Oculopharyngeal Dystrophy Research Articles

Progress on gene therapy, cell therapy, and pharmacological strategies toward the treatment of oculopharyngeal muscular dystrophy.

Oculopharyngeal muscular dystrophy (OPMD) is a muscle-specific, late-onset degenerative disorder whereby muscles of the eyes (causing ptosis), throat (leading to dysphagia), and limbs (causing proximal limb weakness) are mostly affected. The disease is characterized by a mutation in the poly(A)-binding protein nuclear-1 (PABPN1) gene, resulting in a short GCG expansion in the polyalanine tract of PABPN1 protein. Accumulation of filamentous intranuclear inclusions in affected skeletal muscle cells constitutes the pathological hallmark of OPMD. This review highlights the current translational research advances in the treatment of OPMD. In vitro and in vivo disease models are described. Conventional and experimental therapeutic approaches are discussed with emphasis on novel molecular therapies including the use of intrabodies, gene therapy, and myoblast transfer therapy.

Conformational behavior of polyalanine peptides with and without protecting groups of varying chain lengths: population of PP-II structure!

Oculopharyngeal muscular dystrophy (OPMD), a polyalanine myopathy, occurs due to expansion of homo-polyalanine stretch in normal polyadenylating binding protein nuclear 1 (PABPN1) protein from Ala10 to Ala11-17. Therefore, the conformational behavior of polyalanine peptides with n = 10-17, with and without terminal protecting groups, have been investigated with different starting geometries in water by molecular dynamics simulation studies. Alanine peptides are shown to give rise to unordered structure irrespective of starting geometry and not more than two residues at a stretch have the same/similar set of φ, ψ values. However, the final structure with terminal protecting groups look like β-strand. Unprotected poly-Ala peptides adopt twisted β-hairpin/multi hairpin like structure with increasing chain length. The number of residues having φ, ψ values in collagen region is found to be less in peptides with unprotected termini as compared to peptides with protected termini of same chain length. The results have been supported by recent synchrotron radiation circular dichroism spectroscopy of polyproline II and unordered secondary structures. Opening of the helical structure in poly-Ala peptides with protecting groups has been shown to take place from C-terminal and in peptides without protecting groups opening of helix starts from both terminals. Further, opening of helix takes more time in poly-Ala peptides without terminal protecting groups. The deviations in amide bond planarity have been discussed and compared with available experimental and computational results.

First Human Use of High Dose IV Trehalose: Safety, Tolerability and Pharmacokinetic Results from the Oculopharyngeal Muscular Dystrophy (OPMD) Therapy Trial (P7.068)

First Human Use of High Dose IV Trehalose: Safety, Tolerability and Pharmacokinetic Results from the Oculopharyngeal Muscular Dystrophy (OPMD) Therapy Trial (P7.068)

Mitochondrial dysfunction reveals the role of mRNA poly(A) tail regulation in oculopharyngeal muscular dystrophy pathogenesis.

Oculopharyngeal muscular dystrophy (OPMD), a late-onset disorder characterized by progressive degeneration of specific muscles, results from the extension of a polyalanine tract in poly(A) binding protein nuclear 1 (PABPN1). While the roles of PABPN1 in nuclear polyadenylation and regulation of alternative poly(A) site choice are established, the molecular mechanisms behind OPMD remain undetermined. Here, we show, using Drosophila and mouse models, that OPMD pathogenesis depends on affected poly(A) tail lengths of specific mRNAs. We identify a set of mRNAs encoding mitochondrial proteins that are down-regulated starting at the earliest stages of OPMD progression. The down-regulation of these mRNAs correlates with their shortened poly(A) tails and partial rescue of their levels when deadenylation is genetically reduced improves muscle function. Genetic analysis of candidate genes encoding RNA binding proteins using the Drosophila OPMD model uncovers a potential role of a number of them. We focus on the deadenylation regulator Smaug and show that it is expressed in adult muscles and specifically binds to the down-regulated mRNAs. In addition, the first step of the cleavage and polyadenylation reaction, mRNA cleavage, is affected in muscles expressing alanine-expanded PABPN1. We propose that impaired cleavage during nuclear cleavage/polyadenylation is an early defect in OPMD. This defect followed by active deadenylation of specific mRNAs, involving Smaug and the CCR4-NOT deadenylation complex, leads to their destabilization and mitochondrial dysfunction. These results broaden our understanding of the role of mRNA regulation in pathologies and might help to understand the molecular mechanisms underlying neurodegenerative disorders that involve mitochondrial dysfunction.

A long and winding road to the RNA world.

A long and winding road to the RNA world.

Muscle weakness and speech in oculopharyngeal muscular dystrophy.

We documented speech and voice characteristics associated with oculopharyngeal muscular dystrophy (OPMD). Although it is a rare disease, OPMD offers the opportunity to study the impact of myopathic weakness on speech production in the absence of neurologic deficits in a relatively homogeneous group of speakers. Twelve individuals with OPMD and 12 healthy age-matched controls underwent comprehensive assessment of the speech mechanism including spirometry (respiratory support), nasometry (resonance balance), phonatory measures (pitch, loudness, and quality), articulatory measures (diadochokinetic rates, segment duration measures, spectral moments, and vowel space), tongue-to-palate strength measures during maximal isometric and speechlike tasks, quality-of-life questionnaire, and perceptual speech ratings by listeners. Individuals with OPMD had substantially reduced tongue strength compared to the controls. However, little impact on speech and voice measures or on speech intelligibility was observed except for slower diadochokinetic rates. Despite having less than half the maximal tongue strength of healthy controls, the individuals with OPMD exhibited minimal speech deficits. The threshold of weakness required for noticeable speech impairment may not have been reached by this group of adults with OPMD.

The Epidemiology of Neuromuscular Disorders: A Comprehensive Overview of the Literature

In 1991, the first world survey of neuromuscular disorders (NMDs) was published in the peer reviewed literature. Since then, diagnostics have been greatly improved through genetic confirmation and consensus on criteria. This prompted us to search the scientific literature since 1990 for the epidemiology of NMDs. To study occurrence rates, gender and age distribution. Pubmed was searched for 'epidemiology', 'incidence' and 'prevalence' regarding thirty NMDs for peer reviewed literature from 1990-2014. We found incidence rates for ten disorders, ranging from 0.05 to 9 per 100,000/yr. Most NMDs showed prevalence rates between 1 and 10 per 100,000 population, except for multifocal motor neuropathy, Lambert-Eaton myasthenic syndrome, Emery-Dreifuss dystrophy, oculopharyngeal muscular dystrophy, and congenital muscular dystrophies, which were <1/100,000. Post-polio syndrome and Charcot-Marie-Tooth disease revealed prevalences >10/100,000. Information regarding incidence, prevalence, age distribution and gender was complete for eight disorders. No data were found for chronic inflammatory demyelinating polyneuropathy, neuralgic amyotrophy, progressive spinal muscular atrophy, McArdle's and Pompe's disease. For the 17 remaining disorders, information was partially available. Compared to 1991, prevalence rates of Becker muscular dystrophy, facioscapulohumeral dystrophy, myotonic dystrophy and Charcot-Marie-Tooth disease showed increase, yet with highly overlapping ranges with the exception of myotonic dystrophy. The sum of the available prevalence rates comprises only the tip of the iceberg, but is already in range with the prevalence of Parkinson's disease. Although individual NMDs are rare, as a group they are not.

Ocular findings in muscular dystrophies

Muscular dystrophies are a heterogeneous class of inherited disorders presenting with different clinical, genetic, and biochemical features. Musc ular dystrophies include Duchennemuscular dystrophy (DMD) and Becker muscular dystrophy (BMD) myotonic dystrophy (DM), oculopharyngeal muscular dystrophy (OPMD), facioscapulohumeral muscular dy strophy (FSHD), limb-girdle muscular dystrophy (LGMD), distal muscular dystrophy, and congenital muscular dystrophy (CMD)types, each with a wide spectrum of clinical manifestations. Those muscular dystrophies can have similar symptoms or unique and specific presentations. This abstract will review the prevalence, clinical presentation, and management of ocular findings in certain muscular dystrophies.

Gly→Ala Point Mutation and Conformation of Poly-Ala Stretch of PABPN1: A Molecular Dynamics Study

Single nucleotide replacing mutations in genes cause a number of diseases, but sometimes these mutations mimic other genetic mutations such as trinucleotide repeats expansions. A mutation in codon GGG→GCG results in Gly→Ala at the N-terminal of PABPN1 protein that mimics the trinucleotide repeat expansion disease called Oculopharyngeal muscular dystrophy (OPMD). Molecular dynamics simulations in water with peptide models having sequence Ac-A10-GA2GG-NHme (peptide A) and Ac-A10A3GG-NHme (peptide B) reveal an increase in the length of helical segment in peptide B. The α-helical length is found to be stable in peptide B with starting geometry of a right handed helix, while in the case peptide A, the helical length is short. The interactions of water molecules at terminals, side chain-backbone interactions and hydrogen bonds provide stability to resultant conformation. The adopted helix by the poly-Ala stretch may lead to masking some other active parts of the PABPN1 that may trigger the aggregation, decrease in degradation and/or impaired function of protein. Hence, further studies with N-terminal may be helpful to understand unclear disease mechanism.

60. Dysphagia in different types of myopathy

Oculopharyngeal Muscular Dystrophy (OPMD) is a myopathy characterize by ptosis and marked swallowing impairment. Dysphagia may also occur in some mitochondrial diseases. Previous reports focused on the proximal (skeletal) parts of oesophagus only. We tried to analyse proximal and distal oesophageal function and the role of parasympathetic system and myenteric plexus in such disorders. Four male dysphagic patients, 3 affected by sporadic OPMD and 1 with single mitochondrial DNA deletion and “OMPD- like” phenotype, were studied. Both adrenergic and cholinergic functions of autonomic system were investigated. High resolution manometry with 22 perfused channels was used to assess the oesophageal function. Beside the involvement of the proximal portion of the oesophagus (striated muscle), smooth muscles seemed also to be affected in OPMD patients; normal peristaltic waves were found in only about 50% of swallows. In the patient with mitochondrial DNA deletion absent peristalsis involving both striated and smooth muscle in 100% of swallows was observed. Since autonomic tests were normal in all patients, progressive reduction of peristalsis in the oesophageal distal part could be related to myenteric plexus derangement or to smooth cell muscle disease.

Hip flexion weakness is associated with impaired mobility in oculopharyngeal muscular dystrophy: A retrospective study with implications for trial design

Oculopharyngeal muscular dystrophy (OPMD) is a rare myopathy for which validated outcome measures are lacking, posing a barrier to clinical trials. Our goal was to identify factors associated with impaired mobility in OPMD in order to guide development of surrogate endpoints in future clinical trials. One hundred forty-four individuals with OPMD were included in this retrospective, single-center study. We made novel use of parametric time-to-event analysis to model age at initial use of assistive device for ambulation. We hypothesized that limb weakness and other markers of disease severity are associated with earlier use of assistive devices. 23.6% of individuals (34/144) progressed to use of assistive devices (mean age 66.0 ± 9.6 y). Earlier age at assistive device was associated with hip flexion Medical Research Council grade ≤3 (p < 0.0001), earlier disease onset (p < 0.0001), and lack of blepharoptosis surgery (p = 0.011). Markers of dysphagia severity were not associated with earlier progression to assistive devices. Our study is the first to show a statistical association between hip flexion weakness and impaired mobility in OPMD, indicating that hip flexion strength could be explored as a surrogate endpoint for use in clinical trials. Since severity of disease features may be discordant within individuals, composite outcome measures are warranted.

Oculopharyngeal muscular dystrophy as a paradigm for muscle aging.

Symptoms in late-onset neuromuscular disorders initiate only from midlife onward and progress with age. These disorders are primarily determined by identified hereditable mutations, but their late-onset symptom manifestation is not fully understood. Here, we review recent research developments on the late-onset autosomal dominant oculopharyngeal muscular dystrophy (OPMD). OPMD is caused by an expansion mutation in the gene encoding for poly-adenylate RNA binding protein1 (PABPN1). The molecular pathogenesis for the disease is still poorly understood. Despite a ubiquitous expression of PABPN1, symptoms in OPMD are limited to skeletal muscles. We discuss recent studies showing that PABPN1 levels in skeletal muscles are lower compared with other tissues, and specifically in skeletal muscles, PABPN1 expression declines from midlife onward. In OPMD, aggregation of expanded PABPN1 causes an additional decline in the level of the functional protein, which is associated with severe muscle weakness in OPMD. Reduced PABNPN1 expression in muscle cell culture causes myogenic defects, suggesting that PABPN1 loss-of-function causes muscle weakness in OPMD and in the elderly. Molecular signatures of OPMD muscles are similar to those of normal muscle aging, although expression trends progress faster in OPMD. We discuss a working hypothesis that aging-associated factors trigger late-onset symptoms in OPMD, and contribute to accelerated muscle weakness in OPMD. We focus on the pharyngeal and eyelid muscles, which are often affected in OPMD patients. We suggest that muscle weakness in OPMD is a paradigm for muscle aging.

Ageing and muscular dystrophy differentially affect murine pharyngeal muscles in a region-dependent manner.

Key points Millions of elderly individuals have dysphagia, a debilitating and life‐threatening condition in which the ability to swallow is impaired. Several muscles surround the three regions of the pharynx, which are essential for proper swallowing, yet the effects of ageing and disease on these muscles are not well understood. We demonstrate that the fibre size of murine pharyngeal muscles is differentially affected by ageing and muscular dystrophy depending on their location within the pharynx. Using a mouse model of an age‐associated dysphagic disease (oculopharyngeal muscular dystrophy), we show that overexpression of wild‐type polyadenylate binding nuclear protein 1 in muscle tissue prevents age‐related dysphagia and age‐related muscle atrophy of laryngopharyngeal muscles. These results demonstrate that mice are an excellent model for studying mechanisms of ageing and disease on pharyngeal muscle physiology, and such studies could lead to new therapies for individuals with dysphagia. AbstractThe inability to swallow, or dysphagia, is a debilitating and life‐threatening condition that arises with ageing or disease. Dysphagia results from neurological or muscular impairment of one or more pharyngeal muscles, which function together to ensure proper swallowing and prevent the aspiration of food or liquid into the lungs. Little is known about the effects of age or disease on pharyngeal muscles as a group. Here we show ageing affected pharyngeal muscle growth and atrophy in wild‐type mice depending on the particular muscle analysed. Furthermore, wild‐type mice also developed dysphagia with ageing. Additionally, we studied pharyngeal muscles in a mouse model for oculopharyngeal muscular dystrophy, a dysphagic disease caused by a polyalanine expansion in the RNA binding protein, PABPN1. We examined pharyngeal muscles of mice overexpressing either wild‐type A10 or mutant A17 PABPN1. Overexpression of mutant A17 PABPN1 differentially affected growth of the palatopharyngeus muscle dependent on its location within the pharynx. Interestingly, overexpression of wild‐type A10 PABPN1 was protective against age‐related muscle atrophy in the laryngopharynx and prevented the development of age‐related dysphagia. These results demonstrate that pharyngeal muscles are differentially affected by both ageing and muscular dystrophy in a region‐dependent manner. These studies lay important groundwork for understanding the molecular and cellular mechanisms that regulate pharyngeal muscle growth and atrophy, which may lead to novel therapies for individuals with dysphagia.

Oculopharyngeal muscular dystrophy: phenotypic and genotypic studies in a Chinese population.

Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant late-onset neuromuscular degenerative disease characterized by ptosis, dysphagia, and proximal muscle weakness. The genetic basis has been identified as an abnormal (GCN) expansion encoding the polyalanine tract in exon 1 of the polyadenylate-binding protein nuclear 1 gene (PABPN1). OPMD is worldwide distributed, but has rarely been reported in East Asians. In this study, we summarized the clinical and genetic characteristics of 34 individuals from 13 unrelated families in Chinese population. In our cohort, the mean age at onset was 47.2years. Dysphagia, rather than ptosis, was the most common initial symptom. Genetically, we identified seven genotypes in our patients, including one compound heterozygote of (GCN)11/(GCN)12. The genetic heterogeneity implies that there is no single founder effect in Chinese population, and our data also support that the (GCN)11 polymorphism may have a disease-modifying effect. Additionally, the clinical features showed homogeneity within families, which suggests that other genetic factors apart from the already known genotype also play a role in modifying the phenotype.

Redox Biology Poster Prize Winner P55 - Role of Oxidized Protein Repair in Human Skeletal Muscle

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. Indeed methionine sulfoxide is catalytically reduced back to methionine by the methionine sulfoxide reductase (Msr) system. We showed that this Msr system is involved in cellular protection against oxidative stress by preventing apoptosis and limiting irreversible protein oxidative damage. Furthermore, it has been demonstrated that the Msr system is no longer efficient during ageing and senescence as well as that Msr modulates longevity in animal models. In this work we analysed Msr expression in human skeletal muscle. We showed, using both primary and immortalized skeletal muscle cell lines, that the expression of the Msr system increases during differentiation, suggesting a role of this antioxidant system on myofibres formation. Since myoblasts senescence associated with less differentiation capacity and an abnormal production of ROS have been observed in some muscular dystrophies, we wondered about the state of the Msr system in late-onset myopathies, such as oculopharyngeal muscular dystrophy (OPMD). In OPMD we confirmed, at the transcription level, an increased expression of Msr with differentiation, both on immortalized and primary cell cultures, similarly to what we observed on control cell lines. Our aim is to characterize for the first time the role of a major oxidized protein repair system (Msr) in human skeletal muscle homeostasis and, in particular, in myotubes protection during oxidative stress conditions.

G.P.6: Oculopharyngeal Muscular Dystrophy with PABPN1 mutation in two Chinese Singaporean families

Oculopharyngeal muscular dystrophy (OPMD) is a late-onset autosomal dominant disorder presenting with progressive ptosis and dysphagia, due to GCN trinucleotide repeat in PABPN1 . OPMD is rarely seen in the Far East and genetically confirmed case has not been reported in Singapore. We describe two unrelated Chinese Singaporean families with autosomal dominant OPMD. The first patient, a 67-year-old Chinese, presented with progressive ptosis since age 30 and dysphagia for 5 years. He was initially thought to have a mitochondrial myopathy and muscle biopsy performed did show subtle mitochondrial abnormalities—few ragged red and COX negative fibres—but no rimmed vacuoles. However, in view of possible positive family history of similar condition in his father and paternal grandfather (both diseased), OPMD was suspected and genetic screening was performed, which showed heterozygous expansion of GCN in PABPN1 (13 repeats). The second patient, a 52-year-old Chinese man, had bilateral asymmetrical ptosis for about 10 years and progressive dysphagia for 6 years. He was initially diagnosed to have seronegative myasthenia gravis (MG) based on positive single fibre EMG study. His father, at the age of 75, had also similar presentation and was also diagnosed to have seronegative MG, based on single fibre EMG study. However, his condition did not improve with immunosuppressant and plasmapheresis. Genetic screening for OPMD performed on the proband showed 13 GCN repeats in PABPN1 . This is the first report of Singaporean families of Chinese descent with genetically confirmed OPMD, which may be under diagnosed in Singapore. OPMD can mimic other conditions such as mitochondrial myopathy or MG and hence often misdiagnosed, resulting in unnecessary treatment or procedure. It should be considered in any patient who present with late-onset progressive ptosis and dysphagia. Molecular genetic testing of PABPN1 is recommended for suspected case of OPMD.

G.O.5: Mitochondrial dysfunction reveals defective poly(A) tail regulation of specific mRNAs as a primary defect in oculopharyngeal muscular dystrophy

Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant inherited, slow progressing, late onset degenerative muscular disorder where a small group of specific muscles – pharyngeal and eyelid muscles – are primarily affected, leading to dysphagia and ptosis. Its genetic basis is a trinucleotide repeat expansion ranging from (GCG)8 to (GCG)13 in the N-terminus polyalanine domain of the poly(A) binding protein nuclear 1 (PABPN1) gene. Mutated expanded PABPN1 protein accumulates as insoluble nuclear inclusions in muscles of OPMD patients. While the roles of PABPN1 in nuclear polyadenylation and in the regulation of alternative poly(A) site choice are established, the molecular mechanisms behind OPMD remain undetermined. Using a Drosophila model of OPMD, we found that OPMD pathogenesis depends on affected poly(A) tail length regulation of specific mRNAs. We identified a set of mRNAs encoding mitochondrial proteins that are down-regulated during OPMD progression. Reduced levels of these mRNAs correlate with their shortened poly(A) tails. Partial rescue of the levels of these mRNAs when deadenylation is decreased using a deadenylase mutant improves mitochondrial function and reduces muscle weakness. Interestingly, the down-regulation of these mRNAs already occurs in the earliest stages of disease progression, indicating that this defect is one of the first molecular defects in OPMD. Importantly, the down-regulation of mRNAs encoding mitochondrial proteins has been validated in a transgenic mouse model of OPMD. Moreover, a proteomic approach has also validated the down-regulation of mitochondrial proteins in clinically nonaffected muscles of OPMD patients. We propose a model where one of the primary defect in OPMD corresponds to defective poly(A) tail regulation of specific mRNAs encoding mitochondrial proteins, leading to decreased synthesis of mitochondrial proteins and defective mitochondrial activity.

G.P.7: Longitudinal studies of dysphagia in oculopharyngeal muscular dystrophies

To assess the evolution of dysphagia in patients with oculopharyngeal muscular dystrophy (OPMD). OPMD is an autosomal dominant form of late-onset muscular dystrophy. Ptosis and dysphagia are the most common presenting symptoms. In some reports, patients with OPMD who are homozygotes for two (GCN) expansions in the PABPN1 encoding gene have cognitive impairment and reduced life span. But about dysphagia, few things are known. For about 5years, we followed one patient with (GCN)12 homozygotes and another patient with heterozygotes patient, (GCN)17. In addition to clinical evaluation, psychological tests, brain imaging studies and examination by videofluoroscopy (VF) were performed. OPMD started about age 50 years, with bilateral ptosis and dysphagia; external ophthalmoparesis and dysphonia followed within a few years, as well as weakness in four limb muscles. Maximum tongue pressure were lower than in other reports, 9.7 and 10.6kPa. In VF, laryngeal penetration by water and large amounts of pharyngeal residue by solids were seen. Both patients had recurrent aspirations and lost weight. Second patient required feeding gastrostomies. Both patients showed mild cognitive decline, no depression nor psychotic episodes. Dysphagia in oculopharyngeal muscular dystrophy may also progresses faster in homozygote compared with heterozygote patients. It is important to be careful for dysphagia, as it may lead to reduce life expectancy.

G.P.60: Cytoplasmic 5′-nucleotidase 1A are aggregated in type 2 fiber in sporadic inclusion body myositis

Although sporadic inclusion body myositis (sIBM) is classified as an inflammatory myopathy, it is thought to share common pathophysiology with other neurodegenerative diseases in terms of various aggregated proteins, such as TDP-43, amyloid-β, tau and optineurin. Recently, autoantibody targets Cytoplasmic 5′-nucleotidase 1A (NT5C1A) was identified in sera of sIBM patients, suggesting that NT5C1A is a key molecule in the pathogenesis of sIBM. To realize the impact of NT5C1A on the pathogenesis of sIBM, skeltal muscle biopsy samples of 11 patients with sIBM, 5 with polymyositis, 5 with dermatomyositis, 1 with oculopharyngeal muscular dystrophy and 2 healthy control subjects were histologically examined. In all samples from sIBM patients, NT5C1A aggregated in the cytoplasm and/or plasma membrane in small-sized myofibers which were frequently immunostained with fast-myosin heavy chain, a marker for type 2 muscle fiber. We also observed co-localization of NT5C1A with p62 in the perinuclei of some fibers. These findings suggest that functional and structural alteration of NT5C1A might affect the energy metabolism in the type 2 fibers. Co-localization of NT5C1A with p62 in the perinuclear region may indicate the involvement of deficit in nuclear function and protein degradation, suggesting the role of NT5C1A as a bridge between “inflammation” and “degeneration” in sIBM pathogenesis.

Oculopharyngeal muscular dystrophy with marked clinical fluctuations mimicking myasthenia gravis: A case report

AbstractOculopharyngeal muscular dystrophy is typically characterized by late‐onset, slowly progressive bilateral ptosis and dysphagia. We report a 64‐year‐old Japanese man presenting with ptosis, diplopia and swallowing difficulty. He had consistently complained of significant diurnal fluctuations of clinical symptoms since onset at the age of 53 years. He was diagnosed with seronegative myasthenia gravis, and was treated with an acetylcholinestrase inhibitor for 10 years. On admission, a muscle biopsy was carried out, and the result was mild non‐specific myogenic change. However, gene analysis showed heterogeneous polyalanine expansion in the coding region of poly(A) binding protein nuclear. This case indicates that fluctuating motor signs could accompany muscle weakness in oculopharyngeal muscular dystrophy. Diagnosis might be delayed because of the atypical clinical features and slow symptom progression.