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Molecular genetics and therapeutic development for GNE myopathy

Journal of Human Genetics (2025)Cite this article

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Abstract

GNE myopathy is an autosomal recessive distal myopathy resulting from biallelic pathogenic variants in the GNE gene, a key enzyme in sialic acid biosynthesis. Although most pathogenic variants are missense variants, recent advances have enabled the identification of copy number variations, deep intronic variants, and regulatory changes in the promoter region, significantly enhancing diagnostic accuracy. Progress in genetic diagnostics now allows detection of rare and complex variants. Studies of founder variants in specific populations have clarified that certain GNE genotypes are associated with distinct clinical features and disease progression, deepening our understanding of genotype-phenotype relationships in GNE myopathy. The development of approved therapies, such as aceneuramic acid extended-release tablets, as well as ongoing multicenter Phase 2 trials of ManNAc and promising pilot studies of 6′-sialyllactose, underscore the importance of timely and comprehensive genetic diagnosis. Additional approaches, including antioxidant and gene therapies, are also under investigation. Since genetic testing is currently the sole definitive diagnostic approach, continued efforts to identify challenging or novel variants are essential to ensure all affected individuals receive an accurate diagnosis and access to emerging therapies. Advances in molecular genetics and diagnostics are paving the way for precision medicine and improved outcomes in GNE myopathy.

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Funding

This study was supported partly by Intramural Research Grant (5-6, 5-5) for Neurological and Psychiatric Disorders of NCNP, and Health, Labour, and Welfare Sciences Research Grants (JPMH23FC1014).

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Authors and Affiliations

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

    Wakako Yoshioka, Satoru Noguchi & Ichizo Nishino

  2. Department of Clinical Genome Analysis, Medical Genome Center, NCNP, Tokyo, Japan

    Wakako Yoshioka, Satoru Noguchi & Ichizo Nishino

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  1. Wakako Yoshioka
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  2. Satoru Noguchi
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Yoshioka, W., Noguchi, S. & Nishino, I. Molecular genetics and therapeutic development for GNE myopathy. J Hum Genet (2025). https://doi.org/10.1038/s10038-025-01398-y

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