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... Detraining and disuse reduce the lactate and VTs, especially VT1 (Londeree, 1997). The reversibility of many NMD-related changes in neuromuscular functioning in response to exercise suggest the extent to which these alterations are related to activity status rather than muscle pathology (Ferguson et al., 2016;Heskamp et al., 2020). The performance fatigability profile following muscle disuse atrophy causes a slow to fast fiber transition and could (partially) explain the difference in timing of the sEMG Ths in patients, compared to healthy subjects (Ahmetov et al., 2012). ...
In healthy persons, there is an excellent relation between the timing of the (two) surface electromyography (sEMG) thresholds and the (two) ventilatory thresholds during exercise. The primary aim of this study was to determine the relative timing of both sEMG and ventilatory thresholds in patients with neuromuscular disorders compared with healthy subjects during a maximal ergospirometry cycling test. We hypothesized that in patients with neuromuscular disorders, the sEMG thresholds would occur relatively earlier in time than the ventilatory thresholds, compared to healthy subjects, because performance fatigability occurs more rapidly. In total, 24 healthy controls and 32 patients with a neuromuscular disorder performed a cardiopulmonary exercise test on a bicycle using a 10-min ramp protocol, during which we collected ergospirometry data: power at both ventilatory and sEMG thresholds, and sEMG data of lower leg muscles. In line with our hypothesis, normalized values for all thresholds were lower for patients than healthy subjects. These differences were significant for the first ventilatory (p = 0.008) and sEMG threshold (p < 0.001) but not for the second sEMG (p = 0.053) and ventilatory threshold (p = 0.238). Most parameters for test–retest reliability of all thresholds did not show any fixed bias, except for the second ventilatory threshold. The feasibility of the sEMG thresholds was lower than the ventilatory thresholds, particularly of the first sEMG threshold. As expected, the sEMG thresholds, particularly the first threshold, occurred relatively earlier in time than the ventilatory thresholds in patients compared with healthy subjects. A possible explanation could be (a combination of) a difference in fiber type composition, disuse, and limited muscle-specific force in patients with neuromuscular disorders. sEMG measurements during submaximal dynamic exercises are needed to generalize the measurements to daily life activities for future use in prescribing and evaluating rehabilitation interventions.
... Adults with BMD that maintained or increased PA levels showed a relative increase or maintenance of muscle strength compared to those that decreased PA levels. Increased PA has previously been attributed to decelerating fatty infiltration of muscles in FSHD . Based on the present relationship between PA and declines in muscle strength, it seems reasonable to suggest interventions that increase PA in adults with BMD may benefit muscle strength, while potentially also alleviating some concerns around changes in fat mass identified in the present study. ...
Muscular dystrophy (MD) is an umbrella term for muscle wasting conditions, for which longitudinal changes in function and body composition are well established in children with Duchenne (DMD), however, changes in adults with DMD and Beckers (BMD), respectively, remain poorly reported. This study aims to assess 12-month changes in lower-limb strength, muscle size, body composition and physical activity in adults with Muscular Dystrophy (MD).
Adult males with Duchenne MD (DMD; N = 15) and Beckers MD (BMD; N = 12) were assessed at baseline and 12-months for body composition (Body fat and lean body mass (LBM)), Isometric maximal voluntary contraction (Knee-Extension (KEMVC) and Plantar-Flexion (PFMVC)) and physical activity (tri-axial accelerometry).
12-Month change in strength was found as −19% (PFMVC) and −14% (KEMVC) in DMD. 12-Month change in strength in BMD, although non-significant, was explained by physical activity (R ²=0.532–0.585). Changes in LBM (DMD) and body fat (BMD) were both masked by non-significant changes in body mass.
12-Month changes in adults with DMD appear consistent with paediatric populations. Physical activity appears important for muscle function maintenance. Specific monitoring of body composition, and potential co-morbidities, within adults with MD is highlighted.
Implications for rehabilitation
• Quantitative muscle strength assessment shows progressive muscle weakness in adults with Duchenne Muscular Dystrophy is comparable to paediatric reports (−14 to −19%).
• Physical activity should be encouraged in adults with Beckers Muscular Dystrophy, anything appears better than nothing.
• Body composition, rather than body mass, should be monitored closely to identify any increase in body fat.
... While MD populations have also shown physiological improvements following aerobic exercise interventions. 6 Janssen et al. 39 showed increased PA levels, through an aerobic training plan, decelerated muscle fat infiltration in adults with FSHD. Moreover, Jansen et al. 40 showed assisted bicycle training delays functional deterioration in boys with DMD. ...
Muscular dystrophy (MD) is characterized by progressive muscle wasting and weakness, yet few comparisons to non‐MD controls (CTRL) of muscle strength and size in this adult population exist. Physical activity (PA) is promoted to maintain health and muscle strength within MD; however, PA reporting in adults with MD is limited to recall data, and its impact on muscle strength is seldom explored.
This study included 76 participants: 16 non‐MD (CTRL, mean age 35.4), 15 Duchenne MD (DMD, mean age 24.2), 18 Becker's MD (BMD, mean age 42.4), 13 limb‐girdle MD (LGMD, mean age 43.1), and 14 facioscapulohumeral MD (mean age 47.7). Body fat (%) and lean body mass (LBM) were measured using bioelectrical‐impedance. Gastrocnemius medialis (GM) anatomical cross‐sectional area (ACSA) was determined using B‐mode ultrasound. Isometric maximal voluntary contraction (MVC) was assessed during plantar flexion (PFMVC) and knee extension (KEMVC). PA was measured for seven continuous days using triaxial accelerometry and was expressed as daily average minutes being physically active (TPAmins) or average daily percentage of waking hours being sedentary (sedentary behaviour). Additionally, 10 m walk time was assessed.
Muscular dystrophy groups had 34–46% higher body fat (%) than CTRL. DMD showed differences in LBM with 21–28% less LBM than all other groups. PFMVC and KEMVC were 36–75% and 24–92% lower, respectively, in MD groups than CTRL. GM ACSA was 47% and 39% larger in BMD and LGMD, respectively, compared with CTRL. PFMVC was associated with GM ACSA in DMD (P = 0.026, R = 0.429) and CTRL (P = 0.015, R = 0.553). MD groups were 14–38% more sedentary than CTRL groups, while DMD were more sedentary than BMD (14%), LGMD (8%), and facioscapulohumeral MD (14%). Sedentary behaviour was associated with LBM in DMD participants (P = 0.021, R = −0.446). TPAmins was associated with KEMVC (P = 0.020, R = 0.540) in BMD participants, while TPAmins was also the best predictor of 10 m walk time (P < 0.001, R² = 0.540) in ambulant MD, revealed by multiple linear regression.
Quantified muscle weakness and impaired 10 m walking time is reported in adults with MD. Muscle weakness and 10 m walk time were associated with lower levels of TPA in adults with MD. Higher levels of sedentary behaviour were associated with reduced LBM in DMD. These findings suggest a need for investigations into patterns of PA behaviour, and relevant interventions to reduce sedentary behaviour and encourage PA in adults with MD regardless of impairment severity.
Electrical impedance myography (EIM) has been proposed as a noninvasive biomarker of muscle composition in facioscapulohumeral muscular dystrophy (FSHD). Here we determine the associations of EIM parameters with muscle structure measured by MRI.
We evaluated 20 patients with FSHD at 2 centers comparing EIM measurements (resistance, reactance, and phase at 50, 100, and 211 kHz) recorded from bilateral vastus lateralis, tibialis anterior, and medial gastrocnemius muscles to MRI skin and subcutaneous fat thickness, T1 muscle score and quantitative muscle fat fraction (FF).
While reactance and phase both correlated with FF and T1 muscle score, 50 kHz reactance was most sensitive to muscle structure alterations measured by both T1 score (ρ=-0.71, p<.001) and FF (ρ=-0.74, p<.001).
This study establishes the correlation of EIM with structural MRI features in FSHD and supports further evaluation of EIM as a potential biomarker in FSHD clinical trials. This article is protected by copyright. All rights reserved.
To investigate the effect of aerobic exercise training (AET) and cognitive-behavioral therapy (CBT) on chronic fatigue in patients with facioscapulohumeral muscular dystrophy (FSHD).
A multicenter, assessor-blinded, randomized clinical trial (Dutch Trial Register No 1447).
57 patients with FSHD type 1 with severe chronic fatigue were randomly allocated to AET, CBT, or usual care (UC). Outcomes were assessed before treatment, following 16 weeks of intervention, and after a 12-week follow-up. A linear mixed model for repeated measurements was used to study the estimated group differences (NTR1447).
Following treatment, both the AET (28 participants) and CBT (25 participants) intervention groups had less fatigue relative to the UC group (24 participants), with a difference of -9.1 for AET (95% confidence interval [CI] -12.4 to -5.8) and -13.3 for CBT (95% CI -16.5 to -10.2). These beneficial effects lasted through follow-up, with a difference of -8.2 for AET (95% CI -12.4 to -5.8) and -10.2 for CBT (95% CI -14.0 to -6.3). The patients who received CBT had an increase in registered and experienced physical activity, sleep quality, and social participation. The patients who received AET had an increase in registered physical activity and quadriceps strength only. The increase in registered physical activity in both groups and the improvement in social participation following CBT were still present at follow-up.
This RCT shows that AET and CBT can ameliorate chronic fatigue and increase the level of activity in patients with FSHD.
To evaluate the effects of corticosteroids on the lower extremity muscles in boys with Duchenne muscular dystrophy (DMD) using MRI and magnetic resonance spectroscopy (MRS).
Transverse relaxation time (T2) and fat fraction were measured by MRI/MRS in lower extremity muscles of 15 boys with DMD (age 5.0-6.9 years) taking corticosteroids and 15 corticosteroid-naive boys. Subsequently, fat fraction was measured in a subset of these boys at 1 year. Finally, MRI/MRS data were collected from 16 corticosteroid-naive boys with DMD (age 5-8.9 years) at baseline, 3 months, and 6 months. Five boys were treated with corticosteroids after baseline and the remaining 11 served as corticosteroid-naive controls.
Cross-sectional comparisons demonstrated lower muscle T2 and less intramuscular (IM) fat deposition in boys with DMD on corticosteroids, suggesting reduced inflammation/damage and fat infiltration with treatment. Boys on corticosteroids demonstrated less increase in IM fat infiltration at 1 year. Finally, T2 by MRI/MRS detected effects of corticosteroids on leg muscles as early as 3 months after drug initiation.
These results demonstrate the ability of MRI/MRS to detect therapeutic effects of corticosteroids in reducing inflammatory processes in skeletal muscles of boys with DMD. Our work highlights the potential of MRI/MRS as a biomarker in evaluating therapeutic interventions in DMD.
Although the pathophysiology of facioscapulohumeral dystrophy (FSHD) has been controversial over the last decades, progress in recent years has led to a model that incorporates these decades of findings and is gaining general acceptance in the FSHD research community. Here we review how the contributions from many labs over many years led to an understanding of a fundamentally new mechanism of human disease. FSHD is caused by inefficient repeat-mediated epigenetic repression of the D4Z4 macrosatellite repeat array on chromosome 4, resulting in the variegated expression of the DUX4 retrogene, encoding a double-homeobox transcription factor, in skeletal muscle. Normally expressed in the testis and epigenetically repressed in somatic tissues, DUX4 expression in skeletal muscle induces expression of many germline, stem cell, and other genes that might account for the pathophysiology of FSHD. Although some disagreements regarding the details of mechanisms remain in the field, the coalescing agreement on a central model of pathophysiology represents a pivot-point in FSHD research, transitioning the field from discovery-oriented studies to translational studies aimed at developing therapies based on a sound model of disease pathophysiology.
Muscle fatigue, weakness and atrophy are basilar clinical features that accompany facioscapulohumeral dystrophy (FSHD) the third most common muscular dystrophy.
No therapy is available for FSHD.
We describe the effects of 6mo exercise therapy and nutritional supplementation in a 43-year-old woman severely affected by FSHD.
A mixed exercise program combined with nutritional supplementation can be safely used with beneficial effects in selected patients with FSHD.
Facioscapulohumeral muscular dystrophy (FSHD) is an untreatable disease, characterized by asymmetric progressive weakness of skeletal muscle with fatty infiltration. Although the main genetic defect has been uncovered, the downstream mechanisms causing FSHD are not understood. The objective of this study was to determine natural disease state and progression in muscles of FSHD patients and to establish diagnostic biomarkers by quantitative MRI of fat infiltration and phosphorylated metabolites. MRI was performed at 3T with dedicated coils on legs of 41 patients (28 men/13 women, age 34-76 years), of which eleven were re-examined after four months of usual care. Muscular fat fraction was determined with multi spin-echo and T1 weighted MRI, edema by TIRM and phosphorylated metabolites by 3D (31)P MR spectroscopic imaging. Fat fractions were compared to clinical severity, muscle force, age, edema and phosphocreatine (PCr)/ATP. Longitudinal intramuscular fat fraction variation was analyzed by linear regression. Increased intramuscular fat correlated with age (p
Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common muscular dystrophies and is characterized by a non-conventional genetic mechanism activated by pathogenic D4Z4 repeat contractions. By muscle Magnetic Resonance Imaging (MRI) we observed that T2-short tau inversion recovery (T2-STIR) sequences identify two different conditions in which each muscle can be found before the irreversible dystrophic alteration, marked as T1-weighted sequence hyperintensity, takes place. We studied these conditions in order to obtain further information on the molecular mechanisms involved in the selective wasting of single muscles or muscle groups in this disease.
Histopathology, gene expression profiling and real time PCR were performed on biopsies from FSHD muscles with different MRI pattern (T1-weighted normal/T2-STIR normal and T1-weighted normal/T2-STIR hyperintense). Data were compared with those from inflammatory myopathies, dysferlinopathies and normal controls. In order to validate obtained results, two additional FSHD samples with different MRI pattern were analyzed.
Myopathic and inflammatory changes characterized T2-STIR hyperintense FSHD muscles, at variance with T2-STIR normal muscles. These two states could be easily distinguished from each other by their transcriptional profile. The comparison between T2-STIR hyperintense FSHD muscles and inflammatory myopathy muscles showed peculiar changes, although many alterations were shared among these conditions.
At the single muscle level, different stages of the disease correspond to the two MRI patterns. T2-STIR hyperintense FSHD muscles are more similar to inflammatory myopathies than to T2-STIR normal FSHD muscles or other muscular dystrophies, and share with them upregulation of genes involved in innate and adaptive immunity. Our data suggest that selective inflammation, together with perturbation in biological processes such as neoangiogenesis, lipid metabolism and adipokine production, may contribute to the sequential bursts of muscle degeneration that involve individual muscles in an asynchronous manner in this disease.
No treatment exists for facioscapulohumeral muscular dystrophy (FSHD), one of the most common inherited muscle diseases. Although FSHD can be debilitating, little effort has been made to develop targeted therapies. This lack of focus on targeted FSHD therapy perpetuated because the genes and pathways involved in the disorder were not understood. Now, more than 2 decades after efforts to decipher the root cause of FSHD began, this barrier to translation is finally lowering. Specifically, several recent studies support an FSHD pathogenesis model involving overexpression of the myopathic DUX4 gene. DUX4 inhibition has therefore emerged as a promising therapeutic strategy for FSHD. In this study, we tested a preclinical RNA interference (RNAi)-based DUX4 gene silencing approach as a prospective treatment for FSHD. We found that adeno-associated viral (AAV) vector-delivered therapeutic microRNAs corrected DUX4-associated myopathy in mouse muscle. These results provide proof-of-principle for RNAi therapy of FSHD through DUX4 inhibition.
Treatment of dominantly inherited muscle disorders remains a difficult task considering the need to eliminate the pathogenic gene product in a body-wide fashion. We show here that it is possible to reverse dominant muscle disease in a mouse model of facioscapulohumeral muscular dystrophy (FSHD). FSHD is a common form of muscular dystrophy associated with a complex cascade of epigenetic events following reduction in copy number of D4Z4 macrosatellite repeats located on chromosome 4q35. Several 4q35 genes have been examined for their role in disease, including FRG1. Overexpression of FRG1 causes features related to FSHD in transgenic mice and the FRG1 mouse is currently the only available mouse model of FSHD. Here we show that systemic delivery of RNA interference expression cassettes in the FRG1 mouse, after the onset of disease, led to a dose-dependent long-term FRG1 knockdown without signs of toxicity. Histological features including centrally nucleated fibers, fiber size reduction, fibrosis, adipocyte accumulation, and inflammation were all significantly improved. FRG1 mRNA knockdown resulted in a dramatic restoration of muscle function. Through RNA interference (RNAi) expression cassette redesign, our method is amenable to targeting any pathogenic gene offering a viable option for long-term, body-wide treatment of dominant muscle disease in humans.
Facioscapulohumeral muscular dystrophy (FSHD) is an inherited disease, and although strongly suggested, a contribution of inflammation to its pathogenesis has never been demonstrated. In FSHD patients, we found by immunohistochemistry inflammatory infiltrates mainly composed by CD8(+) T cells in muscles showing hyperintensity features on T2-weighted short tau inversion recovery magnetic resonance imaging (T2-STIR-MRI) sequences. Therefore, we evaluated the presence of circulating activated immune cells and the production of cytokines in patients with or without muscles showing hyperintensity features on T2-STIR-MRI sequences and from controls. FSHD patients displaying hyperintensity features in one or more muscles showed higher CD8(+)pSTAT1(+), CD8(+)T-bet(+) T cells and CD14(+)pSTAT1(+), CD14(+)T-bet(+) cells percentages and IL12p40, IFNγ and TNFα levels than patients without muscles displaying hyperintense features and controls. Moreover, the percentages of CD8(+)pSTAT1(+), CD8(+)T-bet(+) and CD14(+)pSTAT1(+) cells correlated with the proportion of muscles displaying hyperintensity features at T2-STIR sequences. These data indicate that circulating activated immune cells, mainly CD8(+) T cells, may favour FSHD progression by promoting active phases of muscle inflammation.
In facioscapulohumeral dystrophy (FSHD) muscle function is impaired and declines over time. Currently there is no effective treatment available to slow down this decline. We have previously reported that loss of muscle strength contributes to chronic fatigue through a decreased level of physical activity, while fatigue and physical inactivity both determine loss of societal participation. To decrease chronic fatigue, two distinctly different therapeutic approaches can be proposed: aerobic exercise training (AET) to improve physical capacity and cognitive behavioural therapy (CBT) to stimulate an active life-style yet avoiding excessive physical strain. The primary aim of the FACTS-2-FSHD (acronym for Fitness And Cognitive behavioural TherapieS/for Fatigue and ACTivitieS in FSHD) trial is to study the effect of AET and CBT on the reduction of chronic fatigue as assessed with the Checklist Individual Strength subscale fatigue (CIS-fatigue) in patients with FSHD. Additionally, possible working mechanisms and the effects on various secondary outcome measures at all levels of the International Classification of Functioning, Disability and Health (ICF) are evaluated.
A multi-centre, assessor-blinded, randomized controlled trial is conducted. A sample of 75 FSHD patients with severe chronic fatigue (CIS-fatigue > or = 35) will be recruited and randomized to one of three groups: (1) AET + usual care, (2) CBT + usual care or (3) usual care alone, which consists of no therapy at all or occasional (conventional) physical therapy. After an intervention period of 16 weeks and a follow-up of 3 months, the third (control) group will as yet be randomized to either AET or CBT (approximately 7 months after inclusion). Outcomes will be assessed at baseline, immediately post intervention and at 3 and 6 months follow up.
The FACTS-2-FSHD study is the first theory-based randomized clinical trial which evaluates the effect and the maintenance of effects of AET and CBT on the reduction of chronic fatigue in patients with FSHD. The interventions are based on a theoretical model of chronic fatigue in patients with FSHD. The study will provide a unique set of data with which the relationships between outcome measures at all levels of the ICF could be assessed.
Dutch Trial Register, NTR1447.
Strength training or aerobic exercise programmes might optimise muscle and cardiorespiratory function and prevent additional disuse atrophy and deconditioning in people with a muscle disease. This is an update of a review first published in 2004.
To examine the safety and efficacy of strength training and aerobic exercise training in people with a muscle disease.
We searched the Cochrane Neuromuscular Disease Group Specialized Register (July 2012), CENTRAL (2012 Issue 3 of 4), MEDLINE (January 1946 to July 2012), EMBASE (January 1974 to July 2012), EMBASE Classic (1947 to 1973) and CINAHL (January 1982 to July 2012).
Randomised or quasi-randomised controlled trials comparing strength training or aerobic exercise programmes, or both, to no training, and lasting at least six weeks, in people with a well-described diagnosis of a muscle disease.We did not use the reporting of specific outcomes as a study selection criterion.
Data collection and analysis:
Two authors independently assessed trial quality and extracted the data obtained from the full text-articles and from the original investigators. We collected adverse event data from included studies.
We included five trials (170 participants). The first trial compared the effect of strength training versus no training in 36 people with myotonic dystrophy. The second trial compared aerobic exercise training versus no training in 14 people with polymyositis and dermatomyositis. The third trial compared strength training versus no training in a factorial trial that also compared albuterol with placebo, in 65 people with facioscapulohumeral muscular dystrophy (FSHD). The fourth trial compared combined strength training and aerobic exercise versus no training in 18 people with mitochondrial myopathy. The fifth trial compared combined strength training and aerobic exercise versus no training in 35 people with myotonic dystrophy type 1.In both myotonic dystrophy trials and the dermatomyositis and polymyositis trial there were no significant differences between training and non-training groups for primary and secondary outcome measures. The risk of bias of the strength training trial in myotonic dystrophy and the aerobic exercise trial in polymyositis and dermatomyositis was judged as uncertain, and for the combined strength training and aerobic exercise trial, the risk of bias was judged as adequate. In the FSHD trial, for which the risk of bias was judged as adequate, a +1.17 kg difference (95% confidence interval (CI) 0.18 to 2.16) in dynamic strength of elbow flexors in favour of the training group reached statistical significance. In the mitochondrial myopathy trial, there were no significant differences in dynamic strength measures between training and non-training groups. Exercise duration and distance cycled in a submaximal endurance test increased significantly in the training group compared to the control group. The differences in mean time and mean distance cycled till exhaustion between groups were 23.70 min (95% CI 2.63 to 44.77) and 9.70 km (95% CI 1.51 to 17.89), respectively. The risk of bias was judged as uncertain. In all trials, no adverse events were reported.
Moderate-intensity strength training in myotonic dystrophy and FSHD and aerobic exercise training in dermatomyositis and polymyositis and myotonic dystrophy type I appear to do no harm, but there is insufficient evidence to conclude that they offer benefit. In mitochondrial myopathy, aerobic exercise combined with strength training appears to be safe and may be effective in increasing submaximal endurance capacity. Limitations in the design of studies in other muscle diseases prevent more general conclusions in these disorders.
Reliability coefficients often take the form of intraclass correlation coefficients. In this article, guidelines are given for choosing among 6 different forms of the intraclass correlation for reliability studies in which n targets are rated by k judges. Relevant to the choice of the coefficient are the appropriate statistical model for the reliability study and the applications to be made of the reliability results. Confidence intervals for each of the forms are reviewed. (23 ref) (PsycINFO Database Record (c) 2006 APA, all rights reserved).
To assess the prevalence of severe fatigue and its relation to functional impairment in daily life in patients with relatively common types of neuromuscular disorders.
598 patients with a neuromuscular disease were studied (139 with facioscapulohumeral dystrophy, 322 with adult onset myotonic dystrophy, and 137 with hereditary motor and sensory neuropathy type I). Fatigue severity was assessed with Checklist Individual Strength (CIS-fatigue). Functional impairments in daily life were measured with the short form 36 item health questionnaire (SF-36).
The three different neuromuscular patient groups were of similar age and sex. Severe experienced fatigue was reported by 61-74% of the patients. Severely fatigued patients had more problems with physical functioning, social functioning, mental health, bodily pain, and general health perception. There were some differences between the three disorders in the effects of fatigue.
Severe fatigue is reported by the majority of patients with relatively common types of neuromuscular disorders. Because experienced fatigue severity is associated with the severity of various functional impairments in daily life, it is a clinically and socially relevant problem in this group of patients.
Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal-dominant disorder localized to 4q35. Neither the gene nor the gene product has been identified. There is presently no established treatment for FSHD. Prospective data on the natural history of this disorder are essential for the effective design of therapeutic trials. We systematically followed 81 well defined FSHD patients for up to 3 years using a standardized protocol that included manual muscle testing (MMT), maximum voluntary isometric contraction testing (MVICT), and functional testing. Muscle strength was strongly associated with measures of muscle mass, age at onset, and duration of disease. Decline in strength over time was slow but detectable with both MVICT and MMT. The magnitude of decline was not associated with either age, gender, age at onset, or duration of disease. This study establishes reliable and valid measures of disease state and progression for use as outcome variables in clinical trials in FSHD, and also provides guidelines for determining sample size and duration of follow-up. A two-armed clinical trial involving 160 patients per group and 1 year of follow-up would provide 80% power to detect complete arrest of the progression of the disease. Trials with fewer patients would thus have adequate power to detect only improvements in strength, unless follow-up duration were extended well beyond 1 year.
To determine the incidence and prevalence of facioscapulohumeral muscular dystrophy (FSHD) in the Netherlands.
Using 3-source capture-recapture methodology, we estimated the total yearly number of newly found symptomatic individuals with FSHD, including those not registered in any of the 3 sources. To this end, symptomatic individuals with FSHD were available from 3 large population-based registries in the Netherlands if diagnosed within a 10-year period (January 1, 2001 to December 31, 2010). Multiplication of the incidence and disease duration delivered the prevalence estimate.
On average, 52 people are newly diagnosed with FSHD every year. This results in an incidence rate of 0.3/100,000 person-years in the Netherlands. The prevalence rate was 12/100,000, equivalent to 2,000 affected individuals.
We present population-based incidence and prevalence estimates regarding symptomatic individuals with FSHD, including an estimation of the number of symptomatic individuals not present in any of the 3 used registries. This study shows that the total number of symptomatic persons with FSHD in the population may well be underestimated and a considerable number of affected individuals remain undiagnosed. This suggests that FSHD is one of the most prevalent neuromuscular disorders.
Facioscapulohumeral muscular dystrophy (FSHD) is characterized by a typical and asymmetric pattern of muscle involvement and disease progression. Two forms of FSHD, FSHD1 and FSHD2, have been identified displaying identical clinical phenotype but different genetic and epigenetic basis.
Autosomal dominant FSHD1 (95% of patients) is characterized by chromatin relaxation induced by pathogenic contraction of a macrosatellite repeat called D4Z4 located on the 4q subtelomere (FSHD1 patients harbor 1 to 10 D4Z4 repeated units). Chromatin relaxation is associated with inappropriate expression of DUX4, a retrogene, which in muscles induces apoptosis and inflammation. Consistent with this hypothesis, individuals carrying zero repeat on chromosome 4 do not develop FSHD1. Not all D4Z4 contracted alleles cause FSHD. Distal to the last D4Z4 unit, a polymorphic site with two allelic variants has been identified: 4qA and 4qB. 4qA is in cis with a functional polyadenylation consensus site. Only contractions on 4qA alleles are pathogenic because DUX4 transcript is polyadenylated and translated into stable protein.
FSHD2 is instead a digenic disease. Chromatin relaxation of D4Z4 locus is caused by heterozygous mutations in the SMCHD1 gene encoding a protein essential for chromatin condensation. These patients also harbor at least one 4qA allele in order to express stable DUX4 transcripts. FSHD1 and FSHD2 may have an additive effect: patients harboring D4Z4 contraction and SMCHD1 mutations display a more severe clinical phenotype than with either defect alone. Knowledge of the complex genetic and epigenetic defects causing these diseases is essential in view of designing novel therapeutic strategies. This article is part of a Special Issue entitled: Neuromuscular Diseases: Pathology and Molecular Pathogenesis.
Magnetic resonance imaging of muscle shows short tau-inversion recovery (STIR) brightness in autosomal dominant facioscapulohumeral muscular dystrophy (FSHD1) suggestive of active inflammation/injury. We measured the longitudinal stability/progression of this potential disease biomarker.
Nine subjects underwent calf MRI imaging over 2 years. Two radiologists evaluated qualitative muscle changes.
In 3/9 subjects, calf muscles demonstrated moderate/severe STIR hyperintensity at Time 1 that had progressed to fatty replacement 2 years later (Time 2). In the remaining subjects, moderate/severe muscle STIR abnormalities, when present, were consistent between exams. Mild STIR+ elevations had roughly similar patterns between exams.
Moderate/severe STIR hyperintensities often foreshadow fatty replacement over a 2-year interval. Whether longer time courses are required to observe muscle degeneration and fatty replacement in some subjects remains to be explored.
In this review, we present an overview of the role of exercise in neuromuscular disease (NMD). We demonstrate that despite the different pathologies in NMDs, exercise is beneficial, whether aerobic/endurance or strength/resistive training, and we explore whether this benefit has a similar mechanism to that of healthy subjects. We discuss further areas for study, incorporating imaginative and novel approaches to training and its assessment in NMD. We conclude by suggesting ways to improve future trials by avoiding previous methodological flaws and drawbacks in this field. Muscle Nerve, 2013.
Recent advances in the understanding of the molecular pathophysiology of facioscapulohumeral muscular dystrophy (FSHD) have identified potential therapeutic targets. Consequently, an accurate understanding of disease progression in FSHD is crucial for the design of future clinical trials. Data from 228 subjects in 3 clinical trials and 1 natural history study were compared to examine disease progression in FSHD. All studies utilized the same techniques for manual muscle testing and maximum voluntary isometric contraction testing. Both techniques yield a total strength score that can be followed over time as an indicator of disease progression. Whereas natural history data showed a decrease in strength over 1year, there was an apparent increase in strength at 6months in 2 of the 3 clinical trials in both the placebo and treatment groups, that persisted for up to 1year for maximum voluntary isometric contraction testing. Variability estimates from the clinical trial data were consistent with those seen in the natural history data. Patients in clinical trials in FSHD may have better outcomes than those in natural history studies, regardless of treatment assignment, emphasizing the importance of placebo groups and the need for caution when interpreting the strength results of controlled and uncontrolled trials.
Facioscapulohumeral muscular dystrophy (FSHD) is a common, dominantly inherited, muscle disease with a distinctive clinical presentation and a wide spectrum of disease severity. In greater than 95% of individuals with FSHD, the genetic defect is a loss of a critical number of D4Z4 macrosatellite repeats on chromosome 4q35. However, D4Z4 contractions are only pathogenic on specific, permissive chromosomal backgrounds. Recent evidence demonstrates that this permissive background facilitates the stable transcription of DUX4 , a retrogene sequence within D4Z4 that codes for a double homeodomain protein of unknown function. These findings implicate DUX4 in the pathophysiology of FSHD and for the first time, offer a target for therapeutic development in FSHD.
Epigenetic modifications can lead to gene derepression.
FSHD results from reactivation of a retrogene.
Genotype analysis by using the p13E-11 probe and other 4q35 polymorphic markers was performed in 122 Italian facioscapulohumeral muscular dystrophy families and 230 normal controls. EcoRI—BlnI double digestion was routinely used to avoid the interference of small EcoRI fragments of 10qter origin that were found in 15% of the controls. An EcoRI fragment ranging between 10 and 28 kb that was resistant to BlnI digestion was detected in 114 of 122 families (93%) comprising 76 familial and 38 isolated cases. Among the unaffected individuals, 3 were somatic mosaics and 7, carrying an EcoRI fragment larger than 20 kb, could be rated as nonpenetrant gene carriers. In a cohort of 165 patients with facioscapulohumeral muscular dystrophy we found an inverse correlation between fragment size and clinical severity. A severe lower limb involvement was observed in 100% of patients with an EcoRI fragment size of 10 to 13 kb (1–2 KpnI repeats left), in 53% of patients with a fragment size of 16 to 20 kb (3–4 KpnI repeats left), and in 19% of patients with a fragment size larger than 21 kb (>4 KpnI repeats left). Our results confirm that the size of the fragment is a major factor in determining the facioscapulohumeral muscular dystrophy phenotype and that it has an impact on clinical prognosis and genetic counseling of the disease. Ann Neurol 1999;45:751–757
Facioscapulohumeral muscular dystrophy (FSHD) is associated with a repeat contraction in the D4Z4 gene locus on chromosome 4q35. We used a one-step quantitative magnetic resonance imaging (MRI) method to evaluate muscle, edema, and fat in patients spanning the range of severity.
Fifteen patients with FSHD were compared with 10 healthy subjects using non-negative linear least-squares fitting of 32-echo relaxation data (T2). The results were compared with a biexponential approach for characterizing muscle/fat ratio and T2 relaxation measurements from fat-suppressed inversion recovery.
Increased T2 signal consistent with edema was common in FSHD subjects, a pattern not present in healthy controls. A varied pattern of edema and fatty replacement in muscles was shown.
As a discrete biomarker, edema may be useful for following the clinical course of FSHD. Future work toward optimizing measurement is discussed.
To investigate the feasibility, safety, and effectiveness of neuromuscular electrical stimulation (NMES) strength training in facioscapulohumeral muscular dystrophy (FSHD) patients.
Uncontrolled before-after trial.
Neuromuscular disease center in a university hospital and a private-practice physical therapy office.
FSHD patients (N=9; 3 women, 6 men; age 55.2+/-10.4y) clinically characterized by shoulder girdle and quadriceps femoris muscle weakness.
Patients underwent 5 months of strength training with NMES bilaterally applied to the deltoideus, trapezius transversalis, vastus lateralis, and vastus medialis muscles for five 20-minute sessions per week.
Plasma creatine kinase (CK) activity; scores for pain and fatigue on visual analog scales (VAS), manual muscle testing (MMT), maximal voluntary isometric contraction (MVIC), 6-minute walking tests (6MWT), and self-reported changes in daily living activities.
NMES strength training was well tolerated (CK activity and pain and fatigue scores on VAS were not modified). Most of the muscle functions (shoulder flexion and extension and knee extension) assessed by MMT were significantly increased. MVIC of shoulder flexion and abduction and the 6MWT distance were also improved.
In FSHD, NMES strength training appears to be safe with positive effects on muscle function, strength, and capacity for daily activities.
The many causes of the muscle edema pattern are best appreciated on MRI. An assessment of the morphology and distribution of the findings, combined with knowledge of background clinical information, is essential in formulating an accurate differential diagnosis.
Type 2 diabetes, cardiovascular diseases, colon cancer, breast cancer, dementia and depression constitute a cluster of diseases, which defines 'a diseasome of physical inactivity'. Both physical inactivity and abdominal adiposity, reflecting accumulation of visceral fat mass, are associated with the occurrence of the diseases within the diseasome. Physical inactivity appears to be an independent and strong risk factor for accumulation of visceral fat, which again is a source of systemic inflammation. Chronic inflammation is involved in the pathogenesis of insulin resistance, atherosclerosis, neurodegeneration and tumour growth. Evidence suggests that the protective effect of exercise may to some extent be ascribed to the anti-inflammatory effect of regular exercise, which can be mediated via a reduction in visceral fat mass and/or by induction of an anti-inflammatory environment with each bout of exercise. The finding that muscles produce and release myokines provides a conceptual basis to understand the mechanisms whereby exercise influences metabolism and exerts anti-inflammatory effects. According to our theory, contracting skeletal muscles release myokines, which work in a hormone-like fashion, exerting specific endocrine effects on visceral fat. Other myokines work locally within the muscle via paracrine mechanisms, exerting their effects on signalling pathways involved in fat oxidation.
The purpose of this study was to implement a quantitative MR imaging method for the determination of muscular and fat content in individual skeletal muscles of patients with facioscapulohumeral muscular dystrophy (FSHD). Turbo Inversion Recovery Magnitude (TIRM) and multiecho MR images were acquired from seven FSHD patients and healthy volunteers. Signal decay in the multiecho MR images was fitted to a biexponential function with fixed relaxation rates for muscle and fat tissue and used to calculate the degree of fatty infiltration in eight muscles in the lower leg. Considerable differences in fatty infiltration between different muscles were observed in FSHD patients, suggesting that this could be used as a biomarker for disease progression. TIRM imaging indicated an inflammatory component of the disease previously only observed in muscle biopsies. Typically, muscle involvement was non-uniform even within one muscle, indicating that MRI can be used as a valuable tool to study pathophysiology and therapy evaluation in FSHD.
Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant, 4q35-linked, slowly progressive muscular dystrophy with no known effective treatment. Since prednisone improves strength in Duchenne dystrophy, we performed a pilot, open-label trial of prednisone in eight subjects fulfilling strict diagnostic criteria for FSHD. Prednisone (1.5 mg/kg/day; maximum 80 mg/day) was administered for 12 weeks. Manual muscle testing, maximum voluntary isometric contraction testing, and muscle mass estimations by dual energy x-ray absorptiometry and urinary creatinine excretion were performed at baseline and at 12 weeks. There were no significant changes in strength or muscle mass. We conclude that prednisone given for 12 weeks does not produce major improvement in strength or increase muscle mass in FSHD. The study did not have sufficient power or length of follow-up to address the possibility that prednisone might arrest or slow disease progression.
This paper describes the assessment of physical activity in chronic fatigue syndrome (CFS) and investigated the following questions: Do patients with CFS have low levels of physical activity; is there a relationship between actual level of physical activity and fatigue; can self-report measures adequately assess actual level of physical activity; what is the role of cognitions with respect to physical activity; and are results with respect to physical activity specific to CFS? Three different types of activity measures were used: self-report questionnaires, a 12-day self-observation list, and a motion-sensing device (Actometer) which was used as a reference for actual activity level. Fifty-one patients with CFS, 50 fatigued patients with multiple sclerosis (MS), and 53 healthy subjects participated in this study. Although none of the self-report questionnaires showed high correlations with the Actometer, questionnaires that require simple ratings of specified activities were related to the Actometer and can be used as acceptable substitutes, in contrast to instruments that require general subjective interpretations of activity that had low or non-significant correlations with the Actometer. Actometer results showed that CFS patients and MS patients had similar activity levels and both groups were significantly less active than healthy subjects. Compared to MS patients, CFS patients were more likely to indicate that they had been less active than other persons they knew. Activities which patients expected to result in higher fatigue levels were less frequently performed. Patients with CFS had significantly higher scores on this measure than MS patients and healthy subjects. Low levels of physical activity were related to severe fatigue in CFS but not in MS. In conclusion, although CFS patients have similar low activity levels than MS patients, there are also important differences between both groups: in CFS cognitive factors are more prominently involved in producing the low activity levels than in MS and in CFS patients activity level is related to fatigue but not in MS.
Genotype analysis by using the p13E-11 probe and other 4q35 polymorphic markers was performed in 122 Italian facioscapulohumeral muscular dystrophy families and 230 normal controls. EcoRI-BlnI double digestion was routinely used to avoid the interference of small EcoRI fragments of 10qter origin that were found in 15% of the controls. An EcoRI fragment ranging between 10 and 28 kb that was resistant to BlnI digestion was detected in 114 of 122 families (93%) comprising 76 familial and 38 isolated cases. Among the unaffected individuals, 3 were somatic mosaics and 7, carrying an EcoRI fragment larger than 20 kb, could be rated as nonpenetrant gene carriers. In a cohort of 165 patients with facioscapulohumeral muscular dystrophy we found an inverse correlation between fragment size and clinical severity. A severe lower limb involvement was observed in 100% of patients with an EcoRI fragment size of 10 to 13 kb (1-2 KpnI repeats left), in 53% of patients with a fragment size of 16 to 20 kb (3-4 KpnI repeats left), and in 19% of patients with a fragment size larger than 21 kb (>4 KpnI repeats left). Our results confirm that the size of the fragment is a major factor in determining the facioscapulohumeral muscular dystrophy phenotype and that it has an impact on clinical prognosis and genetic counseling of the disease.
Changes in physical activity are thought to play an important role in maintaining symptoms in chronic fatigue syndrome (CFS). The aim of this study was to describe intraindividual physical activity patterns in more detail and to identify pervasively passive patients.
With help of a movement-sensing device, physical activity levels were registered continuously over a 12-day period in 277 CFS patients. Within this registration period, the 10 largest activity peaks were computed. The intensity and duration of these activity peaks and their subsequent rest periods were described and compared to those of 47 healthy controls. In addition, the patients' 12 daily activity scores were used to identify patients who were characterised by low levels of physical activity throughout the registration period.
The CFS sample had less intense and shorter activity peaks, while the average rest periods that followed these peaks lasted longer. Approximately one-fourth of the CFS sample differed distinctly from the control group and was labelled as pervasively passive.
The measurements and classification of actual physical activity levels were found to reduce heterogeneity in the CFS population and therefore could provide the opportunity to optimise behavioural intervention protocols for CFS.
The American Thoracic Society has issued guidelines for the 6-minute walk test (6MWT). The 6MWT is safer, easier to administer, better tolerated, and better reflects activities of daily living than other walk tests (such as the shuttle walk test). The primary measurement is 6-min walk distance (6MWD), but during the 6MWT data can also be collected about the patient's blood oxygen saturation and perception of dyspnea during exertion. When conducting the 6MWT do not walk with the patient and do not assist the patient in carrying or pulling his or her supplemental oxygen. The patient should walk alone, not with other patients. Do not use a treadmill on which the patient adjusts the speed and/or the slope. Do not use an oval or circular track. Use standardized phrases while speaking to the patient, because your encouragement and enthusiasm can make a difference of up to 30% in the 6MWD. Count the laps with a lap counter. If the 6MWD is low, thoroughly search for the cause(s) of the impairment. Better 6MWD reference equations will be published in the future, so be sure you are using the best available reference equations.
Facioscapulohumeral muscular dystrophy is a progressive muscle disease which has no agreed treatment. Early suggestions that corticosteroids might be helpful were not supported by a subsequent open label study. The beta 2 adrenergic agonist albuterol, also known as salbutamol, is known to have anabolic effects which might be beneficial for facioscapulohumeral muscular dystrophy. Creatine has been used as a muscle performance enhancer by athletes and it might be helpful in muscular dystrophies including facioscapulohumeral muscular dystrophy.
The objective of the review was to determine whether there is any drug treatment which alters the progression of facioscapulohumeral muscular dystrophy.
We searched the Cochrane Neuromuscular Disease Group specialised register (searched August 2003), MEDLINE (January 1966 to August 2003) and EMBASE (January 1980 to August 2003) for any references to facioscapulohumeral muscular dystrophy. Abstracts from the major neurological meetings and trial bibliographies were also searched for further references to trials. Experts were contacted for information regarding unpublished trials or trials in progress.
We included all randomised or quasi-randomised trials of any drug treatment for facioscapulohumeral muscular dystrophy, in adults with a recognised diagnosis of facioscapulohumeral muscular dystrophy. Trials had to include an assessment of muscle strength at one year.
Data collection and analysis:
All identified trials were independently assessed by both reviewers to ensure that they fulfilled the selection criteria and were then rated for their quality. Trial data were extracted and entered by one reviewer and checked by the other. If appropriate data existed a weighted treatment effect was to be calculated across trials using the Cochrane statistical package, Review Manager. The results were to have been expressed as relative risks and 95% confidence intervals and risk differences and 95% confidence intervals for dichotomous outcomes, and weighted mean differences and 95% confidence intervals for continuous outcomes.
Two published high quality randomised controlled trials fulfilled the selection criteria. One compared creatine supplementation with placebo and the other compared high and low-dose albuterol with placebo. A further unpublished randomised controlled trial of albuterol in facioscapulohumeral muscular dystrophy was identified. The creatine trial showed a non-significant difference in favour of creatine. The albuterol trial showed no significant difference in muscle strength at one year but some secondary measures such as lean body mass and handgrip strength did improve.
There is no evidence from randomised controlled trials to support any drug treatment for facioscapulohumeral muscular dystrophy but only two randomised controlled trials have been published.
In animals and healthy volunteers beta2-adrenergic agonists increase muscle strength and mass, in particular when combined with strength training. In patients with facioscapulohumeral muscular dystrophy (FSHD) albuterol may exert anabolic effects. The authors evaluated the effect of strength training and albuterol on muscle strength and volume in FSHD.
Sixty-five patients were randomized to strength training of elbow flexors and ankle dorsiflexors or non-training. After 26 weeks albuterol (sustained-release, 8 mg BID) was added in a randomized, double-blind, placebo-controlled design. Primary outcome was maximum voluntary isometric strength (MVIC) at 52 weeks. Secondary outcomes comprised dynamic strength and muscle volume.
Training and albuterol were well tolerated. Training of elbow flexors did not result in a significant effect on MVIC, but dynamic strength improved significantly. Elbow flexor MVIC strength increased significantly in albuterol vs placebo treated patients. Ankle dorsiflexor strength decreased in all groups. Eleven out of twelve non-trained muscles in the albuterol group showed a positive effect on MVIC compared to the placebo group (p < 0.05 in seven muscle groups). Muscle volume decreased in the placebo-treated, and increased in the albuterol-treated patients. No synergistic or antagonistic effects were observed between training and albuterol.
In FSHD strength training and albuterol appear safe interventions with limited positive effect on muscle strength and volume. Consequences of prolonged use are presently unclear, which precludes routine prescription.
Exercise programs have been shown to increase strength and endurance in patients with myopathic disorders. The authors investigated the effect of aerobic training in patients with facioscapulohumeral dystrophy (FSHD). Twelve weeks of low-intense aerobic exercise improved maximal oxygen uptake and workload with no signs of muscle damage. The authors conclude that aerobic training is a safe method to increase exercise performance in patients with FSHD.
Using MRI, we evaluated the degree of involvement of muscles in the lower extremities of 18 unselected patients with facioscapulohumeral muscular dystrophy (FSHD). Findings were correlated with fragment size of the mutated gene, age, disease duration and muscle power.
Most affected muscles were the hamstrings followed by the tibialis anterior and the medial gastrocnemius. The vastus-, gluteal- and peroneal muscles were the most unaffected, and the psoas muscle did not show evidence of involvement in any of the investigated subjects. Asymmetric involvement was evident in 15% of the investigated muscles on MRI and 6% on manual muscle strength testing. MRI findings in muscle tended to correlate with disease duration (r = 0.49; p < 0.05), but not with gene fragment size or age. MRI disclosed involvement of muscles performing hip flexion and ankle dorsal flexion that could not be detected by manual muscle strength testing. Otherwise, there was a close correlation (≈ r = 0.75; p < 0.0001) between muscle strength and MRI severity score for other muscle groups.
The present study shows that MRI may disclose muscle involvement in FSHD that is not apparent on manual muscle testing, and suggests that MRI of muscle may be an important assessment tool in clinical trials involving patients with FSHD.
Severe fatigue is reported by the majority of patients with three relatively common types of neuromuscular disorders.
This study aimed to identify predictors of fatigue in a longitudinal study and to develop a model of fatigue in patients with three neuromuscular disorders.
One hundred ninety-eight patients [60 facioscapulohumeral muscular dystrophy (FSHD), 70 adult-onset myotonic dystrophy (MD), and 68 hereditary motor and sensory neuropathy type I (HMSN-I) patients] were studied twice during an 18-month period. Fatigue severity was assessed by the Checklist Individual Strength. A multidimensional assessment method was used, including self-report questionnaires, a daily Self-Observation List, and physical activity (actometer). Muscle strength was determined using the Medical Research Council scale. Structural equation modeling was used to develop and test a model of factors contributing to the persistence of experienced fatigue.
Muscle strength, self-reported physical activity, sleep disturbances, and pain at baseline contributed directly or indirectly to fatigue and impairment at follow-up. Lower muscle strength contributed to lower levels of physical activity, which, in turn, contributed to fatigue severity. The model showed excellent fit for the whole group of neuromuscular disorders. In FSHD, pain also contributed to physical activity. A model with the actometer as measurement for actual physical activity instead of self-report showed an excellent model fit in FSHD and HMSN but an insufficient fit in MD.
The model of perpetuating factors for fatigue in FSHD and HMSN is different from the model in MD. The main difference is in physical (in)activity. These differences have implications for interventions based on these models.
Distinct disease phases in muscles of facioscapulohumeral dystrophy patients identified by MR detected fat infiltration
Janssen BH, Voet NB, Nabuurs CI, et al. Distinct disease
phases in muscles of facioscapulohumeral dystrophy patients identified by MR detected fat infiltration. PLoS
Best practice guidelines on genetic diagnostics of facioscapulohumeral muscular dystrophy: workshop 9th 2010, LUMC, Leiden, The Netherlands
Pw Van Der Maarel
Lemmers RJ, O'Shea S, Padberg GW, Lunt PW, van der
Maarel SM. Best practice guidelines on genetic diagnostics
of facioscapulohumeral muscular dystrophy: workshop 9th
2010, LUMC, Leiden, The Netherlands. Neuromuscul
R J Lemmers
G W Padberg
P W Lunt
S M Van Der Maarel
Lemmers RJ, O'Shea S, Padberg GW, Lunt PW, van der
Maarel SM. Best practice guidelines on genetic diagnostics
of facioscapulohumeral muscular dystrophy: workshop 9th
2010, LUMC, Leiden, The Netherlands. Neuromuscul