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Phenotypic and molecular diversities of spinocerebellar ataxia type 2 in Japan

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Abstract

Background

We intended to clarify the phenotypic and molecular diversities of spinocerebellar ataxia type 2 (SCA2) in Japan.

Methods

DNA was extracted from the peripheral blood of 436 patients, including 126 patients with chronic neuropathy, 108 with amyotrophic lateral sclerosis, and 202 with cerebellar ataxia. We then PCR-amplified and sequenced the ATXN2 gene. The biopsied sural nerves of mutation-positive patients were subjected to light-microscopic and electron-microscopic analyses. Transfection analyses were performed using a Schwann cell line, IMS32.

Results

We found PCR-amplified products potentially corresponding to expanded CAG repeats in four patients. Two patients in the chronic neuropathy group had a full repeat expansion or an intermediate expansion (39 or 32 repeats), without limb ataxia. The sural nerve biopsy findings of the two patients included axonal neuropathy and mixed neuropathy (axonal changes with demyelination). Schwann cells harbored either cytoplasmic or nuclear inclusions on electron microscopic examination. Both patients recently exhibited pyramidal signs. In the third patient in the cerebellar ataxia group, we identified a novel 21-base duplication mutation near 22 CAG repeats (c.432_452dup). The transfection study revealed that the 21-base-duplication mutant Ataxin-2 proteins aggregated in IMS32 and rendered cells susceptible to oxidative stress, similar to a CAG-expanded mutant. The fourth patient, with 41 repeats, had ataxia and spasticity. The two patients with cerebellar ataxia also had peripheral neuropathy.

Conclusions

Patients with expanded CAG repeats can exhibit a neuropathy-dominant phenotype not described previously. The novel 21-base-duplication mutant seems to share the aggregation properties of polyglutamine-expanded mutants.

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Acknowledgments

We thank Dr. Pulst for providing wild-type and mutant GFP-ATXN2 plasmids, and Dr. Watabe of the Tokyo Metropolitan Institute of Medical Science for providing IMS32.

Funding

This study was partly supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MH19K07984 to MH).

Author information

Authors and Affiliations

  1. Department of Neurology, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osakasayama, Osaka, 589-8511, Japan

    Rino Inada, Makito Hirano, Makoto Samukawa, Kazumasa Saigoh, Hidekazu Suzuki & Susumu Kusunoki

  2. Department of Neurology, Kyoto-Konoe Rehabilitation Hospital, Kyoto, Japan

    Nobuyuki Oka

  3. Department of Neurology, Sumitomo Hospital, Osaka, Japan

    Fukashi Udaka

  4. Department of Neurology and Geriatrics, Kagoshima University, Kagoshima, Japan

    Akihiro Hashiguchi & Hiroshi Takashima

  5. Department of Neurology, Izumi City General Hospital, Izumi, Japan

    Yukihiro Hamada

  6. Department of Neurology, Sakai City Medical Center, Sakai, Japan

    Yusaku Nakamura

Authors
  1. Rino Inada
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  2. Makito Hirano
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  3. Nobuyuki Oka
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  7. Fukashi Udaka
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  8. Akihiro Hashiguchi
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  9. Hiroshi Takashima
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  10. Yukihiro Hamada
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  11. Yusaku Nakamura
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  12. Susumu Kusunoki
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Corresponding author

Correspondence to Makito Hirano.

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None of the authors have any conflict of interest, including financial, personal, or other relationships with other people or organizations within 3 years since beginning the work submitted, that could have inappropriately influenced or biased the work presented here.

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Inada, R., Hirano, M., Oka, N. et al. Phenotypic and molecular diversities of spinocerebellar ataxia type 2 in Japan. J Neurol 268, 2933–2942 (2021). https://doi.org/10.1007/s00415-021-10467-z

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  • DOI: https://doi.org/10.1007/s00415-021-10467-z

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