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.

Dysphagia in Oculopharyngeal Muscular Dystrophy: A Rapid Scoping Review

Purpose Dysphagia is a common symptom of the rare genetic disease oculopharyngeal muscular dystrophy (OPMD). There are, however, limited resources and recommendations for speech-language pathologists who treat individuals with this condition. This review provides a consolidation of the literature to understand how the components and outcomes of intervention for dysphagia rehabilitation are described and studied in adults with OPMD. Method A rapid scoping review was completed to identify studies related to dysphagia interventions for adults with OPMD. Data were extracted and analyzed through the lens of the Rehabilitation Treatment Specification System and the International Classification of Functioning, Disability and Health frameworks. Results A total of eight studies met the review criteria. Six of the studies described rehabilitative interventions, and three focused on outcomes of intervention. Rehabilitation interventions were not described in detail, and a wide variety of outcome measures were used. Conclusions There is limited research to guide clinical decision-making and intervention for dysphagia rehabilitation in OPMD at this time. Neurodegenerative disorder research may be beneficial in guiding clinical practice. Further research is required to determine the most effective interventions for individuals with OPMD.

Longitudinal Assessment of Strength, Functional Capacity, Oropharyngeal Function, and Quality of Life in Oculopharyngeal Muscular Dystrophy

ObjectiveOculopharyngeal muscular dystrophy (OPMD) is a late-onset, progressive muscle disease. Disease progression is known to be slow, but details on the natural history remain unknown. We aimed to examine the natural history of OPMD in a large nationwide cohort to determine clinical outcome measures that capture disease progression and can be used in future clinical trials.MethodsPatients, invited by their treating physicians or from the national neuromuscular database, and invited family members, were examined twice, 20 months apart, using fixed dynamometry, MRC grading, maximum bite force and isometric tongue strength, Motor Function Measure (MFM), 10-step stair test, maximum swallowing-, chewing-, and speech-tasks and quality of life assessments.ResultsDisease progression was captured by 8 out of 18 measures over 20 months in forty-three genetically confirmed OPMD patients. The largest deterioration was seen in deltoid muscle strength (-27% (range -17 – -37%)), followed by the quadriceps (-14% (range -6 – -23%)), iliopsoas (-12.2%), tongue (-9.9%) and MRC sum-score (-2.5%). The 10-step stair test (-12.5%), MFM part D1 (-7.1%), and maximum repetition rate of /pa/ (-5.3%) showed a significant decrease as well (all p<0.05). Domain ‘Physical functioning’ of the SF-36 Health Survey significantly deteriorated (p=0.044). No relationship was found between disease progression and genotype or disease duration (p>0.05).ConclusionsDespite the slow disease progression of OPMD, this study showed that several outcome measures detected progression within 20 months. The deltoid muscle strength, measured by fixed dynamometry, showed the greatest decline. This longitudinal data provides clinical outcome measures that can be used as biomarkers in future clinical trials.

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.

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

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.

Nutritional Risk in Oculopharyngeal Muscular Dystrophy: Beyond Dysphagia

Purpose: To document the nutritional risk in adults with oculopharyngeal muscular dystrophy (OPMD) and its association with oropharyngeal dysphagia. Methods: In this cross-sectional study, 33 adults with molecular confirmation of OPMD between 50 and 75 years old were recruited from the registry of a university-affiliated neuromuscular clinic. Nutritional risk was assessed with the French version of Seniors in the Community: Risk Evaluation for Eating and Nutrition II (SCREEN II), whereas the severity of dysphagia was assessed using the French-Canadian version of the Sydney Swallow Questionnaire. Anthropometric measurements were performed with standardized procedures. Results: SCREEN II scores showed high nutritional risk for 81.8% of OPMD participants with 6 factors contributing to nutritional risk in at least 50% of the sample. Pearson’s correlational analysis showed a significant moderate relationship between dysphagia and nutritional risk (r = −0.470; P = 0.006). Conclusion: To our knowledge, this study is the first to investigate the nutritional risk of adults with OPMD. Our results indicate that individuals with OPMD may be at high nutritional risk mostly associated with swallowing difficulty, in the absence of a low body mass index. The present study highlights the need for dietary counseling in OPMD.