Alternative titles; symbols
SNOMEDCT: 723308003; ORPHA: 257; DO: 0090017;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 8q24.3 | Epidermolysis bullosa simplex 5B, with muscular dystrophy | 226670 | Autosomal recessive | 3 | PLEC1 | 601282 |
A number sign (#) is used with this entry because of evidence that epidermolysis bullosa simplex 5B with muscular dystrophy (EBS5B) is caused by homozygous or compound heterozygous mutation in the plectin gene (PLEC; 601282) on chromosome 8q24.
Epidermolysis bullosa simplex with muscular dystrophy (EBS5B) is an autosomal recessive disorder characterized by early childhood onset of progressive muscular dystrophy and blistering skin changes (Fine et al., 1989).
Fine et al. (1991) reported a revised classification of the subtypes of inherited epidermolysis bullosa.
In reports of 2 consensus meetings on EB, Fine et al. (2000, 2008) referred to EB with muscular dystrophy due to PLEC1 mutations as a form of basal simplex EB. Fine et al. (2000, 2008) also eliminated the term 'hemidesmosomal,' which had previously been proposed for this entity (Uitto et al., 1997) because ultrastructural analysis can demonstrate tissue abnormalities of the hemidesmosomes.
For a discussion of genetic heterogeneity of the subtypes of EBS, see EBS1A (131760).
Niemi et al. (1988) described a Finnish sibship with normal parents and 12 members, of which 2, a brother and sister who survived to adulthood, had the combination of epidermolysis bullosa and muscular dystrophy of the limb-girdle type (see 253600). Two male sibs died early from severe skin disease. The skin disease was thought to be of the same type as that for which Salih et al. (1985) reported autosomal recessive inheritance. The parents came from the same small village; thus, the likelihood of heterozygosity for the same gene(s) is high, although consanguinity could not be proved. The combination may represent the coincidence of 2 recessive disorders, which may be closely linked. An alternative possibility is that this represents a pleiotropic syndrome. Favoring the latter possibility is the fact that De Weerdt and Castelein (1972) described a family with the same combination in a pattern of autosomal recessive inheritance.
Fine et al. (1989) described 2 families in which offspring of consanguineous matings had epidermolysis bullosa simplex with features suggestive of junctional or dystrophic epidermolysis bullosa and association with neuromuscular disease. Two patients in the first family had, from birth, a severe blistering disorder with atrophic scarring, nail dystrophy, and scalp alopecia, as well as oral cavity involvement. In the second family a pair of unlike-sex twins, aged 43, were described. The female twin had congenital myasthenia gravis that had been treated by thymectomy. Although the male cotwin did not have myasthenia, congenital myasthenia gravis was present in another brother and in a maternal first cousin, both of whom did not have epidermolysis bullosa. Thus, the myasthenia was probably an independent finding. Marked growth retardation and anemia were also present in the first family reported by Fine et al. (1989). Abanmi et al. (1994) reported growth retardation and anemia in association with autosomal recessive epidermolysis bullosa simplex in an inbred Saudi family with 5 affected sibs.
The 3 patients studied by Gache et al. (1996) were from 2 unrelated families. Two were sisters in their late twenties, the product of a consanguineous union. They had another affected sister out of a total of 11 sibs who died shortly after birth. The third patient had previously been reported by Doriguzzi et al. (1993). This was a male in his late twenties, born of nonconsanguineous healthy parents, who had epidermolysis bullosa and a severe, slowly progressive muscle disease. Two of his brothers presented at birth with a bullous skin disease that proved fatal in early infancy.
McLean et al. (1996) described a 24-year-old Hispanic man with MD-EBS and mutation in the PLEC gene. He developed blisters on the feet, back, thighs, and face at 10 days of age. Blisters continued to recur at sites of mechanical trauma and healed with atrophic scarring. Additionally he had nail dystrophy and dental abnormalities. Development was normal until age 10 years, when stair climbing became difficult and he stopped running. His upper limbs soon became involved and he was unable to comb his hair. By age 13 years he had become permanently confined to a wheelchair. Intelligence was normal, and he graduated from high school and took college courses. Electron microscopy revealed poorly formed hemidesmosomes along the roof of blisters, with a portion of the hemidesmosome remaining attached to the base of the blister. Tonofilaments made no contact with hemidesmosomes. Electromyograph revealed long-standing neuromuscular disease, and muscle biopsy showed group atrophy of muscle fibers.
Pulkkinen et al. (1996) reported ultrastructural studies of plectin in 2 probands from different families with epidermolysis bullosa-muscular dystrophy. In both families the probands were offspring of consanguineous unions. Blistering was first noted in the neonatal period and the blistering tendency continued throughout life. A progressive muscular weakness was noted which commenced in the third decade. Immunofluorescence revealed attenuated plectin expression. Pulkkinen et al. (1996) reported that histopathology indicated dermal-epidermal blister formation and that transmission electron microscopy revealed tissue separation at the level of the hemidesmosomal attachment plaque.
Clinical Variability
Banwell et al. (1999) reported a 20-year-old African American woman with epidermolysis bullosa simplex since birth and progressive ocular, facial, limb, and truncal weakness and fatigability since age 9 years. Laboratory studies showed increased creatine kinase, and electromyography showed a 25% decrement in responses to repetitive stimulation, consistent with a myasthenic syndrome. There were no antiacetylcholine receptor (AChR) antibodies. Muscle biopsy showed necrotic and regenerating fibers and a wide spectrum of ultrastructural abnormalities, including large accumulations of heterochromatic and lobulated nuclei, rare apoptotic nuclei, numerous cytoplasmic and few intranuclear nemaline rods, disarrayed myofibrils, loss of thick filaments, and vacuolar change. Many endplates had an abnormal configuration with chains of small regions over the fiber surface and a few endplates displayed focal degeneration of the junctional folds. In vitro electrophysiologic studies showed normal quantal release, small miniature endplate potentials, and fetal as well as adult AChR channels. Plectin expression was absent in muscle and severe plectin deficiency was noted in skin. Banwell et al. (1999) suggested that plectin is essential for the structural integrity of muscle and skin, as well as for normal neuromuscular transmission.
Bolling et al. (2010) reported a 40-year-old man who was compound heterozygous for a missense mutation (R323Q) and a nonsense mutation (E1614X) in the PLEC1 gene. The patient had lifelong skin blistering with an intradermal split as well as nail dystrophy, and developed shoulder girdle and upper extremity weakness in the third decade of life. At age 30, preoperative evaluation for excision of a large lipoma revealed a left ventricular dilated cardiomyopathy; cardiomyopathy was subsequently confirmed by septal biopsy showing fibrosis and atrophic fibers. While the patient was asymptomatic, electrocardiography showed frequent ectopic beats, including bouts of nonsustained ventricular tachycardia. His 31-year-old sister had similar skin features but declined further evaluation. Their unaffected parents were each heterozygous for 1 of the mutations. Bolling et al. (2010) stated that this was the second case of cardiomyopathy that could be attributed to PLEC1 mutations, citing Schroder et al. (2002), who described a 25-year-old woman with EBS and muscular dystrophy as well as asymptomatic left ventricular hypertrophy.
Selcen et al. (2011) reported another African American patient with EBS and a myasthenic syndrome. He developed skin vesicular skin eruptions at age 6 weeks, and muscle weakness and fatigue at age 3 years. The myopathy was progressive: he had ptosis and facial weakness, became wheelchair-bound by age 18 years, respirator-dependent by age 26, had a gastrostomy at age 35, and died of pneumonia at age 42. His cognitive function and cardiac status were normal. Muscle studies at age 12 showed necrotic and regenerating fibers, and electromyography at age 15 showed a myasthenic syndrome. Detailed muscle studies in his adult life showed variation in fiber size, type 1 fiber predominance, internal nuclei, and subsarcolemmal calcium deposits. Many nuclei were larger than normal, appeared in subsarcolemmal rows or clusters, and contained prominent chromatin bodies. There was loss of plectin immunoreactivity. The endplates had abnormal conformation with loss of cytoskeletal support of the junctional folds. These factors were predicted to decrease quantal efficacy and compromise the safety margin of neuromuscular transmission, resulting in myasthenic symptoms. Genetic analysis identified compound heterozygous mutations in the PLEC1 gene in this patient and the patient reported by Banwell et al. (1999) (601282.0011-601282.0013). Selcen et al. (2011) concluded that the myasthenic features could be attributed to destruction of the junctional folds and the myopathy to defective anchoring of muscle fiber organelles and defects in sarcolemmal integrity.
The transmission pattern of EBS5B in the families reported by Smith et al. (1996) was consistent with autosomal recessive inheritance.
Gache et al. (1996) found that skin samples from 3 MD-EBS patients did not react with 3 antibodies raised against the intermediate filament-associated protein plectin. Immunofluorescence and Western analysis of explanted MD-EBS keratinocytes confirmed a deficiency in expression of plectin, correlated with an impaired interaction of the keratin cytoskeleton with the hemidesmosomes in affected skin. Consistent with lack of reactivity of MD-EBS skin to plectin antibodies, plectin was not detected in skeletal muscles of these patients. Impaired expression of plectin in muscle correlated with an altered labeling pattern of the muscle intermediate filament protein desmin (125660). Gache et al. (1996) also observed a deficient immunoreactivity with a monoclonal antibody raised against the hemidesmosomal protein HD1 (see Hieda et al., 1992). Furthermore, Gache et al. (1996) found by immunofluorescence analysis that HD1 is expressed in Z lines in normal skeletal muscle, whereas this expression was deficient in patient muscle. Colocalization of HD1 and plectin in normal skin and muscle, together with their impaired expression in MD-EBS tissues, strongly suggested that plectin and HD1 are closely related proteins. It appears from these findings that defective expression of plectin results in an aberrant anchorage of cytoskeletal structures in keratinocytes and muscle fibers leading to cell fragility.
Smith et al. (1996) reported results indicating that mutation in the plectin gene is the cause of autosomal recessive muscular dystrophy associated with epidermolysis bullosa simplex. In affected members of 4 families, absence of plectin was indicated by antibody staining. The disease segregated with markers in the 8q24.13-qter region where the plectin gene maps, and a homozygous frameshift mutation (601282.0001) was detected in plectin cDNA. Smith et al. (1996) stated that absence of the large multifunctional cytoskeleton protein plectin could account for structural failure in both muscle and skin.
In a 24-year-old Hispanic man with MD-EBS, McLean et al. (1996) identified homozygosity for a 1-bp deletion in the PLEC gene (601282.0004).
In a proband and her affected sister with EBSMD, Pulkkinen et al. (1996) detected a homozygous 9-bp deletion in exon 22 (2719del9; 601282.0002) of the plectin gene. The proband in a second family demonstrated a single nucleotide deletion (5866delC; 601282.0003) that resulted in a frameshift and a premature termination codon 16 bp downstream of the mutation. Pulkkinen et al. (1996) concluded that plectin is critical for binding of the intermediate keratin filament network to hemidesmosomal complexes. They also postulated that plectin functions in muscle as a putative attachment protein mediating binding of actin to membrane complexes; these functions of plectin would explain the phenotype of cutaneous fragility and muscular weakness in patients with reduced or abnormal plectin expression.
Shimizu et al. (1999) attempted phenotype-genotype correlations in cases of MD-EBS. Clinical, ultrastructural, immunohistochemical, and molecular features of 4 unrelated Japanese patients were recorded. In addition, 6 cases with defined plectin gene mutations reported in the literature were reviewed. All 10 patients showed generalized blistering at birth or soon thereafter, and experienced deformities of the nails. In addition, decayed teeth (5 cases), urethral strictures (3), mild palmoplantar hyperkeratosis (2), infantile respiratory complications (2), alopecia (1), and laryngeal webs (1) were present. All 8 patients who were older than 9 years demonstrated considerable muscle weakness, and most of them ended up being wheelchair-bound. Among the 10 patients, 7 were products of consanguineous marriage, 9 had a premature termination codon mutation in each allele of the plectin gene, and in 7 of these the mutation was homozygous. One patient was homozygous for a 2719del9 in-frame deletion mutation that resulted in elimination of 3 amino acids, gln-glu-ala (QEA), could still walk at the age of 46, and showed mild clinical severity. This patient showed positive, yet attenuated, plectin expression. Thus, plectin immunofluorescence, combined with identification of the underlying plectin mutations, is of value in predicting the severity of the muscle involvement that occurs later in life in patients with MD-EBS.
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