P.179 - PLEC gene mutations cause familial disto-proximal myopathy and long QT syndrome mimicking mitochondrial disease

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Plectin, a giant multifunctional cytolinker protein, plays a crucial role in orchestrating intermediate filament networks in a wide variety of tissues, as epithelia, skeletal muscle and heart. Mutations of the plectin gene (PLEC) on chromosome 8q24 cause autosomal recessive epidermolysis bullosa simplex with muscular dystrophy (EBS-MD), EBS-MD with myasthenic features, EBS with pyloric atresia, EBS-Ogna, and LGMD2Q. Here we report an Italian family with a distinctive muscle phenotype and autosomal recessive transmission in which Whole Exome Sequencing identified homozygous mutations in PLEC gene. Three brothers (two female and one male), age 52, 51 and 46 years, were affected in their thirties by adult-onset myopathy characterized by progressive disto-proximal symmetrical muscle weakness, more severe in distal muscles and upper limbs, mild facial weakness, ptosis and strabismus. There were no skin abnormalities. Cardiac investigation showed arrhythmia and long QT syndrome requiring in one patient an Implantable Cardioverter Defibrillator. Cardiac MRI demonstrated late-gadolinium enhancement in the basal inferolateral part of left ventricle, with sub-epicardic distribution pattern and intramural involvement. A fourth sister had died of sudden death at age 16 years. Myopathological analyses showed the typical hallmarks of mitochondrial diseases with numerous RRFs, a chronic myopathic process with necrosis and regeneration, desmin accumulation in some fibers and markedly reduced plectin staining. Muscle respiratory chain activities were normal. This report expands the phenotypes of plectin-associated disorders and supports the hypothesis that mitochondrial dysfunction contributes to the progression and severity of muscle damage in plectin myopathy. “Plectinopathies” represent a diagnostic challenge for their chameleon presentation and this study supports the value of next generation technologies to improve our abilities in diagnosing complex neuromuscular disorders. Analysis of PLEC should be included in the workout of mitochondrial disorders and distal myopathies.