As described herein, studies on EBS-MD patient samples, MCK-Cre/cKO mice, or plectin-deficient myotubes demonstrated that different PLEC mutations, irrespective of their individual consequences on plectin protein expression, cause a defective structural and functional organization of the extrasarcomeric desmin cytoskeleton, which triggers the formation of desmin protein aggregates in skeletal muscle tissue. This evidence concerns the gene DES and Menkes disease.