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Clinical and imaging characteristics of NOTCH3-negative CADASIL-suspected patients with NOTCH2NLC GGC repeat expansions

Journal of Human Genetics (2026)Cite this article

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Abstract

Neuronal intranuclear inclusion disease (NIID) is an autosomal dominant inherited neurodegenerative disease caused by NOTCH2NLC GGC repeat expansions. A high-intensity signal in the corticomedullary junction (CMJ) on magnetic resonance (MR) diffusion-weighted imaging (DWI) is a well-known characteristic of NIID. However, because of its diverse clinical symptoms and frequent presence of cerebral white matter hyperintensity (WMH) lesions on MRI, patients with NIID may be suspected of having other leukoencephalopathies. The aim of the present study was to identify patients with NOTCH2NLC GGC repeat expansions among those with undiagnosed leukoencephalopathies, recruited from NOTCH3-negative cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)-suspected and GFAP-negative Alexander disease (AxD)-suspected patients. Among 459 NOTCH3-negative CADASIL-suspected patients, 18 (3.9%) showed NOTCH2NLC GGC repeat expansions; however, among 40 GFAP-negative AxD-suspected patients, none exhibited such repeat expansions. On comparing 17 patients with GGC repeat expansions, whose clinical information was available, with 179 CADASIL probands previously reported by us, the former showed significantly higher frequencies of seizure (23.5 vs. 6.9%, respectively), WMH in the corpus callosum (92.9 vs. 9.2%, respectively), paravermis (21.4 vs. 2.7%, respectively), and middle cerebellar peduncle (21.4 vs. 3.4%, respectively), and DWI high-intensity signals in CMJ (61.5 vs. 1.4%, respectively). In conclusion, not only DWI high-intensity signals in CMJ, but also the WMH distribution, particularly a high frequency in the corpus callosum, and presence of seizures are useful for detecting NIID in patients with undiagnosed leukoencephalopathies.

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References

  1. Sone J, Mori K, Inagaki T, Katsumata R, Takagi S, Yokoi S, et al. Clinicopathological features of adult-onset neuronal intranuclear inclusion disease. Brain. 2016;139:3170–86.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Sone J, Tanaka F, Koike H, Inukai A, Katsuno M, Yoshida M, et al. Skin biopsy is useful for the antemortem diagnosis of neuronal intranuclear inclusion disease. Neurology. 2011;76:1372–6.

    Article  CAS  PubMed  Google Scholar 

  3. Sone J, Mitsuhashi S, Fujita A, Mizuguchi T, Hamanaka K, Mori K, et al. Long-read sequencing identifies GGC repeat expansions in NOTCH2NLC associated with neuronal intranuclear inclusion disease. Nat Genet. 2019;51:1215–21.

    Article  CAS  PubMed  Google Scholar 

  4. Ishiura H, Shibata S, Yoshimura J, Suzuki Y, Qu W, Doi K, et al. Noncoding CGG repeat expansions in neuronal intranuclear inclusion disease, oculopharyngodistal myopathy and an overlapping disease. Nat Genet. 2019;51:1222–32.

    Article  CAS  PubMed  Google Scholar 

  5. Okubo M, Doi H, Fukai R, Fujita A, Mitsuhashi S, Hashiguchi S, et al. GGC repeat expansion of NOTCH2NLC in adult patients with leukoencephalopathy. Ann Neurol. 2019;86:962–8.

    Article  CAS  PubMed  Google Scholar 

  6. Chabriat H, Joutel A, Dichgans M, Tournier-Lasserve E, Bousser MG. Cadasil. Lancet Neurol. 2009;8:643–53.

    Article  PubMed  Google Scholar 

  7. Uemura M, Nozaki H, Kato T, Koyama A, Sakai N, Ando S, et al. HTRA1-related cerebral small vessel disease: a review of the literature. Front Neurol. 2020;11:545.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Liao YC, Wei CY, Chang FP, Chou YT, Hsu SL, Chung CP, et al. NOTCH2NLC GGC repeat expansion in patients with vascular leukoencephalopathy. Stroke. 2023;54:1236–45.

    Article  CAS  PubMed  Google Scholar 

  9. Mizuno T, Mizuta I, Watanabe-Hosomi A, Mukai M, Koizumi T. Clinical and genetic aspects of CADASIL. Front Aging Neurosci. 2020;12:91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Mukai M, Mizuta I, Watanabe-Hosomi A, Koizumi T, Matsuura J, Hamano A, et al. Genotype-phenotype correlations and effect of mutation location in Japanese CADASIL patients. J Hum Genet. 2020;65:637–46.

    Article  CAS  PubMed  Google Scholar 

  11. Yoshida T. Clinical characteristics of Alexander disease. Neurodegener Dis Manag. 2020;10:325–33.

    Article  PubMed  Google Scholar 

  12. Yoshida T, Mizuta I, Yasuda R, Mizuno T. Clinical and radiological characteristics of older-adult-onset Alexander disease. Eur J Neurol. 2021;28:3760–7.

    Article  PubMed  Google Scholar 

  13. Yoshida T, Sasayama H, Mizuta I, Okamoto Y, Yoshida M, Riku Y, et al. Glial fibrillary acidic protein mutations in adult-onset Alexander disease: clinical features observed in 12 Japanese patients. Acta Neurol Scand. 2011;124:104–8.

    Article  CAS  PubMed  Google Scholar 

  14. Rutten JW, Haan J, Terwindt GM, van Duinen SG, Boon EM, Lesnik Oberstein SA. Interpretation of NOTCH3 mutations in the diagnosis of CADASIL. Expert Rev Mol Diagn. 2014;14:593–603.

    Article  CAS  PubMed  Google Scholar 

  15. Gong Z, Wang W, Zhao Y, Wang Y, Sun R, Zhang H, et al. Analysis of the pathogenicity and pathological characteristics of NOTCH3 gene-sparing cysteine mutations in vitro and in vivo models. Front Mol Neurosci. 2024;17:1391040.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Boston G, Jobson D, Mizuno T, Ihara M, Kalaria RN. Most common NOTCH3 mutations causing CADASIL or CADASIL-like cerebral small vessel disease: a systematic review. Cereb Circ Cogn Behav. 2024;6:100227.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Wang YC, Fan Y, Yu WK, Shen S, Li JD, Gao Y, et al. NOTCH2NLC expanded GGC repeats in patients with cerebral small vessel disease. Stroke Vasc Neurol. 2023;8:161–8.

    Article  PubMed  Google Scholar 

  18. Tian Y, Zhou L, Gao J, Jiao B, Zhang S, Xiao Q, et al. Clinical features of NOTCH2NLC-related neuronal intranuclear inclusion disease. J Neurol Neurosurg Psychiatry. 2022;93:1289–98.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Liu YH, Chou YT, Chang FP, Lee WJ, Guo YC, Chou CT, et al. Neuronal intranuclear inclusion disease in patients with adult-onset non-vascular leukoencephalopathy. Brain. 2022;145:3010–21.

    Article  PubMed  Google Scholar 

  20. Mao C, Zhou L, Li J, Pang J, Chu S, Jin W, et al. Clinical-neuroimaging-pathological relationship analysis of adult onset Neuronal Intranuclear Inclusion Disease (NIID). BMC Neurol. 2022;22:486.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Liu D, Chen K, Tan S, Yin LL, Li M, Wang YS. Longitudinal course of hyperintensity on diffusion weighted imaging in adult-onset neuronal intranuclear inclusion disease patients. Front Neurol. 2023;14:1178307.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Moody DM, Bell MA, Challa VR. The corpus callosum, a unique white-matter tract: anatomic features that may explain sparing in Binswanger disease and resistance to flow of fluid masses. AJNR Am J Neuroradiol. 1988;9:1051–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Stojanov D, Vojinovic S, Aracki-Trenkic A, Tasic A, Benedeto-Stojanov D, Ljubisavljevic S, et al. Imaging characteristics of cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL). Bosn J Basic Med Sci. 2015;15:1–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Stosser S, Bockler S, Ludolph AC, Kassubek J, Neugebauer H. Juxtacortical lesions are associated with seizures in cerebral small vessel disease. J Neurol. 2019;266:1230–5.

    Article  PubMed  Google Scholar 

  25. Ouin E, Dimitrovic A, Grosset L, Lebenberg J, Guillonnet A, Guichard JP, et al. White matter hyperintensities of the corpus callosum are associated with clinical severity in CADASIL. Stroke. 2023;54:e138–e41.

    Article  CAS  PubMed  Google Scholar 

  26. Hung K, Chen CH, Wu WC, Su JJ, Chen YF, Tang SC. Comparing the imaging characteristics of middle-aged patients with multiple sclerosis and CADASIL: a retrospective cross-sectional study. Mult Scler Relat Disord. 2024;91:105856.

    Article  PubMed  Google Scholar 

  27. Mancuso M, Arnold M, Bersano A, Burlina A, Chabriat H, Debette S, et al. Monogenic cerebral small-vessel diseases: diagnosis and therapy. Consensus recommendations of the European Academy of Neurology. Eur J Neurol. 2020;27:909–27.

    Article  CAS  PubMed  Google Scholar 

  28. Uemura M, Hatano Y, Nozaki H, Ando S, Kondo H, Hanazono A, et al. High frequency of HTRA1 AND ABCC6 mutations in Japanese patients with adult-onset cerebral small vessel disease. J Neurol Neurosurg Psychiatry. 2023;94:74–81.

    Article  PubMed  Google Scholar 

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Acknowledgements

We thank all participants and physicians. This work was supported by a grant-in-aid for Research on Intractable Disease (24FC1011, JPMH23810488) from the Japanese Ministry of Health, Labor, and Welfare, Japan. This work was also supported by JSPS KAKENHI Grant Number 23K27494. We thank Hiromi Yasuike for technical support, and EIGOCLINIC for English language editing.

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Authors and Affiliations

  1. Department of Neurology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan

    Hiraku Matsuura, Daiki Fukunaga, Ikuko Mizuta, Rei Yasuda, Mao Mukai, Akiko Watanabe-Hosomi, Takashi Koizumi, Tomokatsu Yoshida, Tomoyuki Ohara, Takashi Kasai & Toshiki Mizuno

  2. Department of Neuropathology, Institute for Medical Science of Aging, Aichi Medical University, Nagakute, Japan

    Chisato Tamai & Jun Sone

  3. Department of Anatomy and Neurobiology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan

    Takashi Koizumi

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  1. Hiraku Matsuura
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Correspondence to Jun Sone or Toshiki Mizuno.

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JS has received lecture fees from Kowa and Eisai, support for attending meetings and travel from the Japanese Society of Pathology and Asian and Oceanian Myology Center, and applied for patents on NIID. The other authors declare no competing interests.

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Matsuura, H., Fukunaga, D., Mizuta, I. et al. Clinical and imaging characteristics of NOTCH3-negative CADASIL-suspected patients with NOTCH2NLC GGC repeat expansions. J Hum Genet (2026). https://doi.org/10.1038/s10038-026-01470-1

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