Clinical improvement of DM1 patients reflected by reversal of disease-induced gene expression in blood

Background: Myotonic dystrophy type 1 (DM1) is an incurable multisystem disease caused by a CTG-repeat expansion in the DM1 protein kinase (DMPK) gene. The OPTIMISTIC clinical trial demonstrated positive and heterogenous effects of cognitive behavioral therapy (CBT) on the capacity for activity and social participations in DM1 patients. Through a process of reverse engineering, this study aims to identify druggable molecular biomarkers associated with the clinical improvement in the OPTIMISTIC cohort. Methods: Based on full blood samples collected during OPTIMISTIC, we performed paired mRNA sequencing for 27 patients before and after the CBT intervention. Linear mixed effect models were used to identify biomarkers associated with the disease-causing CTG expansion and the mean clinical improvement across all clinical outcome measures. Results: We identified 608 genes for which their expression was significantly associated with the CTG-repeat expansion, as well as 1176 genes significantly associated with the average clinical response towards the intervention. Remarkably, all 97 genes associated with both returned to more normal levels in patients who benefited the most from CBT. This main finding has been replicated based on an external dataset of mRNA data of DM1 patients and controls, singling these genes out as candidate biomarkers for therapy response. Among these candidate genes were DNAJB12, HDAC5, and TRIM8, each belonging to a protein family that is being studied in the context of neurological disorders or muscular dystrophies. Across the different gene sets, gene pathway enrichment analysis revealed disease-relevant impaired signaling in, among others, insulin-, metabolism-, and immune-related pathways. Furthermore, evidence for shared dysregulations with another neuromuscular disease, Duchenne muscular dystrophy, was found, suggesting a partial overlap in blood-based gene dysregulation. Conclusions: DM1-relevant disease signatures can be identified on a molecular level in peripheral blood, opening new avenues for drug discovery and therapy efficacy assessments.</p

Group medical appointments for people with physical illness

This is the protocol for a review and there is no abstract. The objectives are as follows: To assess the effects of group medical appointments (GMAs) on the health status and well-being of patients with a primary physical illness as compared to one-to-one patient-clinician appointments

Lower extremity muscle pathology in myotonic dystrophy type 1 assessed by quantitative MRI

Objective: To determine the value of quantitative MRI in providing imaging biomarkers for disease in 20 different upper and lower leg muscles of patients with myotonic dystrophy type 1 (DM1). Methods: We acquired images covering these muscles in 33 genetically and clinically well-characterized patients with DM1 and 10 unaffected controls. MRIs were recorded with a Dixon method to determine muscle fat fraction, muscle volume, and contractile muscle volume, and a multi-echo spin-echo sequence was used to determine T2 water relaxation time (T2water), reflecting putative edema. Results: Muscles in patients with DM1 had higher fat fractions than muscles of controls (15.6 ± 11.1% vs 3.7 ± 1.5%). In addition, patients had smaller muscle volumes (902 ± 232 vs 1,097 ± 251 cm3), smaller contractile muscle volumes (779 ± 247 vs 1,054 ± 246 cm3), and increased T2water (33.4 ± 1.0 vs 31.9 ± 0.6 milliseconds), indicating atrophy and edema, respectively. Lower leg muscles were affected most frequently, especially the gastrocnemius medialis and soleus. Distribution of fat content per muscle indicated gradual fat infiltration in DM1. Between-patient variation in fat fraction was explained by age (≈45%), and another ≈14% was explained by estimated progenitor CTG repeat length (r2 = 0.485) and somatic instability (r2 = 0.590). Fat fraction correlated with the 6-minute walk test (r = −0.553) and muscular impairment rating scale (r = 0.537) and revealed subclinical muscle involvement. Conclusion: This cross-sectional quantitative MRI study of 20 different lower extremity muscles in patients with DM1 revealed abnormal values for muscle fat fraction, volume, and T2water, which therefore may serve as objective biomarkers to assess disease state of skeletal muscles in these patients

Respiratory muscle function in patients with nemaline myopathy

Publisher Copyright: © 2022 The AuthorsIn this cross-sectional study, we comprehensively assessed respiratory muscle function in various clinical forms of nemaline myopathy (NM) including non-volitional tests for diaphragm function. Forty-two patients with NM were included (10 males (25-74 y/o); 32 females (11-76 y/o)). The NM forms were typical (n=11), mild (n=7), or childhood-onset with slowness of movements (n=24). Forced vital capacity (FVC) and maximal inspiratory pressure were decreased in typical NM in comparison with childhood-onset NM with slowness (32.0 [29.0-58.5] vs 81.0 [75.0-87.0]%, p<0.01, and 35.0 [24.0-55.0] vs 81.0 [65.0-102.5] cmH2O, p<0.01). Eight patients with childhood-onset NM with slowness had respiratory muscle weakness. There was a low correlation between FVC and Motor Function Measure scores (r=0.48, p<0.01). End-inspiratory diaphragm thickness and twitch mouth pressure were decreased in patients requiring home mechanical ventilation compared to non-ventilated patients with normal lung function (1.8 [1.5-2.4] vs 3.1 [2.0-4.6] mm, p=0.049, and -7.9 [-10.9- -4.0] vs -14.9 [-17.3- -12.6], p=0.04). Our results show that respiratory muscle weakness is present in all NM forms, including childhood-onset NM with slowness, and may be present irrespective of the degree of general motor function impairment. These findings highlight the importance for screening of respiratory function in patients with NM to guide respiratory management.Peer reviewe

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

Background and ObjectivesOculopharyngeal 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.MethodsPatients 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.ResultsIn 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).DiscussionAccording 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

Semi-Automated Rasch Analysis with Differential Item Functioning

Rasch analysis is a procedure to develop and validate instruments that aim to measure persons' traits. However, manual Rasch analysis is a complex and time-consuming task, even more so when the possibility of differential item functioning (DIF) is taken into consideration. Furthermore, manual Rasch analysis by construction relies on a modeller's subjective choices. As an alternative approach, we introduce a semi-automated procedure that is based on the optimization of a new criterion, called in-plus-out-of-questionnaire log likelihood with differential item functioning (IPOQLL-DIF) which extends our previous criterion. We illustrate our procedure on artificially generated data as well as on several real-world datasets containing potential DIF items. On these real-world datasets, our procedure found instruments with similar clinimetric properties as those suggested by experts through manual analyses

Group medical appointments for people with physical illness

This is the protocol for a review and there is no abstract. The objectives are as follows: To assess the effects of group medical appointments (GMAs) on the health status and well-being of patients with a primary physical illness as compared to one-to-one patient-clinician appointments

Clinical Outcome Evaluations and CBT Response Prediction in Myotonic Dystrophy

International audienceBackground:The European OPTIMISTIC clinical trial has demonstrated a significant, yet heterogenous effect of Cognitive Behavioural Therapy (CBT) for Myotonic Dystrophy type 1 (DM1) patients. One of its remaining aims was the assessment of efficacy and adequacy of clinical outcome measures, including the relatively novel primary trial outcome, the DM1-Activ-c questionnaire.Objectives:Assessment of the relationship between the Rasch-built DM1-Activ-c questionnaire and 26 commonly used clinical outcome measurements. Identification of variables associated with CBT response in DM1 patients.Methods:Retrospective analysis of the to date largest clinical trial in DM1 (OPTIMISTIC), comprising of 255 genetically confirmed DM1 patients randomized to either standard care or CBT with optionally graded exercise therapy. Correlations of 27 different outcome measures were calculated at baseline (cross-sectional) and of their respective intervention induced changes (longitudinal). Bootstrap enhanced Elastic-Net (BeEN) regression was validated and implemented to select variables associated with CBT response.Results:In cross-sectional data, DM1-Activ-c correlated significantly with the majority of other outcome measures, including Six Minute Walk Test and Myotonic Dystrophy Health Index. Fewer and weaker significant longitudinal correlations were observed. Nine variables potentially associated with CBT response were identified, including measures of disease severity, executive cognitive functioning and perceived social support.Conclusions:The DM1-Activ-c questionnaire appears to be a well suited cross-sectional instrument to assess a variety of clinically relevant dimensions in DM1. Yet, apathy and experienced social support measures were less well captured. CBT response was heterogenous, requiring careful selection of outcome measures for different disease aspects