GNE myopathy: current update and future therapy

Abstract

GNE myopathy is an autosomal recessive muscle disease caused by biallelic mutations in GNE, a gene encoding for a single protein with key enzymatic activities, UDP-N-acetylglucosamine 2-epimerase and N-acetylmannosamine kinase, in sialic acid biosynthetic pathway. The diagnosis should be considered primarily in patients presenting with distal weakness (foot drop) in early adulthood (other onset symptoms are possible too). The disease slowly progresses to involve other lower and upper extremities' muscles, with marked sparing of the quadriceps. Characteristic findings on biopsies of affected muscles include 'rimmed' (autophagic) vacuoles, aggregation of various proteins and fibre size variation. The diagnosis is confirmed by sequencing of the GNE gene. Note that we use a new mutation nomenclature based on the longest transcript (GenBank: NM_001128227), which encodes a 31-amino acid longer protein than the originally described one (GenBank: NM_005476), which has been used previously in most papers. Based upon the pathophysiology of the disease, recent clinical trials as well as early gene therapy trials have evaluated the use of sialic acid or N-acetylmannosamine (a precursor of sialic acid) in patients with GNE myopathy. Now that therapies are under investigation, it is critical that a timely and accurate diagnosis is made in patients with GNE myopathy.

Keywords: MUSCLE DISEASE; MYOPATHY; NEUROMUSCULAR.

Figure 1. Sialic acid biosynthesis pathway

The biosynthesis of sialic acid (Neu5Ac) occurs in the cytoplasm. The initial substrate for this pathway (UDP-GlcNAc) derives from glucose. In the rate-limiting step of the pathway, UDP-GlcNAc is epimerized into ManNAc by GlcNAc 2-epimerase, encoded by the epimerase domain of GNE. ManNAc is phosphorylated by ManNAc kinase encoded by “kinase” domain of GNE. Once Neu5Ac acid is synthesized, it becomes “activated” by the effect of CMP-sialic acid synthetase in the nucleus. CMP-sialic acid, the active form of Neu5Ac is used a donor of sialic acid to nascent proteins in the Golgi for the generation of glycoproteins. CMP-sialic acid also acts as a feedback inhibitor of the UDP-GlcNAc 2-epimerase enzyme by binding to its allosteric site.

Figure 2. Schematic illustration of GNE gene structure

Gene structure for the two most representative transcripts is shown. The longest transcript (NM_001128227) encodes 753 amino acids, including 17 amino acid encoded by exon 1. The originally described transcript shown at the bottom (GenBank: NM_005476), uses an alternative first exon which is non-coding and the initial codon resides in the 43^rd–45^th nucleotides in the second exon, which makes the protein shorter by 31 amino acids. Note exon eight encodes the last part of epimerase domain, junctional region, and initial part of kinase domain. Size of exons is to scale but that of introns is not. Boxes indicate exons. Open box means non-coding region. Blue and pick respectively indicate epimerase and kinase encoding regions. Mutations mentioned in the text are included for reference.

Figure 3

The worldwide prevalence of GNE myopathy is estimated at 1/1,000,000.