Decoding GNE Myopathy: From Molecular Basis to Therapeutic Advances

GNE myopathy is a rare, adult-onset, autosomal recessive muscle disorder caused by biallelic pathogenic variants in the GNE gene, which encodes a key enzyme in the biosynthesis of sialic acid. Deficient GNE enzyme activity results in decreased production of sialic acid and subsequent hyposialylation of muscle glycoproteins, ultimately leading to progressive muscle degeneration and characteristic histopathological changes. The disease typically presents with progressive distal muscle weakness while sparing the quadriceps until advanced stages. Advances in molecular biology have significantly clarified the underlying disease mechanisms and revealed genotype-phenotype correlations. Natural history studies, supported by patient registries, have detailed the disease course and identified extra-muscular manifestations such as thrombocytopenia and sleep apnea. Multiple therapeutic strategies are under active investigation, including sialic acid supplementation, antioxidant therapy, and gene therapy. Several clinical trials targeting sialic acid biosynthetic pathways, such as oral N-acetylneuraminic acid, ManNAc, and 6'- sialyllactose, have advanced to late-stage development, culminating in the approval of the N-acetyl-neuraminic acid extended-release tablet in Japan in 2024. Other emerging therapeutic approaches, including antioxidant- and gene-based interventions, are also currently being explored. This review synthesizes the current understanding of the molecular pathogenesis of GNE myopathy and highlights recent advances and future prospects in targeted molecular and therapeutic approaches. The ultimate aim is to foster international collaboration toward the development of innovative and effective treatments for GNE myopathy.