciousness, cognitive impairment, tremor, limb weakness, and so on. Cerebral MRI showed that 9 patients had linear DWI high signal in the corticomedullary junction. Genetic testing found that the number of CGG repeat ranged from 96 to 158 in the NOTCH2NLC gene. Skin biopsy revealed that all patients showed p62-positive intranuclear inclusions in 18.5 ± 6.3% of the duct epithelial cells of sweat gland. In contrast, urine sediment smears revealed that only 3 patients had p62 positive intranuclear inclusions in 3.5 ± 1.2% of the sedimentary cells. Ultrastructural examinations showed that intranuclear inclusions were also identified in the cell sediment of the 3 patients.

          Conclusion

          Urine cytology may be a new and non-invasive pathological diagnosis technique for some NIID patients, although the positive rate is not as high as that of skin biopsy, which is a sensitive and reliable pathological method for NIID.

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          Most cited references29

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          Long-read sequencing identifies GGC repeat expansions in NOTCH2NLC associated with neuronal intranuclear inclusion disease

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            Noncoding CGG repeat expansions in neuronal intranuclear inclusion disease, oculopharyngodistal myopathy and an overlapping disease

            Noncoding repeat expansions cause various neuromuscular diseases, including myotonic dystrophies, fragile X tremor/ataxia syndrome, some spinocerebellar ataxias, amyotrophic lateral sclerosis and benign adult familial myoclonic epilepsies. Inspired by the striking similarities in the clinical and neuroimaging findings between neuronal intranuclear inclusion disease (NIID) and fragile X tremor/ataxia syndrome caused by noncoding CGG repeat expansions in FMR1, we directly searched for repeat expansion mutations and identified noncoding CGG repeat expansions in NBPF19 (NOTCH2NLC) as the causative mutations for NIID. Further prompted by the similarities in the clinical and neuroimaging findings with NIID, we identified similar noncoding CGG repeat expansions in two other diseases: oculopharyngeal myopathy with leukoencephalopathy and oculopharyngodistal myopathy, in LOC642361/NUTM2B-AS1 and LRP12, respectively. These findings expand our knowledge of the clinical spectra of diseases caused by expansions of the same repeat motif, and further highlight how directly searching for expanded repeats can help identify mutations underlying diseases.
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              Expansion of Human-Specific GGC Repeat in Neuronal Intranuclear Inclusion Disease-Related Disorders

              Neuronal intranuclear inclusion disease (NIID) is a slowly progressing neurodegenerative disease characterized by eosinophilic intranuclear inclusions in the nervous system and multiple visceral organs. The clinical manifestation of NIID varies widely, and both familial and sporadic cases have been reported. Here we have performed genetic linkage analysis and mapped the disease locus to 1p13.3-q23.1; however, whole-exome sequencing revealed no potential disease-causing mutations. We then performed long-read genome sequencing and identified a large GGC repeat expansion within human-specific NOTCH2NLC. Expanded GGC repeats as the cause of NIID was further confirmed in an additional three NIID-affected families as well as five sporadic NIID-affected case subjects. Moreover, given the clinical heterogeneity of NIID, we examined the size of the GGC repeat among 456 families with a variety of neurological conditions with the known pathogenic genes excluded. Surprisingly, GGC repeat expansion was observed in two Alzheimer disease (AD)-affected families and three parkinsonism-affected families, implicating that the GGC repeat expansions in NOTCH2NLC could also contribute to the pathogenesis of both AD and PD. Therefore, we suggest defining a term NIID-related disorders (NIIDRD), which will include NIID and other related neurodegenerative diseases caused by the expanded GGC repeat within human-specific NOTCH2NLC.
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                Author and article information

                Contributors
                Journal
                Front Aging Neurosci
                Front Aging Neurosci
                Front. Aging Neurosci.
                Frontiers in Aging Neuroscience
                Frontiers Media S.A.
                1663-4365
                12 September 2022
                2022
                : 14
                : 977604
                Affiliations
                [1] 1Department of Neurology, The First Affiliated Hospital of Nanchang University , Nanchang, China
                [2] 2Department of Neurology, Peking University First Hospital , Beijing, China
                [3] 3Department of Medical Genetics, The First Affiliated Hospital of Nanchang University , Nanchang, China
                Author notes

                Edited by: Gang Wang, Shanghai Jiao Tong University, China

                Reviewed by: Yun Tian, Central South University, China; Qiying Sun, Central South University, China

                *Correspondence: Daojun Hong, hongdaojun@ 123456hotmail.com

                These authors have contributed equally to this work

                This article was submitted to Alzheimer’s Disease and Related Dementias, a section of the journal Frontiers in Aging Neuroscience

                Article
                10.3389/fnagi.2022.977604
                9510843
                b9235317-48b0-428c-b7ee-0c8bd3d8a26e
                Copyright © 2022 Zhou, Huang, Huang, Peng, Zheng, Yu, Zhu, Deng, Wang and Hong.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 24 June 2022
                : 25 August 2022
                Page count
                Figures: 5, Tables: 2, Equations: 0, References: 30, Pages: 10, Words: 6038
                Funding
                Funded by: National Natural Science Foundation of China, doi 10.13039/501100001809;
                Award ID: Grants, 81460199, 81571219, 82071409, 82171846, 82160252, and U20A20356
                Categories
                Neuroscience
                Original Research

                Neurosciences
                neuronal intranuclear inclusion disease,skin biopsy,urine cytology,notch2nlc gene,pathological diagnosis

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