Skip to main content

Advertisement

SpringerLink
Log in

The clinical characteristics of neuronal intranuclear inclusion disease and its relation with inflammation

  • Original Article
  • Published:
Neurological Sciences Aims and scope Submit manuscript

Abstract

Background

Neuronal intranuclear inclusion disease (NIID) is a great imitator with a broad spectrum of clinical manifestations that include dementia, parkinsonism, paroxysmal symptoms, peripheral neuropathy, and autonomic dysfunction. Hence, it may also masquerade as other diseases such as Alzheimer’s disease, Parkinson’s disease, and Charcot-Marie-Tooth disease. Recent breakthroughs on neuroimaging, skin biopsy, and genetic testing have facilitated the diagnosis. However, early identification and effective treatment are still difficult in cases of NIID.

Objective

To further study the clinical characteristics of NIID and investigate the relationship between NIID and inflammation.

Methods

We systematically evaluated the clinical symptoms, signs, MRI and electromyographical findings, and pathological characteristics of 20 NIID patients with abnormal GGC repeats in the NOTCH2NLC gene. Some inflammatory factors in the patients were also studied.

Results

Paroxysmal symptoms such as paroxysmal encephalopathy, stroke-like episodes, and mitochondrial encephalomyopathy lactic acidosis and stroke (MELAS)-like episode were the most common phenotypes. Other symptoms such as cognitive dysfunction, neurogenic bladder, tremor, and vision disorders were also suggestive of NIID. Interestingly, not all patients showed apparent diffusion-weighted imaging (DWI) abnormality or intranuclear inclusions, while abnormal GGC repeats of NOTCH2NLC were seen in all patients. And fevers were noticed in some patients during encephalitic episodes, usually with increasing leukocyte counts and neutrophil ratios. Both IL-6 (p = 0.019) and TNF-α (p = 0.027) levels were significantly higher in the NIID group than in normal controls.

Conclusion

Genetic testing of NOTCH2NLC may be the best choice in the diagnosis of NIID. Inflammation might be involved in the pathogenesis of NIID.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Data availability

All relevant data are available from the corresponding authors.

References

  1. Sone J, Mori K, Inagaki T et al (2016) Clinicopathological features of adult-onset neuronal intranuclear inclusion disease. Brain 139:3170–3186

    Article  PubMed  PubMed Central  Google Scholar 

  2. Huang XR, Tang BS, Jin P et al (2022) The phenotypes and mechanisms of NOTCH2NLC-related GGC repeat expansion disorders: a comprehensive review. Mol Neurobiol 59:523–534

    Article  CAS  PubMed  Google Scholar 

  3. Cao L, Yan Y, Zhao G (2021) NOTCH2NLC-related repeat expansion disorders: an expanding group of neurodegenerative disorders. Neurol Sci 42:4055–4062

    Article  PubMed  Google Scholar 

  4. Takahashi-Fujigasaki J (2015) Neuronal intranuclear hyaline inclusion disease (NIHID): an update. Brain Nerve 67:199–204

    PubMed  Google Scholar 

  5. Zannolli R, Gilman S, Rossi S et al (2002) Hereditary neuronal intranuclear inclusion disease with autonomic failure and cerebellar degeneration. Arch Neurol 59:1319–1326

    Article  PubMed  Google Scholar 

  6. Schuffler MD, Bird TD, Sumi SM et al (1978) A familial neuronal disease presenting as intestinal pseudoobstruction. Gastroenterology 75:889–898

    Article  CAS  PubMed  Google Scholar 

  7. Sone J, Tanaka F, Koike H et al (2011) Skin biopsy is useful for the antemortem diagnosis of neuronal intranuclear inclusion disease. Neurology 76:1372–1376

    Article  CAS  PubMed  Google Scholar 

  8. Han X, Han M, Liu N et al (2019) Adult-onset neuronal intranuclear inclusion disease presenting with typical MRI changes. Brain Behav 9:e1477

    Article  Google Scholar 

  9. Chen L, Chen A, Lei S et al (2019) Teaching NeuroImages: the zigzag edging sign of adult-onset neuronal intranuclear inclusion disease. Neurology 92:e2295–e2296

  10. Pang J, Yang J, Yuan Y et al (2021) The value of NOTCH2NLC gene detection and skin biopsy in the diagnosis of neuronal intranuclear inclusion disease. Front Neurol 12:624321

    Article  PubMed  PubMed Central  Google Scholar 

  11. Okamura S, Takahashi M, Abe K et al (2020) A case of neuronal intranuclear inclusion disease with recurrent vomiting and without apparent DWI abnormality for the first seven years. Heliyon 6:e4675

    Article  Google Scholar 

  12. Kim R, Kim HJ, Shin JH et al (2022) Serum inflammatory markers and progression of nonmotor symptoms in early Parkinson’s disease. Mov Disord 37:1535–1541

    Article  CAS  PubMed  Google Scholar 

  13. Diaz K, Kohut ML, Russell DW et al (2022) Peripheral inflammatory cytokines and motor symptoms in persons with Parkinson’s disease. Brain Behav Immun Health 21:100442

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Sone J, Mitsuhashi S, Fujita A et al (2019) Long-read sequencing identifies GGC repeat expansions in NOTCH2NLC associated with neuronal intranuclear inclusion disease. Nat Genet 51:1215–1221

    Article  CAS  PubMed  Google Scholar 

  15. Tian Y, Wang JL, Huang W et al (2019) Expansion of human-specific GGC repeat in neuronal intranuclear inclusion disease-related disorders. Am J Hum Genet 105:166–176

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Okubo M, Doi H, Fukai R et al (2019) GGC repeat expansion of NOTCH2NLC in adult patients with leukoencephalopathy. Ann Neurol 86:962–968

    Article  CAS  PubMed  Google Scholar 

  17. Yang D, Cen Z, Wang L et al (2022) Neuronal intranuclear inclusion disease tremor-dominant subtype: A mimicker of essential tremor. Eur J Neurol 29:450–458

    Article  PubMed  Google Scholar 

  18. Sung JH, Ramirez-Lassepas M, Mastri AR et al (1980) An unusual degenerative disorder of neurons associated with a novel intranuclear hyaline inclusion (neuronal intranuclear hyaline inclusion disease). A clinicopathological study of a case. J Neuropathol Exp Neurol 39:107–130

    Article  CAS  PubMed  Google Scholar 

  19. Cao Y, Wu J, Yue Y et al (2022) Expanding the clinical spectrum of adult-onset neuronal intranuclear inclusion disease. Acta Neurol Belg 122:647–658

    Article  PubMed  Google Scholar 

  20. Liang H, Wang B, Li Q et al (2020) Clinical and pathological features in adult-onset NIID patients with cortical enhancement. J Neurol 267:3187–3198

    Article  PubMed  Google Scholar 

  21. Ishihara T, Okamoto T, Saida K et al (2020) Neuronal intranuclear inclusion disease presenting with an MELAS-like episode in chronic polyneuropathy. Neurol Genet 6:e531

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Yu J, Liufu T, Zheng Y et al (2022) CGG repeat expansion in NOTCH2NLC causes mitochondrial dysfunction and progressive neurodegeneration in Drosophila model. Proc Natl Acad Sci U S A 119:e2086318177

    Article  Google Scholar 

  23. Tian Y, Zhou L, Gao J et al (2022) Clinical features of NOTCH2NLC-related neuronal intranuclear inclusion disease. J Neurol Neurosurg Psychiatry 93:1289–1298

    Article  PubMed  Google Scholar 

  24. Deng J, Zhou B, Yu J et al (2022) Genetic origin of sporadic cases and RNA toxicity in neuronal intranuclear inclusion disease. J Med Genet 59:462–469

    Article  CAS  PubMed  Google Scholar 

  25. Ward RJ, Dexter DT, Crichton RR (2015) Ageing, neuroinflammation and neurodegeneration. Front Biosci (Schol Ed) 7:189–204

    Article  PubMed  Google Scholar 

  26. Cervellati C, Trentini A, Pecorelli A et al (2020) Inflammation in neurological disorders: The thin boundary between brain and periphery. Antioxid Redox Signal 33:191–210

    Article  CAS  PubMed  Google Scholar 

  27. Perry VH (2010) Contribution of systemic inflammation to chronic neurodegeneration. Acta Neuropathol 120:277–286

    Article  CAS  PubMed  Google Scholar 

  28. Liberman AC, Trias E, Da SCL et al (2018) Neuroimmune and inflammatory signals in complex disorders of the central nervous system. Neuroimmunomodulat 25:246–270

    Article  CAS  Google Scholar 

  29. Colton CA (2009) Heterogeneity of microglial activation in the innate immune response in the brain. J Neuroimmune Pharmacol 4:399–418

    Article  PubMed  PubMed Central  Google Scholar 

  30. Saha RN, Liu X, Pahan K (2006) Up-regulation of BDNF in astrocytes by TNF-alpha: a case for the neuroprotective role of cytokine. J Neuroimmune Pharmacol 1:212–222

    Article  PubMed  PubMed Central  Google Scholar 

  31. Li Z, Zheng Z, Ruan J (2016) Chronic inflammation links cancer and Parkinson’s disease. Front Aging Neurosci 8:126

    Article  PubMed  PubMed Central  Google Scholar 

  32. Piancone F, Saresella M, La Rosa F et al (2021) Inflammatory responses to monomeric and aggregated alpha-Synuclein in peripheral blood of Parkinson disease patients. Front Neurosci 15:639646

    Article  PubMed  PubMed Central  Google Scholar 

  33. Liu TW, Chen CM, Chang KH (2022) Biomarker of neuroinflammation in Parkinson’s disease. Int J Mol Sci 23:4148

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Baj T, Seth R (2018) Role of Curcumin in regulation of TNF-alpha mediated brain inflammatory responses. Recent Pat Inflamm Allergy Drug Discov 12:69–77

    Article  CAS  PubMed  Google Scholar 

  35. Oberlin LE, Erickson KI, Mackey R et al (2021) Peripheral inflammatory biomarkers predict the deposition and progression of amyloid-beta in cognitively unimpaired older adults. Brain Behav Immun 95:178–189

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Michaud M, Balardy L, Moulis G et al (2013) Proinflammatory cytokines, aging, and age-related diseases. J Am Med Dir Assoc 14:877–882

    Article  PubMed  Google Scholar 

Download references

Author information

Author notes

  1. Yaping Yan and Lanxiao Cao contributed equally to this work

Authors and Affiliations

  1. Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang Province, China

    Yaping Yan, Luyan Gu, Jun Tian, Xinzhen Yin, Baorong Zhang & Guohua Zhao

  2. Department of Neurology, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Yiwu, 322000, Zhejiang Province, China

    Lanxiao Cao & Guohua Zhao

  3. Department of Neurology, The Second People’s Hospital of Jiaxing, Jiaxing, 314099, Zhejiang Province, China

    Congying Xu

  4. Department of Neurology, Hangzhou Traditional Chinese Medicine Hospital, Hangzhou, 310007, Zhejiang Province, China

    Wei Fang

Authors
  1. Yaping Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Lanxiao Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Luyan Gu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Congying Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wei Fang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jun Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Xinzhen Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Baorong Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Guohua Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Baorong Zhang or Guohua Zhao.

Ethics declarations

Ethical information

This study has been approved by the Institutional Review Board and has therefore been approved performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Conflict of interest

The authors of this manuscript declare no relationships with any companies, whose products or services may be related to the subject matter of thearticle.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yan, Y., Cao, L., Gu, L. et al. The clinical characteristics of neuronal intranuclear inclusion disease and its relation with inflammation. Neurol Sci 44, 3189–3197 (2023). https://doi.org/10.1007/s10072-023-06822-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10072-023-06822-9

Keywords

Search

Navigation