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Large phenotypic diversity by genotype in patients with GNE myopathy: 10 years after the establishment of a national registry in Japan

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Abstract

Background

GNE myopathy is an ultra-rare autosomal recessive distal myopathy caused by pathogenic variants of the GNE gene, which encodes a key enzyme in sialic acid biosynthesis. The present study aimed to examine the long-term progression of GNE myopathy, genotype–phenotype correlations, and complications to provide useful information for predicting patient progression and designing clinical trials using a large collection of registry data over a 10-year period.

Methods

We analyzed 220 Japanese patients with GNE myopathy from a national registry in Japan. Diagnoses were confirmed by genetic curators based on genetic analysis reports. We analyzed registration sheets and annually updated items completed by attending physicians.

Results

In total, 197 of 220 participants (89.5%) carried p.D207V or p.V603L in at least one allele. The median disease duration to loss of ambulation was estimated to be 10 years in p.V603L homozygotes (n = 48), whereas more than 90% of p.D207V/p.V603L compound heterozygotes were estimated to be ambulatory even 20 years after disease onset according to Kaplan–Meier analysis (p < 0.001). Moreover, participants with a younger age of onset lost ambulation earlier regardless of genotype. A decline in respiratory function was observed as the disease progressed, particularly in p.V603L homozygotes, whereas none of the p.D207V/p.V603L compound heterozygotes showed a decline.

Conclusions

The present study demonstrated large differences in disease progression and respiratory function between genotypes. Moreover, age of onset was found to be an indicator of disease severity regardless of genotype in GNE myopathy patients. These results may help stratify patients in clinical trials and predict disease progression.

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Availability of data and material

Any data that support the findings of this study are available from the corresponding author, Madoka Mori-Yoshimura, upon reasonable request.

Code availability

All codes for data analysis are available from the corresponding author, Madoka Mori-Yoshimura, upon reasonable request.

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Acknowledgements

We thank the members of Remudy and the Patients Association for Distal Myopathies in Japan (PADM) for their collaboration.

Funding

This work was partly supported by Research on Intractable Diseases of Health and Labor Sciences Research Grants, Comprehensive Research on Disability Health and Welfare Grants, Research and Development Grants for Comprehensive Research for Persons with Disabilities and Practical Research Project for Rare/Intractable Diseases from Japan Agency for Medical Research and Development, AMED, Health and Labor Science Research Grants, and an Intramural Research Grant (29-3, 29-4) for Neurological and Psychiatric Disorders from the NCNP.

Author information

Authors and Affiliations

  1. Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Tokyo, Japan

    Wakako Yoshioka, Yoshihiko Saito & Ichizo Nishino

  2. Department of Clinical Research Support, Clinical Research & Education Promotion Division, National Center Hospital, NCNP, Tokyo, Japan

    Harumasa Nakamura

  3. Department of Clinical Data Science, Clinical Research & Education Promotion Division, NCNP, Tokyo, Japan

    Mari Oba

  4. Department of Neurology, National Center Hospital, National Center of Neurology and Psychiatry (NCNP), 4-1-1 Ogawa-Higashi, Kodaira, Tokyo, 187-8502, Japan

    Madoka Mori-Yoshimura

Authors
  1. Wakako Yoshioka
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  2. Harumasa Nakamura
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  3. Mari Oba
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  4. Yoshihiko Saito
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  5. Ichizo Nishino
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  6. Madoka Mori-Yoshimura
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Contributions

All authors contributed to the study conception and design. WY and MMY participated in planning the study, data analysis and interpretation, and writing the manuscript. MO participated in data analysis and interpretation. SY and HN participated in curating data collection of the registry. IN planned and supervised this study. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Madoka Mori-Yoshimura.

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Conflict of interest

None declared.

Ethical approval

Written informed consent was obtained prior to enrollment from all patients. Patients were informed that inclusion in the database confers no obligation, and that they may be removed from the registry immediately upon request. They were also informed that refusal to participate would not affect subsequent medical care. This study was approved by the Medical Ethics Committee of the NCNP (A2022-017, A2011-079). Data can be shared with third parties only after permission is obtained from the committee responsible for information disclosure.

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Yoshioka, W., Nakamura, H., Oba, M. et al. Large phenotypic diversity by genotype in patients with GNE myopathy: 10 years after the establishment of a national registry in Japan. J Neurol (2024). https://doi.org/10.1007/s00415-024-12396-z

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  • DOI: https://doi.org/10.1007/s00415-024-12396-z

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