Limb-Girdle Muscular Dystrophy with Epidermolysis Bullosa Simplex 23 Description The disease is characterized by skin blistering (epidermolysis bullosa) usually evident in the neonatal period (manifesting as fragility and skin denudation occurring spontaneously or after friction or trauma), associated with a limb-girdle muscular dystrophy (MDEBS) with variable onset, leading to wheelchair bound even at early age, and high mortality [1–3]. Skin blistering continues throughout the life, and it may be associated with enamel hypoplasia and nail dystrophy, abnormal dentition, rapid decay of teeth, urethral strictures, scarring alopecia, palmoplantar hyperkeratosis, pyloric atresia, respiratory complications, and laryngeal webs . The gene responsible for the disease has been identified as that encoding for plectin-1 (PLEC1) [4, 5], and mutations in this gene have been characterized in a limited number of patients due to the very low frequency of the disease (Table 23.1). Plectin is a large cytoskeleton-associated protein which is widely distributed through stratified squamous epithelia, muscle, and the brain. Plectin is localized at membrane attachment sites of intermediate filaments in the epithelial and muscle cells, consistent with a role in anchoring intermediate filaments (including the Z-line of striated muscle) to the membrane. In addition to the hemidesmosomes (complexes that anchor the basal cells of squamous and transitional epithelia to the underlying mesenchyme) in the skin, plectin is expressed in the sarcolemma of muscle fibers, and immunofluorescence staining of the skin and muscle in MDEBS/LGMD2Q patients has revealed absent expression [5, 6]. The loss of expression of a multifunctional protein such as plectin can account for disease in the muscle, skin, and central nervous system. The disease severity has been found to be correlated to the type, localization, and residual protein function of PLEC1 gene mutations . Some patients with MDEBS/LGMD2Q and PLEC1 gene mutations also presented dilated cardiomyopathy  or left ventricular non-compaction cardiomyopathy . Furthermore, PLEC1 gene mutations have been reported in patients with congenital muscular dystrophy and myasthenic symptoms  and in myasthenic syndrome . © Springer International Publishing Switzerland 2018 C. Angelini, Genetic Neuromuscular Disorders, DOI 10.1007/978-3-319-56454-8_23 93 94 23 Limb-Girdle Muscular Dystrophy with Epidermolysis Bullosa Simplex Table 23.1 Genetic data Disease symbol Disease MIM # Gene symbol Gene MIM # Protein Chromosome locus Inheritance LGMD2Q or MDEBS 226670 PLEC1 601282 Plectin-1 8q24.3 Autosomal recessive Conclusion Plectin-1 gene mutations in the muscle result in progressive muscular dystrophy. Additional skin feature includes epidermolysis bullosa, nail dystrophy, and abnormal dentition. Additional phenotypes include myasthenic syndrome, since plectin is also highly expressed at the neuromuscular junction, where it supports junctional folds. Another clinical phenotype is a form of adult-onset dilated cardiomyopathy. Key Points • Infants with EBS around 12 years might manifest myopathy with necrotic and regenerating fibers. • Subsequent appearance of ptosis, paresis, open mouth, and facial diplegia is due to myasthenic syndrome. • Clinicians should investigate patients with fragility of skin and nail dystrophy for muscle symptoms. References 1.Shimizu H, Takizawa Y, Pulkkinen L, et al. Epidermolysis bullosa simplex associated with muscular dystrophy: phenotype-genotype correlations and review of the literature. J Am Acad Dermatol. 1999;41:950–6. 2. Salih MAM, Lake BD, El Hag MA, Atherton DJ. Lethal epidermolytic epidermolysis bullosa: a new autosomal recessive type of epidermolysis bullosa. Br J Dermatol. 1985;113:135–43. 3. Niemi KM, Sommer H, Kero M, Kanerva L, Haltia M. Epidermolysis bullosa simplex associated with muscular dystrophy with recessive inheritance. Arch Dermatol. 1988;124:551–4. 4.Smith FJD, Eady RAJ, Leigh IM, et al. Plectin deficiency results in muscular dystrophy with epidermolysis bullosa. Nat Genet. 1996;13:450–7. 5. Pulkkinen L, Smith FJD, Shimizu H, et al. Homozygous deletion mutations in the plectin gene (PLEC1) in patients with epidermolysis bullosa simplex associated with late-onset muscular dystrophy. Hum Mol Genet. 1996;5:1539–46. 6.Gache Y, Chavanas S, Lacour JP, et al. Defective expression of plectin/HD1 in epidermolysis bullosa simplex with muscular dystrophy. J Clin Invest. 1996;97:2289–98. References 95 7.Bolling MC, Pas HH, de Visser M, et al. PLEC1 mutations underlie adult-onset dilated cardiomyopathy in epidermolysis bullosa simplex with muscular dystrophy. J Invest Dermatol. 2010;130:1178–81. 8.Villa CR, Ryan TD, Collins JJ, et al. Left ventricular non-compaction cardiomyopathy associated with epidermolysis bullosa simplex with muscular dystrophy and PLEC1 mutation. Neuromuscul Disord. 2015;25:165–8. 9.Forrest K, Mellerio JE, Robb S, et al. Congenital muscular dystrophy, myasthenic symptoms and epidermolysis bullosa simplex (EBS) associated with mutations in the PLEC1 gene encoding plectin. Neuromuscul Disord. 2010;20:709–11. 10.Selcen D, Juel VC, Hobson-Webb LD, et al. Myasthenic syndrome caused by plectinopathy. Neurology. 2011;76:327–36.