An autosomal recessive distal myopathy with cardiac involvement due to missense mutations in the kinase domain of the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene

We describe a novel AR form of autosomal recessive myopathy with early adult onset in the anterior compartment of the legs in a total of 27 patients (15 pedigrees). 12 patients also suffered from cardiac involment characterized by cardiac rhythm disorder in the majority of the patients, 4 patients died suddenly, probably due to rhythm disorder. Diastolic dysfunction was found in 3 patients. This feature seems to cosegregating with the myopathy. To confirm the cosegreregation the cardiological examination of all family members in large field study in Bulgaria is in progress. Skeletal muscle biopsies showed myopathic changes with variation of fibre size but no specific morphological changes such as rimmed vacuoles. Immunohistochemistry showed normal expression of laminin α2,β1,β2,γ1,α-DG, α-DG, α-β-γ-δ- SG, dysferlin and collagen VI. We identifed a locus of 2.95 cM between D9S1788 and D9S50, with a Multipoint Lodscore Zmax=11.3. In all pedigrees the affected individuals were homozygous for a founder haplotype. The Xoroxane Gypsies belong genetically to an isolated founder population, due to extreme inbreeding. A homozygous missense mutation I587T was found in all affected individuals. The remaining enzymatic activity of the recombinant mutant protein for epimerase domain was 60% and for the kinase domain 40%. The disease mutation is in linkage disequilibrium with this founder haplotype. Screening for carriers in various gypsy populations gave a carrier frequency of 5–10%. The estimation of the age of mutation by flanking markers is in progress. The I587T mutation has been found in an Italian pedigree with hereditary inclusion body myopathy, haplotype analysis of flanking markers demonstrates that there should be a common founder who introduced the I587T in the gypsy population and the Italian pedigree. However, the same mutation caused a remarkably different phenotype on the genetic background of the gypsy population with cardiac involvement.