GNE myopathy: a multifaceted review of genetic, clinical, and management perspectives

Abstract GNE myopathy is a rare autosomal recessive neuromuscular disorder characterized by progressive distal muscle weakness, early foot drop, and relative sparing of the quadriceps until advanced stages of disease progression. The disorder results from pathogenic variants in the GNE gene, which encodes a bifunctional enzyme involved in sialic acid biosynthesis. Impaired enzyme activity leads to hyposialylation of muscle glycoproteins, contributing to progressive muscle degeneration, although the precise pathophysiological mechanisms remain incompletely understood. The clinical presentation of GNE myopathy is heterogeneous, with variability in age of onset, disease progression, and geographic distribution of founder variants across different populations. Delayed diagnosis, limited disease-specific therapies, and challenges in correlating molecular findings with clinical manifestations continue to complicate disease management. This narrative review critically examines current understanding of the genetic basis, pathophysiology, clinical manifestations, diagnostic approaches, and emerging therapeutic strategies in GNE myopathy, including ManNAc, extended-release N-acetylneuraminic acid (Neu5Ac), and gene therapy. Despite encouraging biochemical and early clinical findings, sustained therapeutic efficacy remains to be established, highlighting ongoing challenges and future directions relevant to the neuromuscular research and clinical community.