Prevalence of GNE p.M712T and hereditary inclusion body myopathy (HIBM) in Sangesar population of Northern Iran.

GNE myopathy or hereditary inclusion body myopathy (HIBM) is an ultra-rare severely disabling autosomal recessive adult onset muscle disease which affects roughly one to three individuals per million worldwide. Genetically, HIBM is caused by mutations in the glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase gene (GNE), resulting in diminished enzyme function and reduced sialic acid biosynthesis. A founder variant GNE p.M712T was first described in patients of Iranian and Middle-Eastern descent living outside of Iran. Asymptomatic heterozygote or carrier frequency has been reported as high as 1 in 11 within the Persian-Jewish community residing in Los Angeles, CA. To investigate the prevalence of the p.M712T variant in Iran, we studied 792 samples collected from random individuals in Sangesar (Mahdishahr) in Northern Iran. DNA samples were obtained by buccal swab, and genotyping was performed by melting curve analysis. The results included 31 of 792 (3.91%) heterozygous carriers and 5 (0.31%) homozygotes for GNE p.M712T. All five homozygous individuals, age 30-64 years, were already symptomatic at the start of the study. Our findings suggest that the prevalence of GNE p.M712T is higher in the Sangesar population, comprised mostly of Muslim and Bahai descendants, compared with the general world population. Additional HIBM distribution studies are warranted within various subpopulations of Iran.

Magnesium may help patients with recessive hereditary inclusion body myopathy, a pathological review.

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.

Four novel mutations associated with autosomal recessive inclusion body myopathy (MIM: 600737).

Recently, mutations in the gene encoding for the bi-functional enzyme UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE/MNK), symbol GNE or GLCNE (MIM: 603824) [EC 5.1.3.14], were associated with IBM2 (MIM: 600737). IBM2 is a recessively inherited vacuolar myopathy with a prevalence rate of 1-2/1000 amongst people of Iranian-Jewish descent. Seven missense mutations were previously described by Eisenberg et al. All families tested from Iranian and Middle Eastern Jewish ancestry have the same homozygous mutation (bp2186t>c). Here we review the mutations in GNE associated with IBM2, and we describe additional four mutations found in individuals suffering from clinically similar disorder who are not of Iranian or Jewish descent. These findings further confirm that homozygous or compound heterozygous mutations of GNE/MNK gene associated with IBM2 are not confined to any single specific region of the enzyme outside its negative feedback regulatory domain located at codons 249-275.