Muscle MRI in Patients With Oculopharyngeal Muscular Dystrophy: A Longitudinal Study

BACKGROUND AND OBJECTIVES: 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. METHODS: 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. RESULTS: 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). DISCUSSION: 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.

Novel Metabolomic Approach for Identifying Pathology-Specific Biomarkers in Rare Diseases: A Case Study in Oculopharyngeal Muscular Dystrophy (OPMD).

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.

Muscle ultrasound is a sensitive biomarker in oculopharyngeal muscular dystrophy.

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.

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.

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.

Muscle MRI in a large cohort of patients with oculopharyngeal muscular dystrophy.

BACKGROUND AND OBJECTIVE: Oculopharyngeal muscular dystrophy (OPMD) is a genetic disorder caused by an abnormal expansion of GCN triplets within the PABPN1 gene. Previous descriptions have focused on lower limb muscles in small cohorts of patients with OPMD, but larger imaging studies have not been performed. Previous imaging studies have been too small to be able to correlate imaging findings to genetic and clinical data. METHODS: We present cross-sectional, T1-weighted muscle MRI and CT-scan data from 168 patients with genetically confirmed OPMD. We have analysed the pattern of muscle involvement in the disease using hierarchical analysis and presented it as heatmaps. Results of the scans were correlated with genetic and clinical data. RESULTS: Fatty replacement was identified in 96.7% of all symptomatic patients. The tongue, the adductor magnus and the soleus were the most commonly affected muscles. Muscle pathology on MRI correlated positively with disease duration and functional impairment. CONCLUSIONS: We have described a pattern that can be considered characteristic of OPMD. An early combination of fat replacement in the tongue, adductor magnus and soleus can be helpful for differential diagnosis. The findings suggest the natural history of the disease from a radiological point of view. The information generated by this study is of high diagnostic value and important for clinical trial development.