Muscle strength, quantity and quality and muscle fat quantity and their association with oxidative stress in patients with facioscapulohumeral muscular dystrophy: Effect of antioxidant supplementation.

The purpose of this study was to identify causes of quadriceps muscle weakness in facioscapulohumeral muscular dystrophy (FSHD). To this aim, we evaluated quadriceps muscle and fat volumes by magnetic resonance imaging and their relationships with muscle strength and oxidative stress markers in adult patients with FSHD (n = 32) and healthy controls (n = 7), and the effect of antioxidant supplementation in 20 of the 32 patients with FSHD (n = 10 supplementation and n = 10 placebo) (NCT01596803). Compared with healthy controls, the dominant quadriceps strength and quality (muscle strength per unit of muscle volume) were decreased in patients with FSHD. In addition, fat volume was increased, without changes in total muscle volume. Moreover, in patients with FSHD, the lower strength of the non-dominant quadriceps was associated with lower muscle quality compared with the dominant muscle. Antioxidant supplementation significantly changed muscle and fat volumes in the non-dominant quadriceps, and muscle quality in the dominant quadriceps. This was associated with improved muscle strength (both quadriceps) and antioxidant response. These findings suggest that quadriceps muscle strength decline may not be simply explained by atrophy and may be influenced also by the muscle intrinsic characteristics. As FSHD is associated with increased oxidative stress, supplementation might reduce oxidative stress and increase antioxidant defenses, promoting changes in muscle function.

DUX4 Role in Normal Physiology and in FSHD Muscular Dystrophy.

In the last decade, the sequence-specific transcription factor double homeobox 4 (DUX4) has gone from being an obscure entity to being a key factor in important physiological and pathological processes. We now know that expression of DUX4 is highly regulated and restricted to the early steps of embryonic development, where DUX4 is involved in transcriptional activation of the zygotic genome. While DUX4 is epigenetically silenced in most somatic tissues of healthy humans, its aberrant reactivation is associated with several diseases, including cancer, viral infection and facioscapulohumeral muscular dystrophy (FSHD). DUX4 is also translocated, giving rise to chimeric oncogenic proteins at the basis of sarcoma and leukemia forms. Hence, understanding how DUX4 is regulated and performs its activity could provide relevant information, not only to further our knowledge of human embryonic development regulation, but also to develop therapeutic approaches for the diseases associated with DUX4. Here, we summarize current knowledge on the cellular and molecular processes regulated by DUX4 with a special emphasis on FSHD muscular dystrophy.

p38 MAPKs - roles in skeletal muscle physiology, disease mechanisms, and as potential therapeutic targets.

p38 MAPKs play a central role in orchestrating the cellular response to stress and inflammation and in the regulation of myogenesis. Potent inhibitors of p38 MAPKs have been pursued as potential therapies for several disease indications due to their antiinflammatory properties, although none have been approved to date. Here, we provide a brief overview of p38 MAPKs, including their role in regulating myogenesis and their association with disease progression. Finally, we discuss targeting p38 MAPKs as a therapeutic approach for treating facioscapulohumeral muscular dystrophy and other muscular dystrophies by addressing multiple pathological mechanisms in skeletal muscle.

Increased resistance towards fatigability in patients with facioscapulohumeral muscular dystrophy.

PURPOSE: In facioscapulohumeral muscular dystrophy (FSHD) fatigue is a major complaint. We aimed to investigate whether during isometric sustained elbow flexions, performance fatigability indexes differ in patients with FSHD with respect to healthy controls. METHODS: Seventeen patients with FSHD and seventeen healthy controls performed two isometric flexions of the dominant biceps brachii at 20% of their maximal voluntary contraction (MVC) for 2 min and then at 60% MVC until exhaustion. Muscle weakness was characterized as a percentage of predicted values. Maximal voluntary strength, endurance time and performance fatigability indices (mean frequency of the power spectrum (MNF), muscle fiber conduction velocity (CV) and fractal dimension (FD)), extracted from the surface electromyogram signal (sEMG) were compared between the two groups. RESULTS: In patients with FSHD, maximal voluntary strength was 68.7% of predicted value (p < 0.01). Compared to healthy controls, FSHD patients showed reduced MVC (p < 0.001; r = 0.62) and lower levels of performance fatigability, characterized by reduced rate of changes in MNF (p < 0.01; r = 0.56), CV (p < 0.05; 0.37) and FD (p < 0.001; r = 0.51) and increased endurance time (p < 0.001; r = 0.63), during the isometric contraction at 60% MVC. CONCLUSION: A decreased reduction in the slopes of all the considered sEMG parameters during sustained isometric elbow flexions suggests that patients with FSHD experience lower levels of performance fatigability compared to healthy controls.

Reduced specific force in patients with mild and severe facioscapulohumeral muscular dystrophy.

BACKGROUND: Specific force, that is the amount of force generated per unit of muscle tissue, is reduced in patients with facioscapulohumeral muscular dystrophy (FSHD). The causes of reduced specific force and its relation with FSHD disease severity are unknown. METHODS: Quantitative muscle magnetic resonance imaging (MRI), measurement of voluntary maximum force generation and quadriceps force-frequency relationship, and vastus lateralis muscle biopsies were performed in 12 genetically confirmed patients with FSHD and 12 controls. RESULTS: Specific force was reduced by ~33% in all FSHD patients independent of disease severity. Quadriceps force-frequency relationship shifted to the right in severe FSHD compared to controls. Fiber type distribution in vastus lateralis muscle biopsies did not differ between groups. CONCLUSIONS: Reduced quadriceps specific force is present in all FSHD patients regardless of disease severity or fatty infiltration. Early myopathic changes, including fibrosis, and non-muscle factors, such as physical fatigue and musculoskeletal pain, may contribute to reduced specific force.

Motion sensor-acquired reachable workspace correlates with patient-reported upper extremity activities of daily living (ADL) function in facioscapulohumeral dystrophy.

BACKGROUND: This study examines the correlation, and clinical meaningfulness, between reachable workspace outcome and reported activities of daily living (ADL) function of individuals with facioscapulohumeral dystrophy (FSHD). METHODS: Twenty-one FSHD subjects with various disease severity (clinical severity scores 1-4) underwent reachable workspace evaluation and completed the Quality of Life in Neurological Disorders (NeuroQoL) upper extremity questionnaire. Spearman and receiver operator curve analyses were performed. RESULTS: Moderate correlation was found between NeuroQoL scores and total (ρ = 0.7609; P < .01), and upper-quadrants relative surface areas (RSAs) (ρ = 0.6969; P < .01). Five specific items (ie, shirt on, shirt off, use spoon, pull on pants, pick-up clothes) demonstrated even higher correlations with total (ρ = 0.8397; P < .01) and above shoulder (ρ = 0.8082; P < .01) RSAs. A total RSA cuffoff value of 0.70 would achieve 100% sensitivity and 94% specificity (area under the curve = 0.975). CONCLUSIONS: Reachable workspace values identify when individuals have difficulties performing ADLs at home. This information improves patient monitoring, and clinical decision making by enabling more timely recommendations for medications, assistive devices, or considerations for clinical trial enrollments.

Rasch analysis to evaluate the motor function measure for patients with facioscapulohumeral muscular dystrophy.

Patient-relevant outcome measures for facioscapulohumeral muscular dystrophy (FSHD) are needed. The motor function measure (MFM) is an ordinal-based outcome measure for neuromuscular disorders, but its suitability to measure FSHD patients is questionable. Here, we performed Rasch analyses on MFM data from 194 FSHD patients to assess clinimetric properties in this patient group. Both the total scale and its three domains were analyzed (D1: standing position and transfers; D2: axial and proximal motor function; D3: distal motor function). Fit to the Rasch model, sample-item targeting, individual item fit, threshold ordering, sex- and age-based differential item functioning, response dependency and unidimensionality were assessed. Rasch analysis revealed multiple limitations of the MFM for FSHD, the most important being a large ceiling effect and suboptimal sample-item targeting, which were most pronounced for domains D2 and D3. There were disordered thresholds for most items, often resulting in items functioning in a dichotomous fashion. It was not possible to remodel the MFM into a Rasch-built interval scale. Remodeling of domain D1 into an interval scale with adequate fit statistics was achieved, but sample-item targeting remained suboptimal. Therefore, the MFM should be used with caution in FSHD patients, as it is not optimally suited to measure functional abilities in this patient group.

Updated size index valid for both neurogenic and myogenic changes.

BACKGROUND: Size index (SI) is a motor unit potential (MUP) parameter in concentric needle electromyography calculated from amplitude and area/amplitude, which can sensitively discriminate between control and neurogenic MUPs. In this study, we investigated the application of SI to myogenic MUPs based on expanded data. METHODS: MUPs were collected from the biceps brachii (BB) and tibialis anterior (TA) muscles. Muscles showing unequivocal neurogenic or myogenic changes by visual inspection were selected for patients. In addition to the original SI, a revised SI (rSI) was defined using the logarithmic scale for area/amplitude. The coefficient for area/amplitude was varied and that achieving the best sensitivity both for BB and TA was selected. RESULTS: Analyzed were 1619, 340, and 498 MUPs from the BB of 26, 10, and 14 subjects (control, neurogenic, and myogenic), respectively, and 1245, 536, and 473 MUPs from the TA of 23, 18, and 13 subjects (control, neurogenic, and myogenic), respectively. For neurogenic MUPs, the original SI and the newly defined rSIn were similarly sensitive (82.1% and 81.8% sensitivity for SI and rSIn, respectively, for BB, and 68.1% and 69.6% for TA), and were more sensitive than area (72.6% for BB and 57.6% for TA), the most sensitive parameter among conventional ones. For myogenic MUPs, the sensitivity of rSIm was 9.0% for BB and 24.5% for TA, which was not significantly different from duration (7.4% for BB and 21.8% for TA), the most sensitive parameter among conventional ones. CONCLUSIONS: SI, rSIn, and rSIm are promising as new MUP parameters.

Facioscapulohumeral muscular dystrophy (FSHD) and multiple sclerosis: a case report.

Facioscapulohumeral muscular dystrophy 1 (FSHD1) is an autosomal dominant neuromuscular disorder, associated with reduction of tandemly arrayed repetitive DNA elements D4Z4 (DRA), at 4q35. Few cases, especially carriers of 1-3 DRA show a syndromic form. Anecdotally the association of FSHD with multiple sclerosis (MS) is reported. Herein we report a 33 years old Caucasian with a molecular diagnosis of FSHD1 with classical phenotype (clinical category A2) and concomitant white matter lesions suggestive of MS. White matter lesions in patients with FSHD have often been described but rarely investigated in order to evaluate a possible diagnosis of MS. We think that MS and FSHD remain clearly distinct diseases, but growing evidences show a widespread and variable activation of the immune system in patients suffering from FSHD probably an hypotheses on a potential common pathogenetic mechanism between these two disorders could should be better investigated.

Evaluation of inflammatory lesions over 2 years in facioscapulohumeral muscular dystrophy.

OBJECTIVE: We followed up patients with facioscapulohumeral muscular dystrophy (FSHD) with sequential examinations over 2 years to investigate whether inflammatory lesions always precede fat replacement, if inflammation can be resolved without muscle degeneration, and if inflammatory lesions in muscle are always followed by fat replacement. METHODS: In this longitudinal study of 10 sequential MRI assessments over 2.5 years, we included 10 patients with FSHD. We used MRI with short TI inversion recovery to identify regions of interest (ROIs) with hyperintensities indicating muscle inflammation. Muscle T2 relaxation time mapping was used as a quantitative marker of muscle inflammation. Dixon sequences quantified muscle fat replacement. Ten healthy controls were examined with a magnetic resonance scan once for determination of normal values of T2 relaxation time. RESULTS: We identified 68 ROIs with T2 elevation in the patients with FSHD. New ROIs with T2 elevation arising during the study had muscle fat content of 6.4% to 33.0% (n = 8) and 47.0% to 78.0% lesions that resolved (n = 6). ROIs with T2 elevation had a higher increase in muscle fat content from visits 1 to 10 (7.9 ± 7.9%) compared to ROIs with normal muscle T2 relaxation times (1.7 ± 2.6%; p < 0.0001). Severe T2 elevations were always followed by an accelerated replacement of muscle by fat. CONCLUSIONS: Our results suggest that muscle inflammation starts in mildly affected muscles in FSHD, is related to a faster muscle degradation, and continues until the muscles are completely fat replaced. CLINICALTRIALSGOV IDENTIFIER: NCT02159612.

Facioscapulohumeral muscular dystrophy 1 patients participating in the UK FSHD registry can be subdivided into 4 patterns of self-reported symptoms.

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant incurable skeletal muscle disease. FSHD1 constitutes 95% of cases and is linked to truncation of the D4Z4 macrosatellite at 4q35. In most cases the condition initially presents with facial and proximal weakness of the upper limbs, but over the course of the disease involves lower limb and truncal muscles. Weakness is progressive and frequently asymmetric, which is a hallmark of the disease. Here we performed an analysis of 643 FSHD1 patients in the UK FSHD patient registry, investigating factors affecting rate of onset of 5 major FSHD symptoms: facial, periscapular, foot dorsiflexor, hip girdle weakness, and hearing loss. We found shorter D4Z4 repeat length associated with accelerated onset of each symptom. Furthermore, paternal inheritance of the pathogenic allele was associated with accelerated onset of foot dorsiflexor weakness, while pregnancy and carrying multiple children to term was associated with slower onset of all muscle symptoms. Lastly, we performed clustering analysis on age of onset of the 4 muscle symptoms across 222 patients. We identified 4 clinical presentations of FSHD1. A classical presentation (74%) and 3 facial sparing phenotypes: a mild presentation (5%) with later facial and periscapular involvement, an early shoulder presentation (10%) with accelerated periscapular weakness and an early foot presentation (9%) with accelerated foot dorsiflexor weakness. The mild presentation was associated with longer D4Z4 repeat lengths, while the early foot presentation had a female bias. We note, however that symptom progression differs significantly in these 4 clinical presentations independently of D4Z4 repeat length and gender, motivating investigation of further modifiers of FSHD1 severity.

Spinal fusion in facioscapulohumeral dystrophy for hyperlordosis: A case report.

RATIONALE: Facioscapulohumeral muscular dystrophy (FSHD) is the third most common muscular dystrophy, which is associated with facial, shoulder girdle, and paraspinal muscle atrophy. Most of the patients develop hypokyphosis and hyperlordosis in the course of the disease, to preserve standing posture. Corrective fusion is contraindicated in these patients as the surgery results with loss of compensatory hyperlordosis and leads to loss of trunk balance while standing. Although spinal fusion in neuromuscular scoliosis is a known treatment option, there are no studies in the literature on the spinal fusion of this specific patient group. PATIENT CONCERNS: In this case report we have presented a 66-year-old woman, who was admitted with back and abdominal pain, inability to sit straight, abdominal discomfort, and numbness in the lower extremities after prolonged sitting. DIAGNOSES: The patient developed severe hyperlordosis causing intra-abdominal disorders, radicular symptoms, and sitting discomfort due to FSHD. INTERVENTIONS: The patient underwent T2-S1 fusion and successful fusion was achieved. OUTCOMES: Individualized Neuromuscular Quality of Life Questionnaire (INQoL) was used to assess preoperative and 3 years postoperative functional outcomes. All domains and total score improved at the end of the follow-up period and successful fusion was verified radiologically. LESSONS: This case suggests that spinal fusion may provide functional improvement in carefully selected patient groups. Patient stratification considering spinal disability is required for further studies in this specific indication.

Bilateral scapulothoracic arthrodesis for facioscapulohumeral muscular dystrophy: function, fusion, and respiratory consequences.

BACKGROUND: Scapulothoracic arthrodesis (STA) has been proposed for the treatment of painful scapular winging in patients with facioscapulohumeral muscular dystrophy (FSHD). However, the rate of osseous fusion is variable, and there is a theoretical risk of reduced respiratory function after bilateral STA. METHODS: This was a retrospective study of 10 STAs, performed sequentially, in 5 FSHD patients. The surgical technique involved use of a semitubular plate and wire construct with autograft (iliac crest) interposed between the scapula and rib cage. Osseous fusion, respiratory function, and shoulder function were evaluated. The mean follow-up period was 141 ± 67 months (range, 24-225 months). RESULTS: Early complications included 1 pneumothorax and 1 pleural effusion. No late complications occurred, and no patients underwent reoperation. On postoperative computed tomography images, complete bony union of the scapula to the ribs was observed in 90% of shoulders (9 of 10). Comparison of preoperative and postoperative pulmonary function test results showed no significant difference in vital capacity (from 87% ± 14% to 85% ± 12%) and forced vital capacity (from 86% ± 16% to 77% ± 15%). Patients gained on average 40° of active forward elevation (from 62° ± 20° to 102° ± 4°) and 22° of abduction (from 58° ± 21° to 89° ± 7°) (P < .001). The mean Subjective Shoulder Value increased from 25% ± 8% to 72% ± 18% (P < .001). All patients were pleased with the results and would recommend the procedure to other persons. CONCLUSION: In patients with FSHD, bilateral STA provides satisfactory shoulder function with a high rate of scapulothoracic fusion and few or no significant respiratory repercussions.

Preserved single muscle fiber specific force in facioscapulohumeral muscular dystrophy.

OBJECTIVE: To investigate single muscle fiber contractile performance in muscle biopsies from patients with facioscapulohumeral muscular dystrophy (FSHD), one of the most common hereditary muscle disorders. METHODS: We collected 50 muscle biopsies (26 vastus lateralis, 24 tibialis anterior) from 14 patients with genetically confirmed FSHD and 12 healthy controls. Single muscle fibers (n = 547) were isolated for contractile measurements. Titin content and titin phosphorylation were examined in vastus lateralis muscle biopsies. RESULTS: Single muscle fiber specific force was intact at saturating and physiologic calcium concentrations in all FSHD biopsies, with (FSHDFAT) and without (FSHDNORMAL) fatty infiltration, compared to healthy controls. Myofilament calcium sensitivity of force is increased in single muscle fibers obtained from FSHD muscle biopsies with increased fatty infiltration, but not in FSHD muscle biopsies without fatty infiltration (pCa50: 5.77-5.80 in healthy controls, 5.74-5.83 in FSHDNORMAL, and 5.86-5.90 in FSHDFAT single muscle fibers). Cross-bridge cycling kinetics at saturating calcium concentrations and myofilament cooperativity did not differ from healthy controls. Development of single muscle fiber passive tension was changed in all FSHD vastus lateralis and in FSHDFAT tibialis anterior, resulting in increased fiber stiffness. Titin content was increased in FSHD vastus lateralis biopsies; however, titin phosphorylation did not differ from healthy controls. CONCLUSION: Muscle weakness in patients with FSHD is not caused by reduced specific force of individual muscle fibers, even in severely affected tissue with marked fatty infiltration of muscle tissue.

Magnetic resonance imaging correlates with electrical impedance myography in facioscapulohumeral muscular dystrophy.

INTRODUCTION: 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 variables with muscle structure measured by MRI. METHODS: We evaluated 20 patients with FSHD at two 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, MRI T1-based muscle severity score (T1 muscle score), and MRI quantitative intramuscular Dixon fat fraction (FF). RESULTS: 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). DISCUSSION: 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.

Functional Outcomes and Complications Following Scapulothoracic Arthrodesis in Patients with Facioscapulohumeral Dystrophy.

BACKGROUND: Facioscapulohumeral dystrophy (FSHD) is an autosomal-dominant myopathy characterized by facial and shoulder girdle muscle weakness with scapular winging. Scapulothoracic arthrodesis is a successful treatment approach for patients with <90° of shoulder elevation. The purpose of the present study was to assess functional outcomes and complications following scapulothoracic arthrodesis in patients with FSHD. METHODS: We retrospectively reviewed the records of 40 patients (64 shoulders) in whom scapulothoracic arthrodesis was performed. To achieve fusion, multiple multifilament cables were used together with autologous bone and allograft bone. Preoperative and postoperative shoulder elevation and abduction; Disabilities of the Arm, Shoulder and Hand (Quick version, qDASH) scores; and pulmonary function were compared. Recorded complications were classified as pulmonary or scapular. RESULTS: The mean age of the patients at the time of the operation was 25.4 years (range, 15 to 60 years), and the mean duration of follow-up was 71.2 months (range, 12 to 185 months). When the preoperative values were compared with those at the latest follow-up, significant improvement was noted in terms of elevation (from a mean [and standard deviation] of 60.6° ± 17.2° to 123.7° ± 26.7°; p < 0.001), abduction (from 52.7° ± 15.8° to 98.8° ± 20.3°; p < 0.001), and qDASH scores (from 34.7 ± 11.4 to 13.3 ± 13.1; p < 0.001). The overall complication rate was 26.6%. There were 7 pulmonary complications (4 pneumothoraxes, 2 pleural effusions, and 1 major atelectasis), and 5 chest tube placements were required. Ten complications (including 3 rib fractures, 1 brachial plexus palsy, 2 cases of implant irritation, 2 nonunions, 1 delayed union, and 1 scapular fracture) were related to the scapular fixation, and 7 revision procedures were required. Scapulothoracic fusion was achieved in all patients but 1, who had a scapular fracture. Pulmonary function tests were performed for 19 patients, and no difference was observed between preoperative and postoperative results. CONCLUSIONS: Scapulothoracic arthrodesis with use of multifilament cables is a successful surgical technique with high fusion rates and low morbidity. Pulmonary complications are common but resolve with careful attention. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.