Objective Oculopharyngeal 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. Methods Patients, 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. Results Disease 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 p0.05). Conclusions Despite 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.

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.

Oculopharyngeal muscular dystrophy (OPMD) is a rare progressive neuromuscular disease. MRI is one of the techniques that is used in neuromuscular disorders to evaluate muscle alterations. The aim of this study was to describe the pattern of fatty infiltration of orofacial and leg muscles using quantitative muscle MRI in a large national cohort and to determine whether MRI can be used as an imaging biomarker of disease progression in OPMD. Patients with OPMD (18 years or older) were invited from the national neuromuscular database or by their treating physicians and were examined twice with an interval of 20 months, with quantitative MRI of orofacial and leg muscles to assess fatty infiltration which were compared with clinical measures. In 43 patients with genetically confirmed OPMD, the muscles that were affected most severely were the tongue (mean fat fraction: 37.0%, SD 16.6), adductor magnus (31.9%; 27.1), and soleus (27.9%; 21.5) muscles. The rectus femoris and tibialis anterior muscles were least severely affected (mean fat fractions: 6.8%; SD 4.7, 7.5%; 5.9). Eleven of 14 significant correlations were found between fat fraction and a clinical task in the corresponding muscles (r = -0.312 to -0.769, CI = -0.874 to -0.005). At follow-up, fat fractions had increased significantly in 17 of the 26 muscles: mean 1.7% in the upper leg muscles (CI = 0.8-2.4), 1.7% (1.0-2.3) in the lower leg muscles, and 1.9% (0.6-3.3) in the orofacial muscles (p < 0.05). The largest increase was seen for the soleus (3.8%, CI = 2.5-5.1). Correlations were found between disease duration and repeat length vs increased fat fraction in 7 leg muscles (r = 0.323 to -0.412, p < 0.05). According to quantitative muscle MRI, the tongue, adductor magnus and soleus show the largest fat infiltration levels in patients with OPMD. Fat fractions increased in several orofacial and leg muscles over 20 months, with the largest fat fraction increase seen in the soleus. This study supports that this technique is sensitive enough to show worsening in fat fractions of orofacial and leg muscles and therefore a responsive biomarker for future clinical trials.

Introduction/Aims: 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.Methods: 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.Results: 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.Discussion: 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.

The identification of metabolomic biomarkers relies on the analysis of large cohorts of patients compared to healthy controls followed by the validation of markers in an independent sample set. Indeed, circulating biomarkers should be causally linked to pathology to ensure that changes in the marker precede changes in the disease. However, this approach becomes unfeasible in rare diseases due to the paucity of samples, necessitating the development of new methods for biomarker identification. The present study describes a novel approach that combines samples from both mouse models and human patients to identify biomarkers of OPMD. We initially identified a pathology-specific metabolic fingerprint in murine dystrophic muscle. This metabolic fingerprint was then translated into (paired) murine serum samples and then to human plasma samples. This study identified a panel of nine candidate biomarkers that could predict muscle pathology with a sensitivity of 74.3% and specificity of 100% in a random forest model. These findings demonstrate that the proposed approach can identify biomarkers with good predictive performance and a higher degree of confidence in their relevance to pathology than markers identified in a small cohort of human samples alone. Therefore, this approach has a high potential utility for identifying circulating biomarkers in rare diseases.

Background: Myotonic dystrophy type 1 (DM1) is a heterogeneous neuromuscular disorder characterized by progressive muscle weakness and myotonia. Dysarthria is a known symptom of DM1, but literature is lacking about the patient's own perception in relationship to dysarthria characteristics and severity. Aims: The aim of the study was to describe the acoustic speech characteristics of dysarthria in patients with DM1, examine the perceptually determined dysarthria severity through speech and language therapy assessment, gather subjective evaluations of speech and intelligibility from patients and relatives and examine the relationship between these outcomes. Methods and Procedures: The speech of 22 adult patients with DM1 (nine females) was acoustically assessed during spontaneous speech, reading, and maximum performance tasks and analysed using the Praat‐software. Dysarthria severity was rated on a severity scale from 0 (no dysarthria) – 5 (very severe dysarthria/anarthria). Patients and relatives rated the speech with a short questionnaire and a visual analogue scale (VAS). Outcomes and Results: Acoustic analysis showed a deviant speech rate (SR), articulation rate (AR), maximum phonation volume (MPV), and fundamental frequency range compared to normative values. Perceptually, the dysarthria severity scores varied between 1 (minimal dysarthria) and 4 (severe dysarthria). In more severe dysarthria, SR, AR, and MPV decreased. Patients were sufficiently satisfied about their speech, with no relationship to dysarthria severity. However, the scores of relatives decreased when perceptual dysarthria severity increased. Conclusion and Implications: As dysarthria severity increased, speech quality and intelligibility declined, particularly when assessed by speech therapists and relatives. Patients with DM1 generally reported minimal conversational restrictions due to dysarthria. Multidimensional measurements may improve the understanding of speech impairment in DM1. Self‐awareness should be a topic in speech therapy interventions. WHAT THIS PAPER ADDS: What is already known on this subject Dysarthria is a common symptom in myotonic dystrophy type 1 (DM1). Research has focused on articulatory accuracy and SR. Cognitive decline in patients with DM1 is known to reduce illness insight in approximately half of the cases. However, its impact on self‐awareness of dysarthria, and how this compares to perceptions of relatives and speech therapists, had not been investigated prior to this study. The combination of acoustic and perceptual speech measures with patients’ own perspectives provides new knowledge of speech monitoring in DM1. What this study adds to existing knowledge This is the first study to investigate speech in patients with DM1 using both acoustic and perceptual analyses, while simultaneously examining the relationship with patients’ self‐awareness of their speech impairments. The results of this study show a relationship between increasing perceptual dysarthria severity and decreasing acoustic speech performance. Patients often rate their own speech more optimistically than relatives and speech therapists, which suggests a possible role of neuropsychological impairment in reduced self‐awareness of speech deficits in DM1, warranting further research. What are the potential or actual clinical implications of this study? The integration of acoustic and perceptual speech assessment allows an objective and accurate diagnosis of dysarthria in DM1. Speech therapy should focus on improving speech clarity and intelligibility by developing exercises for articulatory precision and respiratory control. The discrepancy between how patients perceive their own speech and the opinion of clinicians and relatives suggests that speech therapists may need to focus on raising awareness of the dysarthria and actively involve relatives in the therapeutic process.