Recently, bi-allelic mutations in the gene coding for the bi-functional
enzyme UDP-
N-acetylglucosamine 2-
epimerase/
N-acetylmannosamine kinase (GNE/MNK), symbol GNE or GLCNE (MIM: 603824), were associated with the recessively inherited phenotype of
IBM2 (MIM: 600737). All patients tested so far have bi-allelic missense mutation(s) of
epimerase and/or
kinase domains of GNE gene, which clearly explains the recessive inheritance pattern of this phenotype. Single allelic mutations of
codons 263-266 of GNE have been implicated as the cause of
French type sialuria (MIM: 269921). The dominantly inherited
French type sialuria seems to result from defective allosteric feedback inhibitory regulation of GNE/MNK by
cytidine monophosphate-N-acetylneuraminic acid (
CMP-NANA), resulting in overproduction of cytosolic
N-acetylneuraminic acid, and massive urinary excretion of free
sialic acid. Because GNE is relatively weakly expressed in skeletal muscle cells, and involvement of other organs are not clinically evident in patients affected with
IBM2, it is likely that the missense mutation(s) found in these patients cause a partial reduction of the efficiency of either the
epimerase or the
kinase activity of this
enzyme. Therapeutic
dietary modifications are recommended including reduction of
ethanol consumption, avoidance of excess
selenium,
copper, and
zinc, and dietary promotion of
magnesium (Mg(2+)), which is an essential co-factor for this
enzyme.