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To assess the psychosocial outcomes of facial weakness in facioscapulohumeral muscular dystrophy (FSHD). A cross-sectional survey study. The severity of facial weakness was assessed by patients (self-reported degree of facial weakness) and by physicians (part I FSHD clinical score). Questionnaires on facial function, psychosocial well-being, functioning, pain, and fatigue were completed. Regression analyses were performed to explain variance in psychosocial outcomes by demographic and disease variables. One hundred and thirty-eight patients participated. They reported mild to moderate psychological distress, no to mild fear of negative evaluation, and moderate to good social functioning. However, patients with severe self-reported facial weakness scored lower in social functioning. Patients with more facial dysfunction experienced more fear of negative evaluation and lower social functioning. Furthermore, younger age, presence of pain, fatigue, walking difficulty, and current or previous psychological support were associated with lower psychosocial outcomes. Overall, patients report moderate to good psychosocial functioning in this study. The factors contributing to lower psychosocial functioning are diverse. A multidisciplinary, personalized approach, focusing on coping with physical, emotional, and social consequences of FSHD is supposed to be helpful. Further research is needed to assess the psychosocial outcomes of facial weakness in younger patients. Research on the psychosocial consequences of facial weakness in facioscapulohumeral muscular dystrophy (FSHD) is limited. Patients with FSHD experience mild to moderate psychosocial distress, partly due to overall disease severity, such as reduced mobility, and partly due to facial weakness and reduced facial function. Self-reported degree of facial weakness and facial dysfunction were related to lower psychosocial outcomes (social functioning, fear of negative evaluation, and psychological distress). Physician-reported degree of facial weakness was not related to psychosocial outcomes, suggesting an absence of a strong correlation between observed facial weakness and experienced disease burden in this study. This calls for a multidisciplinary, personalized approach with a focus on coping with physical, emotional, and social consequences of FSHD. [ABSTRACT FROM AUTHOR] more...

Duchenne/Becker muscular dystrophy (DMD/BMD) is the most common form of muscular dystrophy, accounting for over 50% of all cases. In this regard, in Russia we carry out a program of selective screening for DMD/BMD, which mainly involves male patients. The main inclusion criteria are an increase in the level of creatine phosphokinase (>2000 U/L) or an established clinical diagnosis. At the first stage of screening, patients are scanned for extended deletions and duplications in the DMD gene using multiplex ligase-dependent probe amplification (MLPA SALSA P034 and P035 DMD probemix, MRC-Holland). The second stage is the search for small mutations using a custom NGS panel, which includes 31 genes responsible for various forms of limb-girdle muscular dystrophy. In a screening of 1025 families with a referral Duchenne/Becker diagnosis, pathogenic and likely pathogenic variants in the DMD gene were found in 788 families (in 76.9% of cases). In the current study, we analyzed the mutation spectrum of the DMD gene in Russian patients and noted certain differences between the examined cohort and the multi-ethnic cohort. The analysis of the DMD gene mutation spectrum is essential for patients with DMD/BMD because the exact mutation type determines the application of a specific therapeutic method. [ABSTRACT FROM AUTHOR] more...

Background: Promising genetic therapies are being investigated in facioscapulohumeral muscular dystrophy (FSHD). However, the current cost of illness is largely unknown. Objective: This study aimed at determining the socioeconomic burden of FSHD. Methods: Adult patients with FSHD from the Dutch FSHD registry were invited to complete a questionnaire on medical consumption, work productivity and health-related quality of life (HR-QoL) using the EQ-5D-5L. Associated costs were calculated from a societal perspective. A generalized linear model was fitted to the data to investigate whether level of mobility was related to annual costs of illness. Results: 172 patients with FSHD completed the questionnaire (response rate 65%). The per-patient annual direct medical costs of FSHD were estimated at €12,077, direct non-medical costs at €9179 and indirect costs at €5066, adding up to a total cost of illness of €26,322 per patient per year. The direct costs of illness were €21,256, approximately five times higher than the mean per-capita health expenditures in the Netherlands. Major cost-driving factors were formal home care and informal care. A decreased level of mobility was associated with higher direct costs of illness. HR-QoL was significantly reduced in patients with FSHD with a median health utility value of 0.63. Conclusions: We show that FSHD is associated with substantial direct and indirect socioeconomic costs as well as a reduction in HR-QoL. These findings are important for health care decision makers and aids in allocation of research funds and evaluation of the cost-effectiveness of novel therapies. [ABSTRACT FROM AUTHOR] more...

Facioscapulohumeral muscular dystrophy (FSHD) is a genetic disease caused by aberrant DUX4 expression, leading to progressive muscle weakness. No effective pharmaceutical treatment is available. Losmapimod, a small molecule selective inhibitor of p38 α/β MAPK, showed promising results in a phase 1 trial for the treatment of FSHD, prompting additional studies. We report the findings of an open-label phase 2 trial (NCT04004000) investigating the safety, tolerability, pharmacokinetics, pharmacodynamics, and exploratory efficacy of losmapimod in participants with FSHD1. This study was conducted at a single site in the Netherlands from August 2019 to March 2021, with an optional, ongoing open-label extension. Participants aged 18 to 65 years with FSHD1 took 15 mg of losmapimod twice daily for 52 weeks. Primary endpoints were measures of losmapimod safety and tolerability. Secondary endpoints were assessments of losmapimod pharmacokinetics and pharmacodynamics. Fourteen participants were enrolled. No deaths, serious treatment-emergent adverse events (TEAEs), or discontinuations due to TEAEs were reported. Losmapimod achieved blood concentrations and target engagements that were previously associated with decreased DUX4 expression in vitro. Clinical outcome measures showed a trend toward stabilization or improvement. Losmapimod was well tolerated and may be a promising new treatment for FSHD; a larger phase 3 study is ongoing. • Losmapimod had a favorable safety and tolerability profile in individuals with FSHD. • Losmapimod pharmacokinetics were as expected, and target engagement was observed. • Losmapimod treatment showed a trend toward motor function stabilization/improvement. [ABSTRACT FROM AUTHOR] more...

In this retrospective study, we conducted a clinico‐genetic analysis of patients with autosomal recessive limb‐girdle muscular dystrophy (LGMD) and Miyoshi muscular dystrophy (MMD). Patients were identified at the tertiary referral centre for DNA diagnosis in the Netherlands and included if they carried two mutations in CAPN3, DYSF, SGCG, SGCA, SGCB, SGCD, TRIM32, FKRP or ANO5 gene. DNA was screened by direct sequencing and multiplex ligand‐dependent probe amplification (MLPA) analysis. A total of 244 patients was identified; 68 LGMDR1/LGMD2A patients with CAPN3 mutations (28%), 67 sarcoglycanopathy patients (LGMDR3‐5/LGMD2C‐E) (27%), 64 LGMDR12/LGMD2L and MMD3 patients with ANO5 mutations (26%), 25 LGMDR2/LGMD2B and MMD1 with DYSF mutations (10%), 21 LGMDR9/LGMD2I with FKRP mutations (9%) and one LGMDR8/LGMD2H patient with TRIM32 mutations (<1%). The estimated minimum prevalence of AR‐LGMD and MMD in the Netherlands amounted to 14.4 × 10−6. Thirty‐three novel mutations were identified. A wide range in age of onset (0‐72 years) and loss of ambulation (5‐74 years) was found. Fifteen patients (6%) initially presented with asymptomatic hyperCKemia. Cardiac abnormalities were found in 35 patients (17%). Non‐invasive ventilation was started in 34 patients (14%). Both cardiac and respiratory involvement occurs across all subtypes, stressing the need for screening in all included subtypes. [ABSTRACT FROM AUTHOR] more...

A need exists for biomarkers to diagnose, quantify and longitudinally follow facioscapulohumeral muscular dystrophy (FSHD) and many other neuromuscular disorders. Furthermore, the pathophysiological mechanisms leading to muscle weakness in most neuromuscular disorders are not completely understood. Dynamic ultrasound imaging (B-mode image sequences) in combination with speckle tracking is an easy, applicable and patient-friendly imaging tool to visualize and quantify muscle deformation. This dynamic information provides insight in the pathophysiological mechanisms and may help to distinguish the various stages of diseased muscle in FSHD. In this proof-of-principle study, we applied a speckle tracking technique to 2-D ultrasound image sequences to quantify the deformation of the tibialis anterior muscle in patients with FSHD and in healthy controls. The resulting deformation patterns were compared with muscle ultrasound echo intensity analysis (a measure of fat infiltration and dystrophy) and clinical outcome measures. Of the four FSHD patients, two patients had severe peroneal weakness and two patients had mild peroneal weakness on clinical examination. We found a markedly varied muscle deformation pattern between these groups: patients with severe peroneal weakness showed a different motion pattern of the tibialis anterior, with overall less displacement of the central tendon region, while healthy patients showed a non-uniform displacement pattern, with the central aponeurosis showing the largest displacement. Hence, dynamic muscle ultrasound of the tibialis anterior muscle in patients with FSHD revealed a distinctively different tissue deformation pattern among persons with and without tibialis anterior weakness. These findings could clarify the understanding of the pathophysiology of muscle weakness in FSHD patients. In addition, the change in muscle deformation shows good correlation with clinical measures and quantitative muscle ultrasound measurements. In conclusion, dynamic ultrasound in combination with speckle tracking allows the study of the effects of muscle pathology in relation to strength, force transmission and movement generation. Although further research is required, this technique can develop into a biomarker to quantify muscle disease severity. [ABSTRACT FROM AUTHOR] more...

Purpose:The aim of this article is to describe how fatigue affects the lives of people with facioscapulohumeral dystrophy (FSHD), how they experience fatigue, and how they deal with it in order to attune rehabilitation care to patients’ needs. Method:A qualitative study, consisting of 25 semistructured interviews with patients with FSHD and severe fatigue (as measured with the checklist individual strength (CIS) fatigue questionnaire), was conducted to gain insight into the experiences of patients with fatigue. Data were inductively analyzed. Results:Patients describe fatigue as an overwhelming and unpredictable experience and they make a distinction between actual experienced fatigue and fear of becoming tired. Fatigue can, according to patients, be the result of weak muscles, physical overachieving or underachieving and stress. But most of the time patients do not know the actual causes of the fatigue, which makes it hard to deal with. The experienced fatigue has a large impact on participation, social contacts, and the quality of life of patients, and patients try to use many strategies to adapt themselves to the constantly changing situations. Conclusions:Fatigue is a severe problem in FSHD and has a huge impact on patients’ lives. Patients should be helped to reduce fatigue, for instance by offering evidence-based therapies such as aerobic exercise training or cognitive behavioral therapy.Implications for RehabilitationFatigue has significant influence on the quality of lives and participation of people with FSHD.Patients with FSHD are insufficient supported in coping with their fatigue.More attention for fatigue in patients with FSHD in rehabilitation is needed, for instance by a broader implementation of aerobic exercise training or cognitive behavioral therapy. [ABSTRACT FROM PUBLISHER] more...

The slow and highly variable disease progression observed in BMD stresses the need to develop outcome measures for clinical trials. We evaluated the responsiveness of different assessments in a cohort of adult BMD patients followed for 3 years. We included 36 genetically confirmed BMD patients (median age at baseline 42.3 years, range 18.6-67.3) of whom 28 were ambulant at baseline (78%). We conducted ambulatory assessments (6WMT, NSAA, 10-meter walk velocity (TMWv), time to rise from floor velocity (TRFv)), PUL1.2 and bilateral maximal voluntary isometric contraction (grip, knee/hip/elbow flexion and extension). The median change and the standard response mean (SRM) at 1- and 3-year follow-up were calculated. Sample sizes (SS) were calculated assuming 50% reduction in disease progression over a 3 year clinical trial with 1:1 randomization. We observed a large variability across all measures, for example the median at baseline for the 6MWT was 439.10m (range 84.30 to 650.00), median change at 1 year follow-up -8.15 (-151.90 to 182.22) and at 3-years -14.50(-151.90 to 158.72). After 1-year follow-up, the SRM was below 0.8 for all considered outcomes. At 3-year follow-up, TMWv and TRFv showed a responsiveness with SRM above 0.8 (1.91, SS 17 and -0.90, SS 79 respectively). Three strength measurements showed SRM >0.8: right elbow flexion (SRM = -1.01, SS 62), left elbow flexion (SRM = -0.85, SS 88) and left hip flexion (SRM = -0.81, SS 96). Of the 29 patients who completed the PUL1.2 at 3rd year follow-up visit, 20 (69%) obtained the maximum score of 74 points. Only one patient lost ambulation during the study. BMD is hallmarked by large inter-individual variability at baseline and follow-up. A relatively stable disease course is common even with 3 years. The ceiling effect of the PUL1.2 illustrates the need for adequate outcome measures in non-ambulant patients. [ABSTRACT FROM AUTHOR] more...

Despite the growing knowledge on the (epi)genetic background of facioscapulohumeral muscular dystrophy (FSHD), the substantial variability in disease severity that exists between FSHD patients is not fully understood. We hypothesized that smoking and alcohol consumption are disease modifiers in FSHD and contribute to the variability in disease severity, because they are both associated with higher levels of oxidative stress in muscle tissue. Oxidative stress is known to influence FSHD muscle tissue. One hundred and ninety-eight genetically confirmed FSHD patients completed a questionnaire from which the number of packyears of smoking and the lifetime cumulative alcohol units consumed were calculated. Disease severity was determined by the FSDH evaluation score. Multiple linear regression analyses showed that both the number of packyears and the amount of alcohol consumption did not influence disease severity (respectively B = 0.025, ΔR 2 =0.006, p = 0.231; and B = 0.000, ΔR 2 =0.004, p = 0.406). Although smoking and excessive alcohol consumption are unhealthy habits which should be discouraged, these results show that smoking and alcohol consumption have no clinically meaningful modifying effect on disease severity in FSHD patients. However, prospective data should show whether alcohol consumption and smoking influence disease progression rate., Competing Interests: Declaration of Interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.) more...