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A comprehensive study of clinicopathological and genetic features of neuronal intranuclear inclusion disease

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Abstract

Background

The discovery of skin intranuclear inclusions and GGC repeat expansion of NOTCH2NLC has greatly promoted the diagnosis of neuronal intranuclear inclusion disease (NIID). With highly heterogeneous clinical manifestations, NIID patients tend to be underdiagnosed at early stages.

Methods

This study comprehensively studied clinical manifestations, magnetic resonance imaging (MRI), and peripheral nerve conduction in 24 NIID and 166 other neurodegenerative disease (ND) subjects. The nomogram was plotted using the “rms” package, and the t-distributed stochastic neighbor embedding algorithm was performed. Associations between skin intranuclear inclusions and NOTCH2NLC GGC repeats were further analyzed.

Results

The clinical, MRI, and peripheral nerve conduction features seriously overlapped in NIID and ND patients; they were assigned variables according to their frequency and specificity in NIID patients. A nomogram that could distinguish NIID from ND was constructed according to the assigned variables and cutoff values of the above features. The occurrence of skin intranuclear inclusions and NOTCH2NLC GGC repeats ≥ 60 showed 100% consistency, and intranuclear inclusion frequency positively correlated with NOTCH2NLC GGC repeats. A hierarchical diagnostic flowchart for definite NIID was further established.

Conclusion

We provide a novel nomogram with the potential to realize early identification and update the diagnostic flowchart for definitive diagnosis. Moreover, this is the first study to define the association between skin pathology and NOTCH2NLC genetics in NIID.

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Data availability

The data are available upon reasonable request after ethics clearance and approval from the corresponding authors.

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Funding

This work was supported by grants from the National Natural Science Foundation of China to Yuming Xu (U1904207), the Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences to Yuming Xu (2020-PT310-01), the National Natural Science Foundation of China to Jing Yang (82171434), the Excellent Youth Project of Henan Provincial Natural Science Foundation to Jing Yang (222300420070), the Henan Province Young and Middle-Aged Health Science and Technology Innovation Outstanding Youth Training Project to Jing Yang (YXKC2020031), and the Funding for Scientific Research and Innovation Team of The First Affiliated Hospital of Zhengzhou University (QNCXTD2023016).

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Author notes

  1. Minglei Liu and Yuan Gao contributed equally to this work.

Authors and Affiliations

  1. Department of Neurology, The First Affiliated Hospital of Zhengzhou University, No. 1 Eastern Jianshe Road, Zhengzhou, 450052, Henan, China

    Minglei Liu, Yuan Gao, Yanpeng Yuan, Xiaojing Liu, Yangyang Wang, Lanjun Li, Xiaoyun Zhang, Chenyang Jiang, Qingzhi Wang, Yanlin Wang, Changhe Shi, Yuming Xu & Jing Yang

  2. NHC Key Laboratory of Prevention and Treatment of Cerebrovascular Disease, Zhengzhou, Henan, China

    Yuan Gao, Yanpeng Yuan, Xiaojing Liu, Yangyang Wang, Lanjun Li, Yanlin Wang, Yuming Xu & Jing Yang

  3. Henan Key Laboratory of Cerebrovascular Diseases, Zhengzhou University, Zhengzhou, Henan, China

    Yuan Gao, Yanpeng Yuan, Chenyang Jiang, Yanlin Wang, Yuming Xu & Jing Yang

  4. Institute of Neuroscience, Zhengzhou University, Zhengzhou, Henan, China

    Yuan Gao, Yanpeng Yuan, Xiaojing Liu, Yangyang Wang, Lanjun Li, Yanlin Wang, Changhe Shi & Yuming Xu

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  1. Minglei Liu
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Contributions

JY, CS, and YX conceived the project and designed the study. ML, YG, YY, XL, YW, and LL participated in the clinical data acquisition and analysis. ML, YG, YY, and XZ conducted the experiments and analyzed the data. CJ, QW, and YW participated in the literature search and analysis. ML and JY drafted the original manuscript. All the authors approved the final version.

Corresponding authors

Correspondence to Changhe Shi, Yuming Xu or Jing Yang.

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Ethics approval and consent to participate

The study was approved by the Ethics Committee of the First Affiliated Hospital of Zhengzhou University, China (2019-KY-294), and all the subjects signed an informed consent form according to the Declaration of Helsinki.

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The authors declare no competing interests.

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Changhe Shi, Yuming Xu and Jing Yang are senior authors.

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Liu, M., Gao, Y., Yuan, Y. et al. A comprehensive study of clinicopathological and genetic features of neuronal intranuclear inclusion disease. Neurol Sci 44, 3545–3556 (2023). https://doi.org/10.1007/s10072-023-06845-2

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