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Oculopharyngeal muscular dystrophy

A Malerba, P Klein, H Bachtarzi, S A Jarmin, G Cordova, A Ferry, V Strings, M Polay Espinoza, K Mamchaoui, S C Blumen, J Lacau St Guily, V Mouly, M Graham, G Butler-Browne, D A Suhy, C Trollet, G Dickson
Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant, late-onset muscle disorder characterized by ptosis, swallowing difficulties, proximal limb weakness and nuclear aggregates in skeletal muscles. OPMD is caused by a trinucleotide repeat expansion in the PABPN1 gene that results in an N-terminal expanded polyalanine tract in polyA-binding protein nuclear 1 (PABPN1). Here we show that the treatment of a mouse model of OPMD with an adeno-associated virus-based gene therapy combining complete knockdown of endogenous PABPN1 and its replacement by a wild-type PABPN1 substantially reduces the amount of insoluble aggregates, decreases muscle fibrosis, reverts muscle strength to the level of healthy muscles and normalizes the muscle transcriptome...
March 31, 2017: Nature Communications
Maricela García-Castañeda, Ana Victoria Vega, Rocío Rodríguez, Maria Guadalupe Montiel-Jaen, Bulmaro Cisneros, Angel Zarain-Herzberg, Guillermo Avila
Oculopharyngeal muscular dystrophy (OPMD) is linked to mutations in the gene encoding poly(A)-binding protein nuclear 1 (PABPN1). OPMD mutations consist in an expansion of a tract that contains 10 alanines (to 12-17). The disease courses with muscle weakness that begins in adulthood, but the underlying mechanism is unclear. Here we investigated functional effects of PABPN1 and an OPMD mutation (PABPN1-17A), using myotubes transfected with cDNAs encoding these proteins (GFP-tagged). PABPN1 stimulated myoblast fusion (100%), but PABPN1-17A failed to mimic this effect...
March 16, 2017: Journal of Physiology
Li Li, Nelson Ka Lam Ng, Alex Chun Koon, Ho Yin Edwin Chan
Polyalanine (poly(A)) diseases are caused by the expansion of translated GCN triplet nucleotide sequences encoding poly(A) tracts in proteins. To date, nine human disorders have been found to be associated with poly(A) tract expansions, including congenital central hypoventilation syndrome and oculopharyngeal muscular dystrophy. Previous studies have demonstrated that unexpanded wild-type poly(A)-containing proteins localize to the cell nucleus, whereas expanded poly(A)-containing proteins primarily localize to the cytoplasm...
April 7, 2017: Journal of Biological Chemistry
Pascale Richard, Capucine Trollet, Tanya Stojkovic, Alix de Becdelievre, Sophie Perie, Jean Pouget, Bruno Eymard
OBJECTIVE: Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant adult-onset disease characterized by progressive ptosis, dysphagia, and proximal limb weakness. The genetic cause is an expanded (GCN)n mutation in the PABPN1 gene encoding for the polyadenylate-binding protein nuclear 1. We hypothesized a potential correlation between the size of the (GCN)n expansion and the severity of the phenotype. To do this, we characterized the distribution of the genotypes as well as their correlation with age at diagnosis and phenotypical features in a large cohort of heterozygous and homozygous patients with OPMD in France with a confirmed molecular diagnosis of PABPN1...
January 24, 2017: Neurology
Marisa Cruz-Aguilar, Caroline Guerrero-de Ferran, Jose Luis Tovilla-Canales, Angel Nava-Castañeda, Juan C Zenteno
Oculopharyngeal muscular dystrophy (OPMD) is an autosomal-dominant, adult-onset disorder defined by blepharoptosis, dysphagia, and proximal muscle weakness. OPMD arises from heterozygous expansions of a trinucleotide (GCN) tract situated at the 5' region of the polyadenylate RNA binding protein 1 (PABPN1) gene. The frequency of a particular (GCN) expansion in a given population of patients with OPMD is largely influenced by the occurrence of founder mutations. Analysis of large groups of patients with OPMD from different ethnic origins will help to estimate the relative contribution of each expanded allele to the disease...
March 2017: Journal of Investigative Medicine: the Official Publication of the American Federation for Clinical Research
B M van der Sluijs, V Raz, M Lammens, L P van den Heuvel, N C Voermans, B G M van Engelen
BACKGROUND: Oculopharyngeal muscular dystrophy (OPMD) has long been characterized by a combination of bilateral ptosis and dysphagia and subsequent limb girdle weakness. The role of the typical intranuclear inclusion in the pathophysiology is unresolved. OBJECTIVE: The aim of this study was to describe the clinical and histopathological features of oculopharyngeal muscular dystrophy (OPMD). We examined this in a Dutch cohort including presymptomatic Ala-expanded-PABPN1 carriers and late symptomatic patients...
March 3, 2016: Journal of Neuromuscular Diseases
M ª Asunción Acosta Mérida, Joaquín Marchena Gómez, Josefa M ª Afonso Déniz
Oculopharyngeal muscular dystrophy (OPMD), is a rare hereditary myopathy that affects mainly the levator palpebrae and the constrictor pharyngeal muscles, being able to cause severe dysphagia. It can be treated effectively by surgical cricopharyngeal myotomy, as in the case presented below.
December 2016: Revista Española de Enfermedades Digestivas
Sarah Youssof, Carol Romero-Clark, Teddy Warner, Emily Plowman
INTRODUCTION: The Swallowing Quality of Life instrument (SWAL-QOL) is a patient-reported outcome measure of swallowing-related quality of life (SR-QoL). Its psychometric properties in oculopharyngeal muscular dystrophy (OPMD) are not known. METHODS: We administered the SWAL-QOL to U.S. OPMD Registry participants. We described SR-QoL profiles and assessed reliability and validity. RESULTS: The mean composite score in 113 individuals with OPMD was 54...
October 19, 2016: Muscle & Nerve
Hadas Newman, Sergiu C Blumen, Itzhak Braverman, Rana Hanna, Beatrice Tiosano, Ido Perlman, Tamar Ben-Yosef
Purpose: To investigate the genetic basis for severe visual complaints by Bukharan Jewish patients with oculopharyngeal muscular dystrophy (OPMD). Methods: Polymerase chain reaction amplification and direct sequencing were used to test for NRL, PABPN1, and NR2E3 mutations. Complete ophthalmic examination included best-corrected visual acuity, biomicroscopic examination, optical coherence tomography, and fundus autofluorescence. Detailed electroretinography (ERG) testing was conducted including expanded International Society for Clinical Electrophysiology of Vision protocol for light-adapted and dark-adapted conditions, measurements of S-cone function, and ON-OFF light-adapted ERG...
October 1, 2016: Investigative Ophthalmology & Visual Science
Pierre Klein, Martine Oloko, Fanny Roth, Valérie Montel, Alberto Malerba, Susan Jarmin, Teresa Gidaro, Linda Popplewell, Sophie Perie, Jean Lacau St Guily, Pierre de la Grange, Michael N Antoniou, George Dickson, Gillian Butler-Browne, Bruno Bastide, Vincent Mouly, Capucine Trollet
A short abnormal polyalanine expansion in the polyadenylate-binding protein nuclear-1 (PABPN1) protein causes oculopharyngeal muscular dystrophy (OPMD). Mutated PABPN1 proteins accumulate as insoluble intranuclear aggregates in muscles of OPMD patients. While the roles of PABPN1 in nuclear polyadenylation and regulation of alternative poly(A) site choice have been established, the molecular mechanisms which trigger pathological defects in OPMD and the role of aggregates remain to be determined. Using exon array, for the first time we have identified several splicing defects in OPMD...
December 15, 2016: Nucleic Acids Research
Muhammad Riaz, Yotam Raz, Barbara van der Slujis, George Dickson, Baziel van Engelen, John Vissing, Vered Raz
Molecular biomarkers emerge as an accurate diagnostic tool, but are scarce for myopathies. Lack of outcome measures sensitive to disease onset and symptom severity hamper evaluation of therapeutic developments. Cytokines are circulating immunogenic molecules, and their potential as biomarkers has been exploited in the last decade. Cytokines are released from many tissues, including skeletal muscles, but their application to monitor muscle pathology is sparse. We report that the cytokine functional group is altered in the transcriptome of oculopharyngeal muscular dystrophy (OPMD)...
August 9, 2016: Human Molecular Genetics
A V Marusin, Kh A Kurtanov, N R Maksimova, M G Svarovskaya, V A Stepanov
Oculopharyngeal muscular dystrophy (OPMD) is a hereditary neuromuscular disease with autosomal dominant and rarely with autosomal recessive inheritance types. This study included 50 patients with a clinical diagnosis of OPMD, 23 asymptomatic carriers of the mutation from 45 unrelated families, and 56 healthy relatives, as well as population samples of four ethnic groups of Yakutia: Yakuts, Evens, Evenks, Yukaghirs. It was found that the cause of OPMD development in all investigated families is the same increase in...
March 2016: Genetika
Shiro Matsubara, Toshio Shimizu, Takashi Komori, Madoka Mori-Yoshimura, Narihiro Minami, Yukiko K Hayashi
A middle-aged Japanese man presented with slowly progressive asymmetric weakness of legs and arm but had neither ptosis nor dysphagia. He had a family history of similar condition suggestive of autosomal dominant inheritance. A muscle biopsy showed mixture of neurogenic atrophy and myopathy with rimmed vacuoles. Furthermore we found intranuclear inclusions that had a fine structure mimicking that of inclusions reported in oculopharyngeal muscular dystrophy (OPMD). Immunohistochemical staining for polyadenylate-binding nuclear protein 1, which is identified within the nuclear inclusions of OPMD, demonstrated nuclear positivity in this case...
July 2016: Neuromuscular Disorders: NMD
Barbara M van der Sluijs, Hans Knoop, Gijs Bleijenberg, Baziel G M van Engelen, Nicol C Voermans
Research on oculopharyngeal muscular dystrophy focuses mainly on genetic and pathophysiological aspects. Clinically, oculopharyngeal muscular dystrophy is often considered as a disease with a relatively mild initial disease course with no or only mild functional disabilities. However the occurrence of fatigue, pain and functional impairments other than dysphagia has never been studied systematically. The aim of this study is therefore to assess the prevalence of fatigue, pain, and functional limitations, and the social participation and psychological well-being of oculopharyngeal muscular dystrophy patients...
March 2016: Neuromuscular Disorders: NMD
Evan Kalin-Hajdu, Liat Attas-Fox, Xi Huang, Isabelle Hardy, François Codère
PURPOSE: To compare the functional outcome of the polypropylene trapezoid frontalis suspension with the polypropylene modified Crawford frontalis suspension in a large cohort of patients with oculopharyngeal muscular dystrophy. METHODS: Retrospective, nonrandomized comparative case series. Patients with oculopharyngeal muscular dystrophy who underwent bilateral polypropylene frontalis suspension were selected for chart review. Main outcome measures were margin reflex distance, duration of surgery, and ptosis recurrence...
January 2017: Ophthalmic Plastic and Reconstructive Surgery
Marilia Yuri Maeda, Tais Yuri Hashimoto, Isabella Christina Oliveira Neto, Luciano Rodrigues Neves
No abstract text is available yet for this article.
March 2017: Brazilian Journal of Otorhinolaryngology
Matteo Garibaldi, Elena Maria Pennisi, Mirella Bruttini, Veronica Bizzarri, Elisabetta Bucci, Stefania Morino, Caterina Talerico, Antonella Stoppacciaro, Alessandra Renieri, Giovanni Antonini
A 69-year-old woman presented a dropped head, caused by severe neck extensor weakness that had started two years before. She had also developed a mild degree of dysphagia, rhinolalia, eyelid ptosis and proximal limb weakness during the last months. EMG revealed myopathic changes. Muscle MRI detected fatty infiltration in the posterior neck muscles and tongue. Muscle biopsy revealed fiber size variations, sporadic rimmed vacuoles, small scattered angulated fibers and a patchy myofibrillar network. Genetic analysis revealed homozygous (GCN)11 expansions in the PABPN1 gene that were consistent with recessive oculopharyngeal muscular dystrophy (OPMD)...
November 2015: Neuromuscular Disorders: NMD
Sofia Lourenço, Capucine Trollet, S Butler-Browne Gillian, Bertrand Friguet, Isabelle Petropoulos
There is now increasing evidence that reactive oxygen species (ROS) are signalling molecules that regulate growth, differentiation, proliferation and apoptosis, at least in physiological concentration. However, when ROS levels overcome the capacity of cellular antioxidant systems, they damage cellular components such as nucleic acids, lipids and in particular proteins, inflicting alterations to cell structure and function. Oxidation of sulfur-containing aminoacids, like cysteine and methionine, within proteins, can be repaired by specific enzymatic systems...
October 2014: Free Radical Biology & Medicine
Sarah Youssof
INTRODUCTION: Oculopharyngeal muscular dystrophy (OPMD) causes ptosis, dysphagia, and limb weakness. Health-related quality of life (HRQoL) and its relationship to physical symptoms was investigated. METHODS: The 36-item Short Form (SF-36) was completed by 89 participants in the U.S. OPMD Registry. Multiple hierarchical regression was used to determine the relative contributions of dysphagia severity and lower extremity functional impairment to the physical (PCS) and mental (MCS) components of the SF-36...
May 2016: Muscle & Nerve
Clara Maria Schutte, Cecelia M Dorfling, Riaan van Coller, Engela M Honey, Elizabeth Jansen van Rensburg
Autosomal dominantly inherited oculopharyngeal muscular dystrophy (OPMD) is caused by a trinucleotide repeat expansion in exon 1 of the polyadenylate binding protein nuclear 1 (PABPN1) gene on chromosome 14q. A large family with OPMD was recently identified in Pretoria, South Africa (SA). Molecular studies revealed a (GCG)11(GCA)3GCG or (GCN)15 mutant allele. The (GCN)15 mutation detected in this family has been described previously in families from Uruguay and Mexico as a founder effect. To our knowledge, this is the first report of an SA Afrikaner family with molecularly confirmed OPMD...
July 2015: South African Medical Journal, Suid-Afrikaanse Tydskrif Vir Geneeskunde
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