Oculopharyngeal Muscular Dystrophy Patients Research Articles

Eye Muscle MRI in Myasthenia Gravis and Other Neuromuscular Disorders.

MRI of extra-ocular muscles (EOM) in patients with myasthenia gravis (MG) could aid in diagnosis and provide insights in therapy-resistant ophthalmoplegia. We used quantitative MRI to study the EOM in MG, healthy and disease controls, including Graves' ophthalmopathy (GO), oculopharyngeal muscular dystrophy (OPMD) and chronic progressive external ophthalmoplegia (CPEO). Twenty recently diagnosed MG (59±19yrs), nineteen chronic MG (51±16yrs), fourteen seronegative MG (57±9yrs) and sixteen healthy controls (54±13yrs) were included. Six CPEO (49±14yrs), OPMD (62±10yrs) and GO patients (44±12yrs) served as disease controls. We quantified muscle fat fraction (FF), T2water and volume. Eye ductions and gaze deviations were assessed by synoptophore and Hess-charting. Chronic, but not recent onset, MG patients showed volume increases (e.g. superior rectus and levator palpebrae [SR+LPS] 985±155 mm3 compared to 884±269 mm3 for healthy controls, p < 0.05). As expected, in CPEO volume was decreased (e.g. SR+LPS 602±193 mm3, p < 0.0001), and in GO volume was increased (e.g. SR+LPS 1419±457 mm3, p < 0.0001). FF was increased in chronic MG (e.g. medial rectus increased 0.017, p < 0.05). In CPEO and OPMD the FF was more severely increased. The severity of ophthalmoplegia did not correlate with EOM volume in MG, but did in CPEO and OPMD. No differences in T2water were found. We observed small increases in EOM volume and FF in chronic MG compared to healthy controls. Surprisingly, we found no atrophy in MG, even in patients with long-term ophthalmoplegia. This implies that even long-term ophthalmoplegia in MG does not lead to secondary structural myopathic changes precluding functional recovery.

Frequency and type of cancers in myotonic dystrophy: A retrospective cross-sectional study.

Myotonic dystrophies (DMs) are autosomal dominant diseases in which expression of a mutant expanded repeat mRNA leads to abnormal splicing of downstream effector genes thought to be responsible for their multisystem involvement. Cancer risk and cancer-related deaths are increased in DM patients relative to the general population. We aimed at determining the frequency and type of cancers in both DM1 and DM2 vs a non-DM muscular dystrophy cohort. A retrospective, cross-sectional study was carried out on patients with genetically confirmed DM1, DM2, facioscapulohumeral muscular dystrophy (FSHD), and oculopharyngeal muscular dystrophy (OPMD) at our institutions from 2000 to 2020. One hundred eighty-five DM1, 67 DM2, 187 FSHD, and 109 OPMD patients were included. Relative to non-DM, DM patients had an increased cancer risk that was independent of age and sex. Specifically, an increased risk of sex-related (ovarian) and non-sex-related (non-melanoma skin, urological, and hematological) cancers was observed in DM1 and DM2, respectively. The length of CTG repeat expansion was not associated with cancer occurrence in the DM1 group. In addition to current consensus-based care recommendations, our findings prompt consideration of screening for skin, urological, and hematological cancers in DM2 patients, and screening of ovarian malignancies in DM1 female patients.

Assessment of PABPN1 nuclear inclusions on a large cohort of patients and in a human xenograft model of oculopharyngeal muscular dystrophy

Oculopharyngeal muscular dystrophy (OPMD) is a rare muscle disease characterized by an onset of weakness in the pharyngeal and eyelid muscles. The disease is caused by the extension of a polyalanine tract in the Poly(A) Binding Protein Nuclear 1 (PABPN1) protein leading to the formation of intranuclear inclusions or aggregates in the muscle of OPMD patients. Despite numerous studies stressing the deleterious role of nuclear inclusions in cellular and animal OPMD models, their exact contribution to human disease is still unclear. In this study, we used a large and unique collection of human muscle biopsy samples to perform an in-depth analysis of PABPN1 aggregates in relation to age, genotype and muscle status with the final aim to improve our understanding of OPMD physiopathology. Here we demonstrate that age and genotype influence PABPN1 aggregates: the percentage of myonuclei containing PABPN1 aggregates increases with age and the chaperone HSP70 co-localize more frequently with PABPN1 aggregates with a larger polyalanine tract. In addition to the previously described PRMT1 and HSP70 co-factors, we identified new components of PABPN1 aggregates including GRP78/BiP, RPL24 and p62. We also observed that myonuclei containing aggregates are larger than myonuclei without. When comparing two muscles from the same patient, a similar amount of aggregates is observed in different muscles, except for the pharyngeal muscle where fewer aggregates are observed. This could be due to the peculiar nature of this muscle which has a low level of PAPBN1 and contains regenerating fibers. To confirm the fate of PABPN1 aggregates in a regenerating muscle, we generated a xenograft model by transplanting human OPMD muscle biopsy samples into the hindlimb of an immunodeficient mouse. Xenografts from subjects with OPMD displayed regeneration of human myofibers and PABPN1 aggregates were rapidly present—although to a lower extent-after muscle fiber regeneration. Our data obtained on human OPMD samples add support to the dual non-exclusive models in OPMD combining toxic PABPN1 intranuclear inclusions together with PABPN1 loss of function which altogether result in this late-onset and muscle selective disease.

P.79 Late onset oculopharyngeal muscular dystrophy in a POLG1-related progressive external ophthalmoplegia (PEO), a diagnostic challenge

POLG1, a nuclear gene, encodes the catalytic subunit of mitochondrial DNA polymerase γ involved in mtDNA maintenance. Autosomal dominant or recessive inherited phenotypes related to POLG1 mutations display clinical variability, including isolated or syndromic progressive external ophthalmoplegia (PEO). Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset autosomal dominant myopathy characterized by progressive ptosis, dysphagia, and limb weakness. In OPMD patients, the 5’ (GCN)10 repeat region of the PABPN1 gene is abnormally expanded up to 17 repeats. The (GCN)11 enlarged repeat allele is described as a polymorphism or a recessive allele. However, rare cases of patients with a single (GCN)11 heterozygous allele are known to express a late-onset OPMD phenotype. Reporting a patient associating POLG1 compound heterozygous mutations and a PABPN1 (GCN)11 heterozygous expansion with mixed phenotype, we aim to point out the potential clinical overlap and diagnostic challenge linked to these entities. A 74-year-old male patient presented with progressive bilateral ptosis and mild dysphagia at the age of 70. CK and lactate levels were normal. Electrodiagnostic tests demonstrated a mild sensory neuropathy and muscle biopsy showed atrophic and necrotic fibers, increased internal nuclei and twelve COX-negative fibers. Electron microscopy identified electrodense deposits in mitochondria but no intranuclear inclusions. Muscle oxidative phosphorylation analyses demonstrated complexes I and II diminished activities. POLG1 sequencing revealed the previously described c.1760C>T, p.(Pro587Leu) pathogenic variant and the c.233T>A, p.(Met78Lys) novel variant. Segregation study allowed to conclude a trans conformation in the proband. We report a patient presenting with progressive ptosis associated with two potential coexisting etiologies ascertained by polemic evidence. On one hand, biallelic variants were found on his POLG1 gene, associated with features of mitochondrial defects on muscle biopsy. On the other hand, the phenotype also fits with OPMD and is associated with a PABPN1 (GCN)11 heterozygous expansion allele. This peculiar observation illustrates the potential diagnostic challenge that may represent a progressive ptosis, especially in elderly patients. POLG1, a nuclear gene, encodes the catalytic subunit of mitochondrial DNA polymerase γ involved in mtDNA maintenance. Autosomal dominant or recessive inherited phenotypes related to POLG1 mutations display clinical variability, including isolated or syndromic progressive external ophthalmoplegia (PEO). Oculopharyngeal muscular dystrophy (OPMD) is an adult-onset autosomal dominant myopathy characterized by progressive ptosis, dysphagia, and limb weakness. In OPMD patients, the 5’ (GCN)10 repeat region of the PABPN1 gene is abnormally expanded up to 17 repeats. The (GCN)11 enlarged repeat allele is described as a polymorphism or a recessive allele. However, rare cases of patients with a single (GCN)11 heterozygous allele are known to express a late-onset OPMD phenotype. Reporting a patient associating POLG1 compound heterozygous mutations and a PABPN1 (GCN)11 heterozygous expansion with mixed phenotype, we aim to point out the potential clinical overlap and diagnostic challenge linked to these entities. A 74-year-old male patient presented with progressive bilateral ptosis and mild dysphagia at the age of 70. CK and lactate levels were normal. Electrodiagnostic tests demonstrated a mild sensory neuropathy and muscle biopsy showed atrophic and necrotic fibers, increased internal nuclei and twelve COX-negative fibers. Electron microscopy identified electrodense deposits in mitochondria but no intranuclear inclusions. Muscle oxidative phosphorylation analyses demonstrated complexes I and II diminished activities. POLG1 sequencing revealed the previously described c.1760C>T, p.(Pro587Leu) pathogenic variant and the c.233T>A, p.(Met78Lys) novel variant. Segregation study allowed to conclude a trans conformation in the proband. We report a patient presenting with progressive ptosis associated with two potential coexisting etiologies ascertained by polemic evidence. On one hand, biallelic variants were found on his POLG1 gene, associated with features of mitochondrial defects on muscle biopsy. On the other hand, the phenotype also fits with OPMD and is associated with a PABPN1 (GCN)11 heterozygous expansion allele. This peculiar observation illustrates the potential diagnostic challenge that may represent a progressive ptosis, especially in elderly patients.

Muscle ultrasound is a sensitive biomarker in oculopharyngeal muscular dystrophy.

Oculopharyngeal muscular dystrophy (OPMD) is a late-onset, progressive muscle disease. Quantitative muscle ultrasound (QMUS) assesses structural changes in muscles and is a sensitive biomarker in neuromuscular disorders. Our aim of this study was to determine whether QMUS can detect muscle pathology and can be used as longitudinal imaging biomarker in OPMD. Genetically confirmed OPMD patients, recruited by their treating physicians or from the national neuromuscular database, were examined twice, 20 months apart, using QMUS of orofacial and limb muscles, and measurements of functional capacity and muscle strength. Absolute echo intensity (AEI) and muscle thickness of all muscles were analyzed and correlated with clinical data. The tongue, deltoid, iliopsoas, rectus femoris, and soleus muscles showed increased AEI at baseline compared with normal values in 43 OPMD patients, with the rectus femoris being most often affected (51%).The AEI and muscle thickness of 9 of 11 muscles correlated significantly with the motor function measure, 10-step stair test, swallowing capacity, dynamometry, Medical Research Council grade, tongue strength, and bite force (r=0.302 to -0.711). Between baseline and follow-up, deterioration in AEI was found for the temporalis, tongue, and deltoid muscles, and decreased muscle thickness was detected for the temporalis, masseter, digastric, tongue, deltoid, iliopsoas, and soleus muscles (P< .05). No relation was found between the change in AEI and repeat length or disease duration. QMUS detected muscle pathology and disease progression in OPMD over 20 months. We conclude that QMUS should be considered as a biomarker in treatment trials.

Clinical and genetic features of a large homogeneous cohort of oculopharyngeal muscular dystrophy patients from the Canary Islands.

Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant, late-onset myopathy characterized by ptosis, dysphagia, and progressive proximal limb muscle weakness. The disease is produced by a short expansion of the (GCN)n triplet in the PABPN1 gene. The size of expansion has been correlated to the disease onset and severity. We report the clinical features of a large cohort of OPMD patients harboring the (GCN)15 allele from the Canary Islands. A retrospective observational study was performed analyzing the clinical, demographic, and genetic data of 123 OPMD patients. Clinical data from this cohort were compared with clinical data collected in a large European study including 139 OPMD patients. A total of 113 patients (94.2%) carried the (GCN)15 expanded PABN1 allele. Age of symptoms' onset was 45.1years. The most frequent symptom at onset was ptosis (85.2%) followed by dysphagia (12%). The severity of the disease was milder in the Canary cohort compared to European patients as limb weakness (35.1% vs. 50.4%), the proportion of patients that require assistance for walking or use a wheelchair (9.3% vs. 27.4%), and needed of surgery because of severe dysphagia (4.6% vs. 22.8%) was higher in the European cohort. Nearly 95% of patients with OPMD from the Canary Islands harbored the (GCN)15 expanded allele supporting a potential founder effect. Disease progression seemed to be milder in the (GCN)15 OPMD Canary cohort than in other cohorts with shorter expansions suggesting that other factors, apart from the expansion size, could be involved in the progression of the disease.

Patulous Eustachian Tube Patients With Oculopharyngeal Muscular Dystrophy.

To describe cases of patulous Eustachian tube (PET) or patent ET conditions in oculopharyngeal muscular dystrophy (OPMD). Four cases of PET or patent ET conditions with OPMD. Clinical case records, objective ET function tests (tubo-tympano-aerodynamic graphy and sonotubometry), and swallowing function (videoendoscopic examination and Food Intake Level Scale) were analyzed. Two cases of definite PET, one case of possible PET, and one case lacking aural symptoms with findings of patent ET. All patients have ptosis, and three cases have dysphagia. Body mass index indicated that three cases were underweight. Magnetic resonance imaging in case 4 showed atrophy and fat replacement of palatine and masticatory muscles. It is important to consider PET or patent ET conditions when OPMD patients describe aural symptoms.

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

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.

Behavioural Impairment and Frontotemporal Dementia in Oculopharyngeal Muscular Dystrophy.

Some patients with Oculopharyngeal Muscular Dystrophy (OPMD) develop frontotemporal dementia (FTD). The prevalence and clinical correlates of behavioural impairment, including FTD, is unknown in OPMD.24 OPMD patients and their proxies completed a questionnaire concerning behavioural impairment (ALS-FTD-Q). We examined proportions with mild or severe behavioural changes, according to validated cut-off proxy scores. We examined correlations with the Hospital Anxiety and Depression Scale (HADS), the Short Form Health Survey (SF-36), motor symptoms, genotype and disease duration.In this small patient sample, behavioural impairment was present in 29%of OPMD patients; in 17%the severity of symptoms was compatible with bvFTD. Correlations were small to medium.

Transillumination Assisted Cricopharyngeal Myotomy.

Cricopharyngeal muscle myotomy (CPM) is a common intervention for relief of dysphagia in patients with Oculo-pharyngeal muscular dystrophy (OPMD). Because of difficulties in approaching and dissecting cricopharyngeal muscle in these patients, we used transillumination for the myotomy (TA-CPM). Transillumination is a simple technique to improve the guidance and navigation of the surgeon in determining the location and depth of myotomy. The purpose of this study is to evaluate the efficacy and safety of transillumination in CPM in OPMD patients. An observational cohort of patients with OPMD who underwent CPM due to dysphagia at one medical center between 2010 and 2019. Two groups of patients are included, according to whether transillumination was used during their surgery. Patients were evaluated before and after surgery (1week and 1month) for their dysphagia score with a standardized questionnaire. The surgical team preferences, experience and complexity with and without transillumination were evaluated. Ten OPMD patients (8 heterozygotes, 2 homozygotes for the commonmutation) underwent CPM for relieving dysphagia symptoms at medium size medical center in Israel between 2010 and 2019. Five patients had TA-CPM and the 5 patients had CPM without transillumination. All patients showed an improvement at follow-up examinations, 1week and 1month postoperative, including a decrease in dysphagia score and in choking and aspiration events, compared to their preoperative state. TA-CPM improved the surgical approach, reduced the difficulty of CPM and was preferred by the surgical team. From the patients' point of view, TA-CPM was as good as a non-transillumination approach in improving dysphagia. TA-CPM is a cheap, fast and simple technique to improve the surgical outcomes in CPM for patients with OPMD. TA-CPM navigates the surgeon, helps with anatomical orientation, improve the surgeon's comfortable, may shorten the duration of surgery and reduces potential errors. Improvement in dysphagia score was similar in both groups. This technique may improve myotomy procedures for dysphagia of other etiologies. IV. Case series (with or without comparison). Endoscopic transillumination assisted myotomy.

FSHD / OPMD / MYOTONIC DYSTROPHY: P.240 Targeting unfolded protein response to resolve aggresomes accumulation in oculopharyngeal muscular dystrophy

Oculopharyngeal muscular dystrophy (OPMD) is a rare late-onset genetic myopathy, affecting mainly eyelid and pharyngeal muscles leading to ptosis and dysphagia, respectively. OPMD is caused by a mutation in Poly-A Binding Protein Nuclear 1 (PABPN1) gene, that codes for a protein essential for proper mRNA biogenesis in nucleus. Accordingly, mutated PABPN1 in OPMD results in PABPN1 intranuclear aggregates in muscle that sequestrate mRNA and proteins and thus induce a wide range of deleterious consequences on muscle homeostasis (mitochondrial dysfunctions, calcium homeostasis disruption, fibrosis, force impairment, atrophy). We previously demonstrated that mouse model of OPMD presents muscle Endoplasmic Reticulum (ER) stress, i.e. an accumulation of misfolded proteins in ER lumen, and that restoring the physiological and resolutive Unfolded Protein Response (UPR) through guanabenz acetate treatment is efficient to decrease PABPN1 nuclear aggregates and improve muscle function in OPMD mouse (Malerba et al Hum Mol Genet 2019). To validate these results in human, we now analyze muscle biopsies from OPMD patients compared to healthy donors and observe a disruption of both key genes and proteins of UPR signalling in OPMD muscles. Interestingly, we find that the alteration is positively correlated with the clinical state of the muscle. Furthermore, we detect GRP78 (BiP), the most important ER chaperone, trapped in PABPN1 nuclear aggregates, suggesting a reduced folding capacity in ER. As a consequence, OPMD muscles present an accumulation of large beta-sheet protein aggregates called aggresomes. Consistently, we observe that human OPMD myoblasts are more sensible to develop aggresomes than healthy myoblasts in response to ER stress. Overall, our results unravel an impairment of ER folding and UPR as well as an aggresomes accumulation in human OPMD muscle. Thus, restoring the protein folding in ER as well as improving the aggresomes clearance could be a promising therapeutic strategy against OPMD.

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

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.

Age-Associated Salivary MicroRNA Biomarkers for Oculopharyngeal Muscular Dystrophy.

Small non-coding microRNAs (miRNAs) are involved in the regulation of mRNA stability. Their features, including high stability and secretion to biofluids, make them attractive as potential biomarkers for diverse pathologies. This is the first study reporting miRNA as potential biomarkers for oculopharyngeal muscular dystrophy (OPMD), an adult-onset myopathy. We hypothesized that miRNA that is differentially expressed in affected muscles from OPMD patients is secreted to biofluids and those miRNAs could be used as biomarkers for OPMD. We first identified candidate miRNAs from OPMD-affected muscles and from muscles from an OPMD mouse model using RNA sequencing. We then compared the OPMD-deregulated miRNAs to the literature and, subsequently, we selected a few candidates for expression studies in serum and saliva biofluids using qRT-PCR. We identified 126 miRNAs OPMD-deregulated in human muscles, but 36 deregulated miRNAs in mice only (pFDR < 0.05). Only 15 OPMD-deregulated miRNAs overlapped between the in humans and mouse studies. The majority of the OPMD-deregulated miRNAs showed opposite deregulation direction compared with known muscular dystrophies miRNAs (myoMirs), which are associated. In contrast, similar dysregulation direction was found for 13 miRNAs that are common between OPMD and aging muscles. A significant age-association (p < 0.05) was found for 17 OPMD-deregulated miRNAs (13.4%), whereas in controls, only six miRNAs (1.4%) showed a significant age-association, suggesting that miRNA expression in OPMD is highly age-associated. miRNA expression in biofluids revealed that OPMD-associated deregulation in saliva was similar to that in muscles, but not in serum. The same as in muscle, miRNA expression levels in saliva were also found to be associated with age (p < 0.05). Moreover, the majority of OPMD-miRNAs were found to be associated with dysphagia as an initial symptom. We suggest that levels of specific miRNAs in saliva can mark muscle degeneration in general and dysphagia in OPMD.

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

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. The aim of this study was to systematically investigate oropharyngeal functioning in a large OPMD population. 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. 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). 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.

Severe Ocular Complications After Blepharoptosis Correction in the Oculopharyngeal Muscular Dystrophy Patient: Literature Review and Case Presentation.

Blepharoptosis correction in oculopharyngeal muscular dystrophy (OPMD) patients may result in severe ocular complications owing to lagophthalmos and ophthalmoplegia. Managing the acute episode to prevent further aggravation of the keratopathy or blindness is of paramount importance. A review of the literature for severe chemosis, keratopathy, and corneal ulceration in the patient population was performed using the PubMed database, with key words including ptosis surgery, ptosis correction, ptosis repair, and oculopharyngeal muscular dystrophy. A retrospective review of all patients with blepharoptosis from a single surgeon from September 2009 and May 2017 was performed, selecting those with OPMD who underwent blepharoptosis correction. Our literature review revealed a total of 15 articles after excluding repeated articles and selecting those meeting our inclusion criteria. A total of 232 OPMD patients underwent blepharoptosis correction. Severe ocular complications were noted in 7 patients, with treatment unspecified. For 9 years, 2 OPMD patients at our institute underwent blepharoptosis correction, with one developing severe acute keratitis, chemosis, and corneal ulceration due to lagophthalmos and ophthalmoplegia. Use of the temporary drawstring tarsorrhaphy and topical eye drop treatment for 2 weeks led to resolution of corneal ulcerations without necessitating further intervention. Severe ocular complications may occur after blepharoptosis correction in OPMD patients, potentially owing to lagophthalmos and ophthalmoplegia. Temporary drawstring tarsorrhaphy is an effective option to treat these adverse outcomes.

Pharmacological modulation of the ER stress response ameliorates oculopharyngeal muscular dystrophy.

Oculopharyngeal muscular dystrophy (OPMD) is a rare late onset genetic disease leading to ptosis, dysphagia and proximal limb muscles at later stages. A short abnormal (GCN) triplet expansion in the polyA-binding protein nuclear 1 (PABPN1) gene leads to PABPN1-containing aggregates in the muscles of OPMD patients. Here we demonstrate that treating mice with guanabenz acetate (GA), an FDA-approved antihypertensive drug, reduces the size and number of nuclear aggregates, improves muscle force, protects myofibers from the pathology-derived turnover and decreases fibrosis. GA targets various cell processes, including the unfolded protein response (UPR), which acts to attenuate endoplasmic reticulum (ER) stress. We demonstrate that GA increases both the phosphorylation of the eukaryotic translation initiation factor 2α subunit and the splicing of Xbp1, key components of the UPR. Altogether these data show that modulation of protein folding regulation is beneficial for OPMD and promote the further development of GA or its derivatives for treatment of OPMD in humans. Furthermore, they support the recent evidences that treating ER stress could be therapeutically relevant in other more common proteinopathies.

Diagnostics of short tandem repeat expansion variants using massively parallel sequencing and componential tools

Short tandem repeats (STRs) are scattered throughout the human genome. Some STRs, like trinucleotide repeat expansion (TRE) variants, cause hereditable disorders. Unambiguous molecular diagnostics of TRE disorders is hampered by current technical limitations imposed by traditional PCR and DNA sequencing methods. Here we report a novel pipeline for TRE variant diagnosis employing the massively parallel sequencing (MPS) combined with an opensource software package (FDSTools), which together are designed to distinguish true STR sequences from STR sequencing artifacts. We show that this approach can improve TRE diagnosis, such as Oculopharyngeal muscular dystrophy (OPMD). OPMD is caused by a trinucleotide expansion in the PABPN1 gene. A short GCN expansion, (GCN[10]), coding for a 10 alanine repeat is not pathogenic, but an alanine expansion is pathogenic. Applying this novel procedure in a Dutch OPMD patient cohort, we found expansion variants from GCN[11] to GCN[16], with the GCN[16] as the most abundant variant. The repeat expansion length did not correlate with clinical features. However, symptom severity was found to correlate with age and with the initial affected muscles, suggesting that aging and muscle-specific factors can play a role in modulating OPMD.

Involvement of pelvic girdle and proximal leg muscles in early oculopharyngeal muscular dystrophy

Although limb girdle weakness is not part of the major diagnostic criteria of oculopharyngeal muscular dystrophy (OPMD), it has frequently been observed in the Dutch and other OPMD cohorts. In the Dutch cohort, this might be related to the relatively old age or the severity of the genetic defect. This patient-control study (14 OPMD patients and 12 controls) investigated the involvement of limb girdle muscles with a multidimensional approach in early OPMD. We assessed functional abilities, disease impact, physical activity, muscle strength, histopathology and fatty infiltration using questionnaires, actometer, functional tests, manual and quantitative muscle testing, muscle biopsy and muscle MRI. The study showed that involvement of pelvic girdle and proximal leg can be a relatively early feature of OPMD, resulting in impaired daily life activities. The fat fraction of the hip adductors and hamstrings was significantly higher in OPMD patients than in controls. Future studies should include assessment of hip flexors, hip adductors and hamstrings (muscle strength measurements and MRI), functional tests and questionnaires. These findings are important in future diagnostics, management and for the design of outcome measures in trials.

P.354 - Nuclear PABPN1 aggregates in OPMD: correlation study and therapy

Oculopharyngeal muscular dystrophy (OPMD) is a rare late onset genetic disease manifested primarily by progressive weakness of the eyelid and pharyngeal muscles, leading to ptosis and dysphagia. A short abnormal triplet expansion in the polyA-binding protein nuclear 1 (PABPN1) gene leads to the accumulation of nuclear insoluble aggregates in muscles of OPMD patients. While the roles of PABPN1 in post-transcriptional gene regulation are established, the molecular basis of OPMD and the exact contribution of these PABPN1 aggregates remain poorly understood. We are currently investigating the role they might have in the pathology, searching triggers that induce their formation, and testing drugs to remove them. Using a large collection of OPMD patient's muscle biopsies, we are evaluating the percentage, size and characteristics of these aggregates using immunofluorescent and electronic microscopy. Any potential correlation of these parameters with age and genotype is carefully monitored. Results obtained so far suggest an increase in the percentage of nuclear aggregates together with age. Although there are controversies regarding the role of aggregates in OPMD, it is commonly accepted that aggregates and/or the early oligomeric species are toxic (Abu-Baker et al., 2013; Davies et al., 2006). Decreasing their number in OPMD models greatly ameliorate the muscle phenotype. Within the frame of an European OPMD network, we are testing drugs to reduce aggregate formation. Among them, guanabenz acetate (GA) has been identified as a good candidate in drosophila OPMD model (Barbezier et al., 2011). Here we show that GA is also efficient in cell and mouse OPMD models: treatment with GA decreases the percentage of nuclear aggregates and ameliorates muscle strength and atrophy in mice. Altogether these studies will shed light on the exact contribution of aggregate in OPMD and help design potential therapeutic targets.

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OBJECTIVES/SPECIFIC AIMS: Oculopharyngeal muscular dystrophy (OPMD) is a rare, late-onset muscular dystrophy that causes severe swallowing impairment (dysphagia). Although promising therapies are in the pipeline, validated dysphagia outcome measures for use in OPMD trials have not been established. Videofluoroscopic swallow studies (VFSS) are considered the clinical gold standard for dysphagia assessment, yet the optimal objective measure of VFSS in OPMD is not known. Our aim was to investigate the utility of the Modified Barium Swallow Impairment Profile (MBSImP) as an objective measure of VFSS in OPMD patients. METHODS/STUDY POPULATION: This was a single-center, prospective, cross-sectional study. In total, 26 individuals with OPMD underwent VFSS and other measures of dysphagia including 50-mL water swallow time (ST). Validity was assessed by examining correlations with an OPMD Global Severity Score (GSS) and with dysphagia duration. RESULTS/ANTICIPATED RESULTS: The MBSImP demonstrated moderate correlations with GSS (Pearson r=0.52, p=0.006) and ST (r=0.39, p=0.049). The relationship between MBSImP and dysphagia duration appeared nonlinear, and levelled off with long dysphagia duration. In contrast, ST did not correlate significantly with GSS (r=0.27, p=0.18), nor with disease duration (r=0.05, p=0.83). DISCUSSION/SIGNIFICANCE OF IMPACT: Objective measurement of VFSS is a promising outcome measure in OPMD. With long disease duration, the MBSImP may not be sufficiently sensitive to detect disease progression. More sensitive measures for scoring dysphagia severity on VFSS should be explored for application to future s of OPMD.