Skip to main content
SpringerLink
Log in

Genotypic and phenotypic spectrum of CADASIL in Japan: the experience at a referral center in Kumamoto University from 1997 to 2014

  • Original Communication
  • Published:
Journal of Neurology Aims and scope Submit manuscript

Abstract

This study elucidates the genotypic and phenotypic spectrum and histopathological findings related to cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) in Japan. For this single-center retrospective observational study, we enrolled 215 patients who were clinically suspected of having CADASIL and were examined at Kumamoto University from 1997 to 2014, and we diagnosed CADASIL in 70 patients. We found 19 different NOTCH3 mutations in the patients, with the NOTCH3 Arg133Cys mutation being found most frequently. We also found the Arg75Pro mutation, a cysteine-sparing NOTCH3 mutation. CADASIL patients with this Arg75Pro mutation were frequently found throughout Japan, and fewer patients with the Arg75Pro mutation showed MRI hyperintensity in the anterior temporal pole compared with patients with other NOTCH3 mutations. Significantly more CADASIL patients with the NOTCH3 Arg133Cys mutation had hyperintensity in the external capsule compared with CADASIL patients with the other mutations not including the NOTCH3 Arg75Pro mutation. We also showed postmortem pathological findings of the first Japanese CADASIL case with the NOTCH3 Arg133Cys mutation, and histopathological findings of fresh frozen skin biopsy specimens of CADASIL patients. In conclusions, the spectrum of NOTCH3 mutations in Japanese CADASIL patients may be partially explained by founder effects. Genotype–phenotype correlations may exist in CADASIL, which should be considered so as to make an accurate diagnosis of CADASIL in each population. Fresh frozen skin biopsy specimens may aid detection of Notch3 deposits on vascular walls for an improved diagnosis of CADASIL.

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

Similar content being viewed by others

References

  1. Chabriat H, Joutel A, Dichgans M et al (2009) CADASIL. Lancet Neurol 8:643–653

    Article  PubMed  Google Scholar 

  2. Joutel A, Corpechot C, Ducros A et al (1996) Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia. Nature 383:707–710

    Article  CAS  PubMed  Google Scholar 

  3. Joutel A, Andreux F, Gaulis S et al (2000) The ectodomain of the Notch3 receptor accumulates within the cerebrovasculature of CADASIL patients. J Clin Invest 105:597–605

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Tikka S, Baumann M, Siitonen M et al (2014) CADASIL and CARASIL. Brain Pathol 24:525–544

    Article  CAS  PubMed  Google Scholar 

  5. Pescini F, Nannucci S, Bertaccini B et al (2012) The cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) scale: a screening tool to select patients for NOTCH3 gene analysis. Stroke 43:2871–2876

    Article  PubMed  Google Scholar 

  6. Opherk C, Peters N, Herzog J et al (2004) Long-term prognosis and causes of death in CADASIL: a retrospective study in 411 patients. Brain 127:2533–2539

    Article  PubMed  Google Scholar 

  7. Kim YE, Yoon CW, Seo SW et al (2014) Spectrum of NOTCH3 mutations in Korean patients with clinically suspicious cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Neurobiol Aging 35:726.e1–726.e6

    Article  CAS  Google Scholar 

  8. Lee YC, Liu CS, Chang MH et al (2009) Population-specific spectrum of NOTCH3 mutations, MRI features and founder effect of CADASIL in Chinese. J Neurol 256:249–255

    Article  CAS  PubMed  Google Scholar 

  9. Uyama E, Tokunaga M, Suenaga A et al (2000) Arg133Cys mutation of Notch3 in two unrelated Japanese families with CADASIL. Intern Med 39:732–737

    Article  CAS  PubMed  Google Scholar 

  10. Uchino M, Hirano T, Uyama E et al (2002) Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and CADASIL-like disorders in Japan. Ann N Y Acad Sci 977:273–278

    Article  CAS  PubMed  Google Scholar 

  11. Abe K, Murakami T, Matsubara E et al (2002) Clinical Features of CADASIL. Ann N Y Acad Sci 977:266–272

    Article  PubMed  Google Scholar 

  12. Ishida C, Sakajiri K, Yoshita M et al (2006) CADASIL with a novel mutation in exon 7 of NOTCH3 (C388Y). Intern Med 45:981–985

    Article  PubMed  Google Scholar 

  13. Mizuno T, Muranishi M, Torugun T et al (2008) Two Japanese CADASIL families exhibiting Notch3 mutation R75P not involving cysteine residue. Intern Med 47:2067–2072

    Article  PubMed  Google Scholar 

  14. Headache Classification Committee of the International Headache Society (IHS) (2013) The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia 33:629–808

    Article  Google Scholar 

  15. Pantoni L, Pescini F, Nannucci S et al (2010) Comparison of clinical, familial, and MRI features of CADASIL and NOTCH3-negative patients. Neurology 74:57–63

    Article  CAS  PubMed  Google Scholar 

  16. Fazekas F, Chawluk JB, Alavi A et al (1987) MR signal abnormalities at 1.5 T in Alzheimer’s dementia and normal aging. Am J Neuroradiol 8:421–426

    Google Scholar 

  17. Scheltens P, Barkhof F, Valk J et al (1992) White matter lesions on magnetic resonance imaging in clinically diagnosed Alzheimer’s disease. Evidence for heterogeneity. Brain 115:735–748

    Article  PubMed  Google Scholar 

  18. Stenson PD, Mort M, Ball EV et al (2014) The Human Gene Mutation Database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine. Hum Genet 133:1–9

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Ueda A, Hirano T, Takahashi K et al (2009) Detection of granular osmiophilic material of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy by light microscopy in frozen sections. Neuropathol Appl Neurobiol 35:618–622

    Article  CAS  PubMed  Google Scholar 

  20. Adzhubei IA, Schmidt S, Peshkin L et al (2010) A method and server for predicting damaging missense mutations. Nat Methods 7:248–249

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Tavtigian SV, Deffenbaugh AM, Yin L et al (2006) Comprehensive statistical study of 452 BRCA1 missense substitutions with classification of eight recurrent substitutions as neutral. J Med Genet 43:295–305

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  22. Peters N, Opherk C, Bergmann T et al (2005) Spectrum of mutations in biopsy-proven CADASIL: implications for diagnostic strategies. Arch Neurol 62:1091–1094

    Article  PubMed  Google Scholar 

  23. Tikka S, Mykkänen K, Ruchoux MM et al (2009) Congruence between NOTCH3 mutations and GOM in 131 CADASIL patients. Brain 132:933–939

    Article  PubMed Central  PubMed  Google Scholar 

  24. Mykkänen K, Savontaus ML, Juvonen V et al (2004) Detection of the founder effect in Finnish CADASIL families. Eur J Hum Genet 12:813–819

    Article  PubMed  Google Scholar 

  25. Kim Y, Choi EJ, Choi CG et al (2006) Characteristics of CADASIL in Korea: a novel cysteine-sparing Notch3 mutation. Neurology 66:1511–1516

    Article  CAS  PubMed  Google Scholar 

  26. Scheid R, Heinritz W, Leyhe T et al (2008) Cysteine-sparing NOTCH3 mutations: CADASIL or CADASIL variants? Neurology 71:774–776

    Article  CAS  PubMed  Google Scholar 

  27. Bersano A, Ranieri M, Ciammola A et al (2012) Considerations on a mutation in the NOTCH3 gene sparing a cysteine residue: a rare polymorphism rather than a CADASIL variant. Funct Neurol 27:247–252

    PubMed Central  PubMed  Google Scholar 

  28. Ge W, Kuang H, Wei B et al (2014) A novel cysteine-sparing NOTCH3 mutation in a Chinese family with CADASIL. PLoS One 9:e104533

    Article  PubMed Central  PubMed  Google Scholar 

  29. Brass SD, Smith EE, Arboleda-Velasquez JF et al (2009) Case records of the Massachusetts General Hospital. Case 12-2009. A 46-year-old man with migraine, aphasia, and hemiparesis and similarly affected family members. N Engl J Med 360:1656–1665

    Article  CAS  PubMed  Google Scholar 

  30. Joutel A, Favrole P, Labauge P et al (2001) Skin biopsy immunostaining with a Notch3 monoclonal antibody for CADASIL diagnosis. Lancet 358:2049–2051

    Article  CAS  PubMed  Google Scholar 

  31. Lesnik Oberstein SA, van Duinen SG, van den Boom R et al (2003) Evaluation of diagnostic NOTCH3 immunostaining in CADASIL. Acta Neuropathol 106:107–111

    Article  CAS  PubMed  Google Scholar 

  32. Malandrini A, Gaudiano C, Gambelli S et al (2007) Diagnostic value of ultrastructural skin biopsy studies in CADASIL. Neurology 68:1430–1432

    Article  CAS  PubMed  Google Scholar 

  33. Markus HS, Martin RJ, Simpson MA et al (2002) Diagnostic strategies in CADASIL. Neurology 59:1134–1138

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We are indebted to Dr. Ikuko Mizuta and Prof. Toshiki Mizuno for kind assistance in the NOTCH3 gene analysis, Ms. Hiroko Katsura and Ms. Mika Oka for excellent technical assistance, and Ms. Judith B. Gandy for providing professional English editing of the manuscript. This research was supported by Grants-in-Aid for Science Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (numbers 24249036 and 25860717).

Conflicts of interest

The authors declare that they have no financial or other conflicts of interest.

Ethical standard

The Human Ethics Review Committee of Kumamoto University approved the study protocol. All patients or their family members provided signed consent forms.

Author information

Authors and Affiliations

  1. Department of Neurology, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-0811, Japan

    Akihiko Ueda, Mitsuharu Ueda, Akihito Nagatoshi & Yukio Ando

  2. Department of Clinical Laboratory, Kumamoto University Hospital, Kumamoto, Japan

    Mitsuharu Ueda, Katsuyoshi Ikeda & Yukio Ando

  3. Department of Stroke and Cerebrovascular Medicine, Kyorin University, Mitaka, Tokyo, Japan

    Teruyuki Hirano

  4. Department of Pathology and Experimental Medicine, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan

    Takaaki Ito

  5. Laboratory of Neuropathology, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan

    Nobutaka Arai

  6. Department of Neurology, Kumamoto Takumadai Rehabilitation Hospital, Kumamoto, Japan

    Eiichiro Uyama

  7. Department of Cerebrovascular Medicine and Neurology, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan

    Kota Mori

  8. Department of Clinical Medicine, National Institute for Minamata Disease, Minamata, Japan

    Masaaki Nakamura

  9. Department of Cell Biology and Anatomy, Hamamatsu University School of Medicine, Hamamatsu, Japan

    Satoru Shinriki

Authors
  1. Akihiko Ueda
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mitsuharu Ueda
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Akihito Nagatoshi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Teruyuki Hirano
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Takaaki Ito
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Nobutaka Arai
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Eiichiro Uyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kota Mori
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Masaaki Nakamura
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Satoru Shinriki
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Katsuyoshi Ikeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Yukio Ando
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Mitsuharu Ueda.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 299 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ueda, A., Ueda, M., Nagatoshi, A. et al. Genotypic and phenotypic spectrum of CADASIL in Japan: the experience at a referral center in Kumamoto University from 1997 to 2014. J Neurol 262, 1828–1836 (2015). https://doi.org/10.1007/s00415-015-7782-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00415-015-7782-8

Keywords

Search

Navigation