PLEC and Menkes disease: 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.