Molecular pathogenesis and therapeutic strategy in GNE myopathy

GNE myopathy is an autosomal recessive disease, which is characterized by gradually progressive muscle atrophy and weakness, and preferentially involves the distal muscles of lower extremities, especially the tibialis anterior muscle. GNE myopathy is caused by mutations in the UDP-N-acetylglucosamine 2-epimerase/Nacetylmannosamine kinase (GNE) gene which encodes the bifunctional enzyme catalyzing the rate-limiting step in sialic acid biosynthesis. GNE myopathy model mouse, in which Gne is knocked out with human GNE transgene with D176V, recaptured the symptoms of human GNE myopathy. The supplementation of ManNAc, NeuAc, and sialyllactose prevented the onset of the disorder and also recovered the muscle function from symptomatic status, suggesting hyposialylation is one of key factors in the pathogenesis of this disorder. Based on the studies with GNE myopathy model, the clinical trials are conducted at the three places in the world (USA, Japan, and Israel). Expectedly GNE myopathy will be treatable in the near future.