Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026850 (muscular dystrophy)
 5,870 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

With few exceptions, epidermolysis bullosa (EB) simplex is an autosomal dominant disorder characterized by rather localized and recurrent nonscarring blister formation; mucous membranes and other organs are usually uninvolved. Recently, two patients were described with an autosomal recessive form of EB simplex associated with muscular dystrophy. We now describe four additional patients with autosomal recessive EB simplex, three of whom had associated muscular dystrophy or congenital myasthenia gravis. These patients had generalized cutaneous findings, including milia, atrophic scarring, nail dystrophy, and scalp alopecia, which have been classically attributed to either junctional or dystrophic EB. Each patient had significant oral cavity involvement, and in two, marked growth retardation and anemia were also present. Our findings suggest that autosomal recessive EB simplex may be characterized by rather severe cutaneous and extracutaneous disease activity, and may be associated with at least two distinct neuromuscular diseases.
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PMID:Autosomal recessive epidermolysis bullosa simplex. Generalized phenotypic features suggestive of junctional or dystrophic epidermolysis bullosa, and association with neuromuscular diseases. 266 9

Anchoring complexes are specialized focal attachment sites within the cutaneous basement membrane zone (BMZ) and play a crucial role in dermo-epidermal adhesion. Structural weakness that may be caused by the binding of autoantibodies to components of the anchoring complex or by aberrant expression of these components as a result of genetic defects can lead to subepidermal blisters. Autoimmune subepidermal blistering disorders include bullous pemphigoid, pemphigoid gestationis, lichen planus pemphigoides, linear IgA disease, cicatricial pemphigoid, anti-p200, anti-p105, and anti-p450 pemphigoid, epidermolysis bullosa acquisita, and bullous systemic lupus erythematosus. The autoantigen in the skin of patients with dermatitis herpetiformis remains to be identified. More than 300 distinct mutations in 10 different genes corresponding to structural components of the BMZ have been described that result in skin fragility and dermo-epidermal separation associated with characteristic extracutaneous manifestations. This group of genodermatoses, collectively referred to as epidermolysis bullosa (EB), consists of distinct variants, such as EB simplex, EB with muscular dystrophy, EB with pyloric atresia, generalized atrophic benign EB, Herlitz junctional EB, and dystrophic EB. Recent advances in the molecular characterization of BMZ components have led to a better understanding of the interaction between these molecules as well as the autoimmune response against these proteins. In addition, by the elucidation of genetic defects in the different variants of EB, genotype-phenotype correlations now begin to arise and genetic counseling has been improved.
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PMID:Autoimmune and inherited subepidermal blistering diseases: advances in the clinic and the laboratory. 1109 26

Epidermolysis bullosa (EB) is an inherited mechano-bullous disorder of the skin, and is divided into three major categories: EB simplex (EBS), dystrophic EB, and junctional EB (JEB). Mutations in the plectin gene (PLEC1) cause EBS associated with muscular dystrophy, whereas JEB associated with pyloric atresia (PA) results from mutations in the alpha6 and beta4 integrin genes. In this study, we examined three EB patients associated with PA from two distinct families. Electron microscopy detected blister formation within the basal keratinocytes leading to the diagnosis of EBS. Surprisingly, immunohistochemical studies using monoclonal antibodies to a range of basement membrane proteins showed that the expression of plectin was absent or markedly attenuated. Sequence analysis demonstrated four novel PLEC1 mutations. One proband was a compound heterozygote for a nonsense mutation of Q305X and a splice-site mutation of 1344G-->A. An exon-trapping experiment suggested that the splice-site mutation induced aberrant splicing of the gene. The second proband harbored a heterozygous maternal nonsense mutation, Q2538X and homozygous nonsense mutations R1189X. Analysis of the intragenic polymorphisms of PLEC1 suggested that R1189X mutations were due to paternal segmental uniparental isodisomy. These results indicate that PLEC1 is a possible causative gene in this clinical subtype, EBS associated with PA. Furthermore, two patients out of our three cases died in infancy. In terms of clinical prognosis, this novel subtype is the lethal variant in the EBS category.
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PMID:Epidermolysis bullosa simplex associated with pyloric atresia is a novel clinical subtype caused by mutations in the plectin gene (PLEC1). 1568 71

Plectin, a large multidomain adhesive protein with versatile binding functions, is expressed in a number of tissues and cell types. In the skin, plectin is a critical component of hemidesmosomes, interacting with keratin intermediate filaments and beta4 integrin. Mutations in the plectin gene (PLEC1) result in fragility of skin, demonstrating blister formation at the level of hemidesmosomes. These blistering disorders belong to the spectrum of epidermolysis bullosa (EB) phenotypes, and three distinct variants because of plectin mutations have been identified. First, EB with muscular dystrophy, an autosomal recessive syndrome, is frequently caused by premature termination codon-causing mutations leading to the absence of plectin both in the skin and in the muscle. Second, a heterozygous missense mutation (R2110W) in PLEC1 has been documented in patients with EB simplex of the Ogna type, a rare autosomal dominant disorder. Finally, recent studies have disclosed plectin mutations in patients with EB with pyloric atresia, an autosomal recessive syndrome, frequently with lethal consequences. Collectively, these observations attest to the phenotypic spectrum of plectin mutations, and provide the basis for accurate genetic counselling with prognostic implications, as well as for prenatal diagnosis in families at the risk of recurrence of the disease.
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PMID:Progress in epidermolysis bullosa: the phenotypic spectrum of plectin mutations. 1581 Aug 81

Plectin is a cytoskeletal linker protein that has a dumbbell-like structure with a long central rod and N- and C-terminal globular domains. Mutations in the gene encoding plectin (PLEC1) cause two distinct autosomal recessive subtypes of epidermolysis bullosa (EB): EB simplex with muscular dystrophy (EBS-MD), and EB simplex with pyloric atresia (EBS-PA). Here, we demonstrate that normal human fibroblasts express two different plectin isoforms including full-length and rodless forms of plectin. We performed detailed analysis of plectin expression patterns in six EBS-MD and three EBS-PA patients. In EBS-PA, expression of all plectin domains was found to be markedly attenuated or completely lost; in EBS-MD, the expression of the N- and C-terminal domains of plectin remained detectable, although the expression of rod domains was absent or markedly reduced. Our data suggest that loss of the full-length plectin isoform with residual expression of the rodless plectin isoform leads to EBS-MD, and that complete loss or marked attenuation of full-length and rodless plectin expression underlies the more severe EBS-PA phenotype. These results also clearly account for the majority of EBS-MD PLEC1 mutation restriction within the large exon 31 that encodes the plectin rod domain, whereas EBS-PA PLEC1 mutations are generally outside exon 31.
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PMID:Plectin expression patterns determine two distinct subtypes of epidermolysis bullosa simplex. 2005 59

Plectin is a cytoskeletal linker protein which has a long central rod and N- and C-terminal globular domains. Mutations in the gene encoding plectin (PLEC) cause two distinct autosomal recessive subtypes of epidermolysis bullosa: EB simplex (EBS) with muscular dystrophy (EBS-MD), and EBS with pyloric atresia (EBS-PA). Previous studies have demonstrated that loss of full-length plectin with residual expression of the rodless isoform leads to EBS-MD, whereas complete loss or marked attenuation of expression of full-length and rodless plectin underlies the more severe EBS-PA phenotype. However, muscular dystrophy has never been identified in EBS-PA, not even in the severe form of the disease. Here, we report the first case of EBS associated with both pyloric atresia and muscular dystrophy. Both of the premature termination codon-causing mutations of the proband are located within exon 32, the last exon of PLEC. Immunofluorescence and immunoblot analysis of skin samples and cultured fibroblasts from the proband revealed truncated plectin protein expression in low amounts. This study demonstrates that plectin deficiency can indeed lead to both muscular dystrophy and pyloric atresia in an individual EBS patient.
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PMID:Plectin deficiency leads to both muscular dystrophy and pyloric atresia in epidermolysis bullosa simplex. 2066 83

Epidermolysis bullosa (EB) is a rare hereditary disorder characterized by formation of blisters following minor trauma. It has been traditionally categorized by the level of basement membrane zone separation into EB simplex (EBS), junctional EB (JEB), and dystrophic EB (DEB). Recently, hemidesmosomal EB has been proposed as a fourth category, which includes EB with muscular dystrophy and EB with pyloric atresia. We report here on a case of concomitant occurrence of EB and pyloric atresia, a rare form of EB.
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PMID:Case of epidermolysis bullosa with pyloric atresia. 2202 70

Hereditary epidermolysis bullosa (EB) is a heterogeneous group of rare genetic diseases characterized by fragile skin and/or mucous membrane, and it may be either local or generalized. It is caused by mutations in genes encoding different proteins involved mainly in the structure and function of the dermal-epidermal junction. Nineteen genes have so far been identified. They are classified by level of skin cleavage (from top to bottom) into four groups: EB simplex, junctional EB, dystrophic EB and Kindler syndrome. Clinically suspected diagnosis is confirmed by immunohistochemical examination of a skin biopsy at specialized centres in order to determine the level of cleavage and the deficient protein. This first step may be followed by genetic analysis. The severity of the disease is highly variable, ranging from localized forms with little effect on quality of life to rapidly lethal forms. In generalized severe forms, the extent and chronicity of lesions, as well as mucosal involvement, can lead to systemic complications: malnutrition, pain, joint contractures, chronic inflammation, amyloidosis, cutaneous squamous cell carcinoma. Some specific forms are associated with other cutaneous signs (nail involvement, alopecia, hyperpigmentation, palmoplantar keratoderma) or extracutaneous involvement (muscular dystrophy or pyloric atresia). No curative treatment of EB is available today. EB requires multidisciplinary medical care, nursing, psychological and social management. This is best provided by a specialized network, involving reference centres, centres of expertise and daily caregivers. The goal of treatment is the prevention and treatment of lesions with specific non-adherent dressings and the prevention, detection and treatment of complications. It is essential not to traumatize the skin (bandaging, friction, etc.). Protein, gene or cell replacement therapy, and allogeneic bone marrow, cord blood or pluripotent stem-cell transplantation are currently being assessed. The aim of these French recommendations (national diagnostic and treatment protocol [PNDS]) is to provide healthcare professionals with guidance on the course of EB and on optimal patient management.
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PMID:[Hereditary epidermolysis bullosa: French national guidelines (PNDS) for diagnosis and treatment]. 2793 49