Late onset oculopharyngeal muscular dystrophy with prominent neurogenic features and short GCG trinucleotide expansion

2010 ◽  
Vol 43 (1) ◽  
pp. 141-142 ◽  
Author(s):  
Giovanni Piccolo ◽  
Andrea Cortese ◽  
Eleonora Tavazzi ◽  
Laura Piccolo ◽  
Jenny Sassone ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Late Onset ◽  
Oculopharyngeal Muscular Dystrophy ◽  
Trinucleotide Expansion

scholarly journals Activation of the ubiquitin-proteasome system contributes to oculopharyngeal muscular dystrophy through muscle atrophy

PLoS Genetics ◽  
2022 ◽  
Vol 18 (1) ◽  
pp. e1010015
Author(s):  
Cécile Ribot ◽  
Cédric Soler ◽  
Aymeric Chartier ◽  
Sandy Al Hayek ◽  
Rima Naït-Saïdi ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Muscle Atrophy ◽  
Late Onset ◽  
Oral Treatment ◽  
Ubiquitin Proteasome System ◽  
Proteasome Activity ◽  
Functional Study ◽  
Oculopharyngeal Muscular Dystrophy ◽  
Ubiquitin Proteasome ◽  
And Function

Oculopharyngeal muscular dystrophy (OPMD) is a late-onset disorder characterized by progressive weakness and degeneration of specific muscles. OPMD is due to extension of a polyalanine tract in poly(A) binding protein nuclear 1 (PABPN1). Aggregation of the mutant protein in muscle nuclei is a hallmark of the disease. Previous transcriptomic analyses revealed the consistent deregulation of the ubiquitin-proteasome system (UPS) in OPMD animal models and patients, suggesting a role of this deregulation in OPMD pathogenesis. Subsequent studies proposed that UPS contribution to OPMD involved PABPN1 aggregation. Here, we use a Drosophila model of OPMD to address the functional importance of UPS deregulation in OPMD. Through genome-wide and targeted genetic screens we identify a large number of UPS components that are involved in OPMD. Half dosage of UPS genes reduces OPMD muscle defects suggesting a pathological increase of UPS activity in the disease. Quantification of proteasome activity confirms stronger activity in OPMD muscles, associated with degradation of myofibrillar proteins. Importantly, improvement of muscle structure and function in the presence of UPS mutants does not correlate with the levels of PABPN1 aggregation, but is linked to decreased degradation of muscle proteins. Oral treatment with the proteasome inhibitor MG132 is beneficial to the OPMD Drosophila model, improving muscle function although PABPN1 aggregation is enhanced. This functional study reveals the importance of increased UPS activity that underlies muscle atrophy in OPMD. It also provides a proof-of-concept that inhibitors of proteasome activity might be an attractive pharmacological approach for OPMD.

P3-149: DEMENTIA SYNDROME IN OCULOPHARYNGEAL MUSCULAR DYSTROPHY: A TRINUCLEOTIDE EXPANSION DISORDER COMMONLY PRESENTING WITH MUSCLE WEAKNESS

2014 ◽  
Vol 10 ◽  
pp. P682-P683 ◽  
Author(s):  
Meredith C. Frederick ◽  
Randy Woltjer ◽  
Lisa C. Silbert ◽  
Morad Daniel ◽  
Adam A. Nelson ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Muscle Weakness ◽  
Oculopharyngeal Muscular Dystrophy ◽  
Dementia Syndrome ◽  
Trinucleotide Expansion

scholarly journals A Japanese case of oculopharyngeal muscular dystrophy (OPMD) with PABPN1 c.35G > C; p.Gly12Ala point mutation

BMC Neurology ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Yo-suke Nishii ◽  
Yu-ichi Noto ◽  
Rei Yasuda ◽  
Takamasa Kitaoji ◽  
Shinji Ashida ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Point Mutation ◽  
Trinucleotide Repeat ◽  
Late Onset ◽  
Lower Limbs ◽  
Oculopharyngeal Muscular Dystrophy ◽  
Muscle Involvement ◽  
Case Presentation ◽  
Japanese Case ◽  
Expansion Mutation

Abstract Background Oculopharyngeal muscular dystrophy (OPMD) is a late-onset muscular dystrophy characterised by slowly progressive ptosis, dysphagia, and proximal limb muscle weakness. A common cause of OPMD is the short expansion of a GCG or GCA trinucleotide repeat in PABPN1 gene. Case presentation A 78-year-old woman presented with ptosis and gradually progressive dysphagia. Her son had the same symptoms. A physical examination and muscle imaging (MRI and ultrasound) showed impairment of the tongue, proximal muscles of the upper limbs, and flexor muscles of the lower limbs. Needle-electromyography (EMG) of bulbar and facial muscles revealed a myopathic pattern. Based on the characteristic muscle involvement pattern and needle-EMG findings, we suspected that the patient had OPMD. Gene analysis revealed PABPN1 c.35G > C point mutation, which mimicked the effect of a common causative repeat expansion mutation of OPMD. Conclusion We herein describe the first reported Japanese case of OPMD with PABPN1 point mutation, suggesting that this mutation is causative in Asians as well as in Europeans, in whom it was originally reported.

scholarly journals Guanabenz treatment improves Oculopharyngeal muscular dystrophy phenotype

2018 ◽  
Author(s):  
Alberto Malerba ◽  
Fanny Roth ◽  
Pradeep Harish ◽  
Jamila Dhiab ◽  
Ngoc Lu-Nguyen ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Mouse Model ◽  
Genetic Disease ◽  
Late Onset ◽  
Oculopharyngeal Muscular Dystrophy ◽  
Systemic Delivery ◽  
Active Constituent ◽  
Eukaryotic Translation ◽  
Pharyngeal Muscles ◽  
The Unfolded Protein Response

AbstractOculopharyngeal muscular dystrophy (OPMD) is a rare late onset genetic disease affecting most profoundly eyelid and pharyngeal muscles, leading respectively to ptosis and dysphagia, and proximal limb muscles at later stages. A short abnormal (GCG) triplet expansion in the polyA– binding protein nuclear 1 (PABPN1) gene leads to PABPN1-containing aggregates in the muscles of OPMD patients. It is commonly accepted that aggregates themselves, the aggregation process and/or the early oligomeric species of PABPN1 are toxic in OPMD. Decreasing PABPN1 aggregate load in animal models of OPMD ameliorates the muscle phenotype. In order to identify a potential therapeutic molecule that would prevent and reduce aggregates, we tested guanabenz acetate (GA), an FDA-approved antihypertensive drug, in OPMD cells as well as in the A17 OPMD mouse model. We demonstrate that treating mice with GA reduces the size and number of nuclear aggregates, improves muscle force, protects myofibres from the pathology-derived turnover and decreases fibrosis. GA is known to target various cell processes, including the unfolded protein response (UPR), which acts to attenuate endoplasmic reticulum (ER) stress. Here we used a cellular model of OPMD to demonstrate that GA increases both the phosphorylation of the eukaryotic translation initiator factor 2α subunit (eIF2α) and the splicing of Xbp1, key components of the UPR. Altogether these data suggest that modulation of protein folding regulation can be beneficial for OPMD and support the further development of guanabenz or its derivatives for treatment of OPMD in humans.Significance StatementOculopharyngeal muscular dystrophy (OPMD) is a rare late onset incurable genetic disease characterized by the formation of insoluble aggregates in skeletal muscles. It has been shown that the reduction of aggregates correlates with an improvement of the disease. Here we used a mouse model of OPMD to show that Guanabenz acetate, the active constituent of a marketed but recently discontinued drug for hypertension, decreases the number and the size of aggregates after systemic delivery and improves many aspects of the disease. We also describe experimental evidences explaining the mechanism behind the efficacy of such compound for OPMD.

scholarly journals Recent Progress in Oculopharyngeal Muscular Dystrophy

2021 ◽  
Vol 10 (7) ◽  
pp. 1375
Author(s):  
Satoshi Yamashita
Keyword(s):  
Muscular Dystrophy ◽  
Recent Progress ◽  
Trinucleotide Repeat ◽  
Late Onset ◽  
Oculopharyngeal Muscular Dystrophy ◽  
Limb Weakness ◽  
Medical Needs ◽  
Therapeutic Benefits ◽  
Initial Symptoms ◽  
Swallowing Problems

Oculopharyngeal muscular dystrophy (OPMD) is a late-onset intractable myopathy, characterized by slowly progressive ptosis, dysphagia, and proximal limb weakness. It is caused by the abnormal expansion of the alanine-encoding (GCN)n trinucleotide repeat in the exon 1 of the polyadenosine (poly[A]) binding protein nuclear 1 gene (11–18 repeats in OPMD instead of the normal 10 repeats). As the disease progresses, the patients gradually develop a feeling of suffocation, regurgitation of food, and aspiration pneumonia, although the initial symptoms and the progression patterns vary among the patients. Autologous myoblast transplantation may provide therapeutic benefits by reducing swallowing problems in these patients. Therefore, it is important to assemble information on such patients for the introduction of effective treatments in nonendemic areas. Herein, we present a concise review of recent progress in clinical and pathological studies of OPMD and introduce an idea for setting up a nation-wide OPMD disease registry in Japan. Since it is important to understand patients’ unmet medical needs, realize therapeutically targetable symptoms, and identify indices of therapeutic efficacy, our attempt to establish a unique patient registry of OPMD will be a helpful tool to address these urgent issues.

scholarly journals Swallowing, Chewing and Speaking: Frequently Impaired in Oculopharyngeal Muscular Dystrophy

2020 ◽  
Vol 7 (4) ◽  
pp. 483-494
Author(s):  
Rosemarie H.M.J.M. Kroon ◽  
Corinne G.C. Horlings ◽  
Bert J.M. de Swart ◽  
Baziel G.M. van Engelen ◽  
Johanna G. Kalf
Keyword(s):  
Muscular Dystrophy ◽  
Late Onset ◽  
Neuromuscular Disorder ◽  
Bite Force ◽  
Oculopharyngeal Muscular Dystrophy ◽  
Tongue Strength ◽  
Asymptomatic Carriers ◽  
Swallowing Capacity ◽  
Thin Liquids

Background: Oculopharyngeal muscular dystrophy (OPMD) is a late onset progressive neuromuscular disorder. Although dysphagia is a pivotal sign in OPMD it is still not completely understood. Objective: The aim of this study was to systematically investigate oropharyngeal functioning in a large OPMD population. Methods: Forty-eight genetically confirmed OPMD patients completed questionnaires, performed clinical tests on swallowing, chewing, speaking, tongue strength and bite force, and underwent videofluoroscopy of swallowing. Descriptive statistics was used for all outcomes and logistic regression to investigate predictors of abnormal swallowing. Results: Eighty-two percent reported difficulties with swallowing, 27% with chewing and 67% with speaking. Patients performed significantly worse on all oropharyngeal tests compared to age-matched controls except for bite force. Also asymptomatic carriers performed worse than controls: on chewing time, swallowing speed and articulation rate. During videofluoroscopy, all patients (except one asymptomatic) had abnormal residue and 19% aspirated. Independent predictors of abnormal residue were reduced swallowing capacity for thin liquids (OR 10 mL = 0.93; 20 mL = 0.95) and reduced tongue strength for thick liquids (OR 10 mL = 0.95); 20 mL = 0.90). Aspiration of thin liquids was predicted by disease duration (OR = 1.11) and post-swallow residue with 20 mL (OR = 4.03). Conclusion: Next to pharyngeal dysphagia, chewing and speaking are also frequently affected in OPMD patients, even in asymptomatic carriers. Residue after swallowing is a very early sign, while aspiration is a later sign in OPMD. For clinical follow-up monitoring of subjective complaints, swallowing capacity and tongue strength seems relevant.

scholarly journals A polyalanine antibody for the diagnosis of oculopharyngeal muscular dystrophy and polyalanine-related diseases

2017 ◽  
Vol 1 ◽  
pp. 1
Author(s):  
Shawn J. Stochmanski ◽  
François Blondeau ◽  
Martine Girard ◽  
Pascale Hince ◽  
Daniel Rochefort ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
Trinucleotide Repeat ◽  
Late Onset ◽  
Cag Repeat ◽  
Spinocerebellar Ataxia Type ◽  
Causative Mutation ◽  
Oculopharyngeal Muscular Dystrophy ◽  
Spinocerebellar Ataxia Type 3 ◽  
Repeat Tract ◽  
Repeat Expansions

Eighteen severe human diseases have so far been associated with trinucleotide repeat expansions coding for either polyalanine (encoded by a GCN repeat tract) or polyglutamine (encoded by a CAG repeat tract).  Among them, oculopharyngeal muscular dystrophy (OPMD), spinocerebellar ataxia type-3 (SCA3), and Huntington’s disease (HD) are late-onset autosomal-dominant disorders characterized by the presence of intranuclear inclusions (INIs).  We have previously identified the OPMD causative mutation as a small expansion (from 2 in normal to 7 in disease) of a GCG repeat tract in the PABPN1 gene.  In addition, -1 ribosomal frameshifting has been reported to occur in expanded CAG repeat tracts in the ATXN3 (SCA3) and HTT (HD) genes, resulting in the translation of a hybrid CAG/GCA repeat tract and the production of a polyalanine-containing peptide.  Previous studies on OPMD suggest that polyalanine-induced toxicity is very sensitive to the dosage and length of the alanine stretch.  Here we report the characterization of a polyclonal antibody that selectively recognizes pathological expansions of polyalanine in PABPN1.  Furthermore, our antibody also detects the presence of alanine proteins in INIs of SCA3 and HD patient samples.

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