Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011168 (dysphagia)
 15,644 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Autosomal dominant oculopharyngeal muscular dystrophy (OPMD) is an adult-onset disease with a world-wide distribution. It usually presents in the sixth decade with progressive swallowing difficulties (dysphagia), eyelid drooping (ptosis) and proximal limb weakness. Unique nuclear filament inclusions in skeletal muscle fibres are its pathological hallmark. We isolated the poly(A) binding protein 2 gene (PABP2) from a 217-kb candidate interval on chromosome 14q11 (B.B. et al., manuscript submitted). A (GCG)6 repeat encoding a polyalanine tract located at the N terminus of the protein was expanded to (GCG)8-13 in the 144 OPMD families screened. More severe phenotypes were observed in compound heterozygotes for the (GCG)9 mutation and a (GCG)7 allele that is found in 2% of the population, whereas homozygosity for the (GCG)7 allele leads to autosomal recessive OPMD. Thus the (GCG)7 allele is an example of a polymorphism which can act either as a modifier of a dominant phenotype or as a recessive mutation. Pathological expansions of the polyalanine tract may cause mutated PABP2 oligomers to accumulate as filament inclusions in nuclei.
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PMID:Short GCG expansions in the PABP2 gene cause oculopharyngeal muscular dystrophy. 946 47

Autosomal dominant oculopharyngeal muscular dystrophy (OPMD) usually begins with ptosis or dysphagia during the fifth or sixth decade of life. We studied 7 patients with OPMD symptoms starting before the age of 36 years. All were found to be homozygotes for the dominant (GCG)9 OPMD mutation. On average, disease onset was 18 years earlier than in heterozygotes, and patients had a significantly larger number of muscle nuclei containing intranuclear inclusions (INIs) (9.4 vs 4.9%).
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PMID:Homozygotes for oculopharyngeal muscular dystrophy have a severe form of the disease. 1040 88

Autosomal dominant oculopharyngeal muscular dystrophy (OPMD) is an adult-onset disease with worldwide distribution. It usually presents in the fifth or sixth decades with progressive dysphagia, eyelid ptosis, and proximal limb weakness. Unique intranuclear filament inclusions in skeletal muscle fibers are its morphological hallmark. Surgical correction of the ptosis and cricopharyngeal myotomy are the only therapies available. Autosomal dominant OPMD is caused by short (GCG)8-13 riplet-repeat expansions in the polyadenylation binding protein 2 (PABP2) gene, which is localized in chromosome 14q11. Autosomal recessive OPMD is caused by a double dose of a (GCG)7 PABP2 allele. The GCG expansions cause lengthening of a predicted polyalanine tract in the protein. The expanded polyalanine domains may cause polyalanine nuclear toxicity by accumulating as nondegradable nuclear filaments.
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PMID:Oculopharyngeal muscular dystrophy. 1071 89

Clinicopathological and molecular genetic findings on a new Japanese family with oculopharyngeal muscular dystrophy are reported. The family has 54 members, ten of whom are affected (seven male and three female), in 3 generations. Three affected males, one affected female and one unaffected female of seven living siblings in the third generation were examined. Bilateral ptosis developed in the 4th and 5th decades in the three male cases, and in the 7th decade in the female, and this was followed by diplopia, nasal voice, dysphagia and muscle weakness. In addition, severe external ophthalmoplegia, dysphonia, and proximal amyotrophy were prominent in this family. Electromyographs revealed myogenic/neurogenic changes, and computed tomography disclosed selective muscle wasting with fatty replacement, predominantly in the lower extremities. Muscle biopsy in the four affected patients showed variation in fiber size, and the presence of small angulated fibers and occasional rimmed vacuoles. Electron microscopic examination revealed an accumulation of filamentous inclusions in muscle fiber nuclei. DNA analysis identified that (GCG)(6) in the PABP2 gene was expanded to (GCG)(11) in the four affected cases examined. All studies were negative in the one unaffected. These results confirm that OPMD is caused by GCG short expansion and provides insights into the genetic mechanisms which may contribute to adult onset myopathy, confined to oculopharyngeal muscles.
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PMID:Oculopharyngeal muscular dystrophy in a Japanese family with a short GCG expansion (GCG)(11) in PABP2 gene. 1073 63

Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant myopathy with almost benign course. Its clinical features include ptosis, dysphagia, and proximal limb muscle weakness. The OPMD gene has been localized to chromosome 14, causing expansions of GCG triplets. Scattered families with OPMD belonging to different ethnic groups have been described worldwide. We describe one from northern Germany. In genetic diagnosis, expansion of GCG triplets to 11 was observed, which proved that myopathy, which is very rare in Germany.
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PMID:[Oculopharyngeal muscle dystrophy. Genetic diagnosis in a family in Germany]. 1113 82

Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant disorder of late onset that commonly presents with ptosis and dysphagia. The genetic basis of the condition has been identified recently as a stable trinucleotide repeat expansion in exon 1 of the poly(A) binding protein 2 gene (PABP2), in which (GCG)(6) is the normal repeat length. The prevalence of OPMD is greatest in patients of French-Canadian origin. It is not clear if expansion repeat length is a reliable test in other populations. In this study, we analysed the phenotypic and genotypic characteristics of 31 patients with OPMD in the UK. Ptosis was the first reported symptom in two-thirds of the patients, and half of the subjects studied had evidence of ophthalmoplegia. All but one family had a pathological expansion in the PABP2 gene, ranging from (GCG)(8) to (GCG)(13). In contrast to the French-Canadian population, (GCG)(10) was almost as common as (GCG)(9), evidence against a strong founder effect in the UK population. There was a weak association between repeat length and age of disease onset. Patients with longer repeat lengths, such as (GCG)(13), developed severe limb weakness early in the disease. We were unable to detect the (GCG)(7) polymorphism in over 200 normal controls, suggesting that the frequency of this expansion is lower than that found in the French-Canadian population. One family was negative for the expansion. Affected members presented with the classical features of OPMD, namely ptosis, dysphagia and cytoplasmic inclusions on muscle biopsy, although with some atypical features, such as early age of onset, high serum levels of creatine kinase and a profound ophthalmoplegia. This family is an example of a GCG expansion-negative oculopharyngeal syndrome requiring further genetic investigation. We conclude that PABP2 analysis is a reliable non-invasive diagnostic test for OPMD in the UK population.
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PMID:Oculopharyngeal muscular dystrophy: phenotypic and genotypic studies in a UK population. 1122 52

Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset disorder characterized by progressive eyelid drooping (ptosis), swallowing difficulties (dysphagia), and proximal limb weakness. The autosomal dominant form of this disease is caused by expansions of a (GCG)6 repeat to (GCG)8-13 in the PABPN1 gene. These mutations lead to the expansion of a polyalanine stretch from 10 to 12-17 alanines in the N-terminal domain of PABPN1. Mutated PABPN1 (mPABPN1) induces the formation of muscle intranuclear inclusions that are thought to be the hallmark of this disease. In this review, we discuss: 1) OPMD genetics and PABPN I function studies; 2) diseases caused by polyalanine expansions and cellular polyalanine toxicity; 3) mPABPN1-induced intranuclear inclusion toxicity; 4) role of oligomerization of mPABPNI in the formation and toxicity of OPMD intranuclear inclusions and; 5) recruitment of subcellular components to the OPMD inclusions. We present a potential molecular mechanism for OPMD pathogenesis that accounts for these observations.
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PMID:Progress in understanding the pathogenesis of oculopharyngeal muscular dystrophy. 1261 77

Oculopharyngeal muscular dystrophy is a hereditary pathology transmitted in an autosomal dominant manner. The clinical symptoms are palpebral ptosis, oropharyngeal dysphagia and proximal limb weakness. Upper gastro-esophageal endoscopy is recommended to study the dysphagia, a video-radiology study with barium and an esophageal manometry to study the pharyngeo-esophageal motor disorder. Muscle biopsy reveals the presence of atrophic fibers substituted by an increase in fat and connective tissue. In 1998 Brais described the genetic alteration responsible for this pathology, a limited expansion of the triplet of GCG nucleotides in PABP2 gene on chromosome 14q11. Normal individuals have the homozygotic form (GCG)6 of this triplet, whereas patients with the described syndrome have the heterozygotic form (GCG)6-(GCG)9 or (GCG)6-(GCG)10. We present three siblings from the same family with diagnoses and genetic confirmations of oculopharyngeal dystrophy. Two of the patients underwent cricopharyngeal myotomy to relieve the dysphagia.
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PMID:Diagnosis and treatment of oculopharyngeal dystrophy: a report of three cases from the same family. 1282 21

Oculopharyngeal muscular dystrophy (OPMD) is a muscle disease of late onset associated with progressive ptosis of the eyelids, dysphagia, and unique tubulofilamentous intranuclear inclusions (INIs). OPMD is usually transmitted as an autosomal dominant trait (OMIM 164300). A rarer allelic autosomal recessive form has also been observed (OMIM 257950). Both forms are caused by short (GCG)8-13 expansions in the polyadenylate-binding protein nuclear 1 gene (PABPN1) located on chromosome 14q11.1. The mutations cause the lengthening of an N-terminal polyalanine domain. Both slippage and unequal recombination have been proposed as the mutation mechanisms. The size of the mutation has not yet been conclusively shown to inversely correlate with the severity of the phenotype. Mutated PABPN1 proteins have been shown to be constituents of the INIs. The INIs also contain ubiquitin, proteasome subunits, HSP 40, HSP 70, SKIP, and abundant poly(A)-mRNA. The exact mechanism responsible for polyalanine toxicity in OPMD is unknown. Various intranuclear inclusion dependent and independent mechanisms have been proposed based on the major known function of PABPN1 in polyadenylation of mRNA and its shuttling from the nucleus to the cytoplasm. OPMD is one of the few triplet-repeat diseases for which the function of the mutated gene is known. Because of the increasing number of diseases caused by polyalanine expansions and the pathological overlap with CAG/polyglutamine diseases, what pathological insight is gained by the study of OPMD could lead to a better understanding of a much larger group of developmental and degenerative diseases.
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PMID:Oculopharyngeal muscular dystrophy: a late-onset polyalanine disease. 1452 87

We reported a 52-year-old woman with oculopharyngeal muscular dystrophy (OPMD) harboring expanded (GCG) 13 mutation of the poly (A) binding protein 2 gene. She presented not only ptosis and dysphagia but distal dominant muscle atrophy in four extremities. CT demonstrated distal muscle atrophy with marked fat replacement in the biceps femoris, semitendinosus, membraneous, soleus, and gastrocnemius muscles. Although OPMD is considered to be a muscle disease, this patient showed even neurogenic features in the electrophysiological and pathological findings. Although previous reports indicate that OPMD is genetically homogeneous disease, some cases with OPMD may show some atypical features associated with neurogenic involvement.
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PMID:[Preferential distal muscle involvement in case of oculopharyngeal muscular dystrophy with (GCG) 13 expansion]. 1472 64


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