Abstract
Distal myopathy with rimmed vacuoles or hereditary inclusion body myopathy, for which new nomenclature "GNE myopathy" is now proposed, is an autosomal recessive disease that preferentially affects tibialis anterior and hamstrings muscles in young adults. The disease is caused by mutations, mostly missense, in GNE gene that encodes a protein with two enzymatic activities in sialic acid biosynthetic pathway: UDP-GlcNAc 2-epimerase and ManNAc kinase. Accordingly, sialic acid production is reduced in patients' cells and cells are hyposialylated. This hyposialylation status can be recovered by simply giving sialic acid. Furthermore, myopathic manifestations were virtually completely suppressed by oral administration of sialic acid in our model mice. Similar efficacy was seen also by ManNAc, precursor of sialic acid, or sialyllactose, a conjugate form of sialic acid. Based upon these in vitro and in vivo results, phase I clinical trial for sialic acid supplementation therapy for human patients was performed in October 2010-June 2011 in Japan and in September 2011-April 2012 in the US, the latter using slow release tablets of sialic acid. Natural history of the patients needs to be established for precise evaluation of the efficacy in the near future phase II clinical trial.
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