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Original research
Clinical phenotypic diversity of NOTCH2NLC-related disease in the largest case series of inherited peripheral neuropathy in Japan
  1. Masahiro Ando1,
  2. Yujiro Higuchi1,
  3. Jun-Hui Yuan1,
  4. Akiko Yoshimura1,
  5. Mika Dozono1,
  6. Takahiro Hobara1,
  7. Fumikazu Kojima1,
  8. Yutaka Noguchi1,
  9. Mika Takeuchi1,
  10. Jun Takei1,
  11. Yu Hiramatsu1,
  12. Satoshi Nozuma1,
  13. Tomonori Nakamura1,
  14. Yusuke Sakiyama1,
  15. Akihiro Hashiguchi1,
  16. Eiji Matsuura1,
  17. Yuji Okamoto1,2,
  18. Jun Sone3,
  19. Hiroshi Takashima1
  1. 1 Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima, Japan
  2. 2 Department of Physical Therapy, Kagoshima University of School of Health Sciences, Kagoshima, Japan
  3. 3 Department of Neuropathology, Aichi Medical University, Aichi, Japan
  1. Correspondence to Dr Hiroshi Takashima, Department of Neurology and Geriatrics, Kagoshima University Graduate School of Medical and Dental Sciences Department of Neurology and Geriatrics, Kagoshima 890-8520, Japan; thiroshi{at}m3.kufm.kagoshima-u.ac.jp

Abstract

Background NOTCH2NLC GGC repeat expansions have been associated with various neurogenerative disorders, including neuronal intranuclear inclusion disease and inherited peripheral neuropathies (IPNs). However, only a few NOTCH2NLC-related disease studies in IPN have been reported, and the clinical and genetic spectra remain unclear. Thus, this study aimed to describe the clinical and genetic manifestations of NOTCH2NLC-related IPNs.

Method Among 2692 Japanese patients clinically diagnosed with IPN/Charcot–Marie–Tooth disease (CMT), we analysed NOTCH2NLC repeat expansion in 1783 unrelated patients without a genetic diagnosis. Screening and repeat size determination of NOTCH2NLC repeat expansion were performed using repeat-primed PCR and fluorescence amplicon length analysis-PCR.

Results NOTCH2NLC repeat expansions were identified in 26 cases of IPN/CMT from 22 unrelated families. The mean median motor nerve conduction velocity was 41 m/s (range, 30.8–59.4), and 18 cases (69%) were classified as intermediate CMT. The mean age of onset was 32.7 (range, 7–61) years. In addition to motor sensory neuropathy symptoms, dysautonomia and involuntary movements were common (44% and 29%). Furthermore, the correlation between the age of onset or clinical symptoms and the repeat size remains unclear.

Conclusions These findings of this study help us understand the clinical heterogeneity of NOTCH2NLC-related disease, such as non-length-dependent motor dominant phenotype and prominent autonomic involvement. This study also emphasise the importance of genetic screening, regardless of the age of onset and type of CMT, particularly in patients of Asian origin, presenting with intermediate conduction velocities and dysautonomia.

  • NEUROPATHY
  • HMSN (CHARCOT-MARIE-TOOTH)
  • NEUROGENETICS
  • MRI

Data availability statement

Data are available upon reasonable request. Not applicable.

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Data availability statement

Data are available upon reasonable request. Not applicable.

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Footnotes

  • Twitter @pinetwitt

  • Contributors MA, YH and HT conceived the project and designed the study. MA, YH, JY and AY contributed to the analysis and interpretation of data. TH, FK, YN, MT, YH, SN, TN, YS and YO participated in analysis of clinical data. MD, AH, EM and JS contributed to pathological analysis. MA produced the original manuscript and all authors approved the final version. TH takes full responsibility for the overall content as the guarantor.

  • Funding This work was supported by Grants-in-Aid from the Research Committee of Ataxia, Health Labour Sciences Research Grant, the Ministry of Health, Labour and Welfare, Japan (201610002B). This work was also supported by the Research program for conquering intractable disease from Japan Agency for Medical Research and Development (201442014A, 201442071A and 17929553), JSPS KAKENHI Grant Numbers JP18H02742, JP20K16604, JP21K15702, JP21H02842, 15K09312, 19H03577 and MHLW FC program (JPMH19189624 and JPMH21445246).

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  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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