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Contains fulltext : 235675.pdf (Publisher’s version ) (Open Access) 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.

The diagnosis of facioscapulohumeral muscular dystrophy (FSHD) can be challenging in patients not displaying the classical phenotype or with atypical clinical features. Despite the identification by magnetic resonance imaging (MRI) of selective patterns of muscle involvement, their specificity and added diagnostic value are unknown. We aimed to identify the radiological features more useful to distinguish FSHD from other myopathies and test the diagnostic accuracy of MRI. A retrospective cohort of 295 patients (187 FSHD, 108 non-FSHD) studied by upper and lower-limb muscle MRI was analyzed. Scans were evaluated for the presence of 15 radiological features. A random forest machine learning algorithm was used to identify the most relevant for FSHD diagnosis. Different patterns were created by their combination and diagnostic accuracy of each of them was tested. The combination of trapezius involvement and bilateral subscapularis muscle sparing achieved the best diagnostic accuracy (0.89, 95% Confidence Interval [0.85–0.92]) with 0.90 [0.85–0.94] sensitivity and 0.88 [0.80–0.93] specificity. This pattern correctly identified 91% atypical FSHD patients of our cohort. The combination of trapezius involvement, bilateral subscapularis and iliopsoas sparing and asymmetric involvement of upper and lower-limb muscles was pathognomonic for FSHD, yielding a specificity of 0.99 [0.95–1.00]. We identified MRI patterns that showed a high diagnostic power in promptly discriminating FSHD from other muscle disorders, with comparable performance irrespective of typical or atypical clinical features. Upper girdle in addition to lower-limb muscle imaging should be extensively implemented in the diagnostic workup to support or exclude a diagnosis of FSHD.

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.

Background High quality care of patients with neuromuscular diseases requires a personalised approach that focuses on achieving and maintaining a level of functioning that enables them to be in a state of well-being. The capability approach states that well-being should be understood in terms of capabilities, the substantial opportunities that people have to be and do things they have reasons to value. In this Rehabilitation and Capability care for patients with Neuromuscular diseases (ReCap-NMD) study, we want to investigate whether providing care based on the capability approach (capability care) has an added value in the rehabilitation of patients with neuromuscular diseases (NMD). Methods Two groups of 30 adult patients with facioscapulohumeral muscular dystrophy or myotonic dystrophy type 1 will be included. The first group will receive rehabilitation care as usual with a follow-up period of 6 months. Then, based on theory, and experiences of patients and healthcare professionals, capability care will be developed. During the following 3 months, the multidisciplinary outpatient rehabilitation care team will be trained in providing this newly developed capability care. Subsequently, the second group will receive capability care, with a follow-up period of 6 months. A mixed methods approach is used with both qualitative and quantitative outcome measures to evaluate the effect of capability care and to perform a process evaluation. The primary outcome measure will be the Canadian Occupational Performance Measure. Discussion The ReCap-NMD study is the first study to design and implement a healthcare intervention based on the capability approach. The results of this study will expand our knowledge on how the capability approach can be applied in delivering and evaluating healthcare, and will show whether implementing such an intervention leads to a higher well-being for patients with NMD. Trial registration Registered at Trialregister.nl (Trial NL8946) on 12th of October, 2020.

Background: FSHD is caused by specific genetic mutations resulting in activation of the Double Homeobox 4 gene (DUX4). DUX4 targets hundreds of downstream genes eventually leading to muscle atrophy, oxidative stress, abnormal myogenesis, and muscle inflammation. We hypothesized that DUX4-induced aberrant expression of genes triggers a sustained autoimmune response against skeletal muscle cells. Objective: This study aimed at the identification of autoantibodies directed against muscle antigens in FSHD. Moreover, a possible relationship between serum antibody reactivity and DUX4 expression was also investigated. Methods: FSHD sera (N = 138, 48±16 years, 48% male) and healthy control sera (N = 20, 47±14 years, 50% male) were analyzed by immunoblotting for antibodies against several skeletal muscle protein extracts: healthy muscle, FSHD muscle, healthy and FSHD myotubes, and inducible DUX4 expressing myoblasts. In addition, DUX4 expressing myoblasts were analyzed by immunofluorescence with FSHD and healthy control sera. Results: The results showed that the reactivity of FSHD sera did not significantly differ from that of healthy controls, with all the tested muscle antigen extracts. Besides, the immunofluorescent staining of DUX4-expressing myoblasts was not different when incubated with either FSHD or healthy control sera. Conclusion: Since the methodology used did not lead to the identification of disease-specific autoantibodies in the FSHD cohort, we suggest that autoantibody-mediated pathology may not be an important disease mechanism in FSHD. Nevertheless, it is crucial to further unravel if and which role the immune system plays in FSHD pathogenesis. Other innate as well as adaptive immune players could be involved in the complex DUX4 cascade of events and could become appealing druggable targets.

Contains fulltext : 229514.pdf (Publisher’s version ) (Open Access) 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.

Facioscapulohumeral muscular dystrophy (FSHD) is caused by a complex epigenetic mechanism finally leading to the misexpression of DUX4 in skeletal muscle. Detecting DUX4 and quantifying disease progression in FSHD is extremely challenging, thus increasing the need for surrogate biomarkers. We applied a shotgun proteomic approach with two different setups to analyze the protein repertoire of interstitial fluids obtained from 20 muscles in different disease stages classified by magnetic resonance imaging (MRI) and serum samples from 10 FSHD patients. A total of 1156 proteins were identified in the microdialysates by data independent acquisition, 130 of which only found in muscles in active disease stage. Proteomic profiles were able to distinguish FSHD patients from controls. Two innate immunity mediators (S100-A8 and A9) and Dermcidin were upregulated in muscles with active disease and selectively present in the sera of FSHD patients. Structural muscle and plasminogen pathway proteins were downregulated. Together with the upstream inhibition of myogenic factors, this suggests defective muscle regeneration and increased fibrosis in early/active FSHD. Our MRI targeted exploratory approach confirmed that inflammatory response has a prominent role, together with impaired muscle regeneration, before clear muscle wasting occurs. We also identified three proteins as tissue and possibly circulating biomarkers in FSHD.

Facioscapulohumeral Muscular Dystrophy (FSHD) is in the top three list of all dystrophies with an approximate 1:8000 incidence. It is not a life-threatening disease; however, the progression of the disease extends over being wheelchair bound. Despite some drug trials continuing, including DUX4 inhibition, TGF-ß inhibition and resokine which promote healthier muscle, there is not an applicable treatment option for FSHD today. Still, there is a need for new agents to heal, stop or at least slow down muscle wasting. Current FSHD studies involving nutraceuticals as vitamin C, vitamin E, coenzyme Q10, zinc, selenium, and phytochemicals as curcumin or genistein, daidzein flavonoids provide promising treatment strategies. In this review, we present the clinical and molecular nature of FSHD and focus on nutraceuticals and phytochemicals that may alleviate FSHD. In the light of the association of impaired pathophysiological FSHD pathways with nutraceuticals and phytochemicals according to the literature, we present both studied and novel approaches that can contribute to FSHD treatment.

Facioscapulohumeral dystrophy (FSHD) is associated with the upregulation of the DUX4 transcription factor and its target genes. However, low-frequency DUX4 upregulation in patient myocytes is difficult to detect and examining the relationship and dynamics of DUX4 and target gene expression has been challenging. Using RNAScope in situ hybridization with highly specific probes, we detect the endogenous DUX4 and target gene transcripts in situ in patient skeletal myotubes during 13-day differentiation in vitro. We found that the endogenous DUX4 transcripts primarily localize as foci in one or two nuclei as compared with the accumulation of the recombinant DUX4 transcripts in the cytoplasm. We also found the continuous increase of DUX4 and target gene-positive myotubes after Day 3, arguing against its expected immediate cytotoxicity. Interestingly, DUX4 and target gene expression become discordant later in differentiation with the increase of DUX4-positive/target gene-negative as well as DUX4-negative/target gene-positive myotubes. Depletion of DUX4-activated transcription factors, DUXA and LEUTX, specifically repressed a DUX4-target gene, KDM4E, later in differentiation, suggesting that after the initial activation by DUX4, target genes themselves contribute to the maintenance of downstream gene expression. Together, the study provides important new insights into the dynamics of the DUX4 transcriptional network in FSHD patient myocytes.

Muscle inflammation is an important component of disease pathophysiology in several muscular dystrophies. Hyperintensities on MRI sequences with short TI inversion recovery (STIR) reflect edema, or inflammation (STIR+). Conventionally, STIR evaluation has been done by visual inspection. In this study, we developed a quantitative STIR method, and tested its ability to identify STIR+ lesions in healthy controls and patients with Facioscapulohumeral muscular dystrophy and compared the results with visual STIR evaluation and quantitative T2 relaxation time mapping. The method was based on pixel-by-pixel histograms of the distribution of signal intensities from muscles. Signal intensities from healthy control muscles were averaged and used to define an upper reference limit. Muscles with >2.5% pixels above the limit were defined as being STIR+. The new method showed agreement with T2 relaxation time mapping in 95% of muscles. The visual STIR method only showed agreement with the quantitative STIR method and T2 relaxation time mapping in 88 and 84%, respectively. STIR sequences are available on most MR scanners and the post-processing used in the new quantitative method can be performed using free software. We therefore believe that the new method can play an important role in identifying STIR+ lesions in patients with neuromuscular diseases.

Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common forms of muscular dystrophy and presents with weakness of the facial, scapular and humeral muscles, which frequently progresses to the lower limbs and truncal areas, causing profound disability. Myopathy results from epigenetic de-repression of the D4Z4 microsatellite repeat array on chromosome 4, which allows misexpression of the developmentally regulated DUX4 gene. DUX4 is toxic when misexpressed in skeletal muscle and disrupts several cellular pathways, including myogenic differentiation and fusion, which likely underpins pathology. DUX4 and the D4Z4 array are strongly conserved only in primates, making FSHD modeling in non-primate animals difficult. Additionally, its cytotoxicity and unusual mosaic expression pattern further complicate the generation of in vitro and in vivo models of FSHD. However, the pressing need to develop systems to test therapeutic approaches has led to the creation of multiple engineered FSHD models. Owing to the complex genetic, epigenetic and molecular factors underlying FSHD, it is difficult to engineer a system that accurately recapitulates every aspect of the human disease. Nevertheless, the past several years have seen the development of many new disease models, each with their own associated strengths that emphasize different aspects of the disease. Here, we review the wide range of FSHD models, including several in vitro cellular models, and an array of transgenic and xenograft in vivo models, with particular attention to newly developed systems and how they are being used to deepen our understanding of FSHD pathology and to test the efficacy of drug candidates., Summary: Owing to its complex etiology and the toxicity of DUX4, modeling facioscapulohumeral muscular dystrophy (FSHD) is uniquely challenging. Here, we review the approaches that overcame these difficulties to develop highly relevant FSHD models.

Case A 32-year-old male right-hand dominant school-bus driver with facioscapulohumeral dystrophy (FSHD) was referred to an upper limb specialist for consideration for scapulothoracic fusion (STF) because of limited upper limb function and cosmetic issues. Staged bilateral STFs were performed with seven high-strength suture tapes tensioned to secure a standard tubular plate in situ. Conclusion STF may be a desirable treatment option for patients with FSHD. The use of high-strength suture tapes in cases of STF allows for secure fixation of the scapulothoracic joint. This potentially confers a reduction in operative time while ensuring adequate tensioned fixation and minimizing the risk of iatrogenic pneumothorax.

Reports of patients with concomitant diagnoses of two inherited genetic disorders, sometimes referred to as "double trouble," have appeared intermittently in the medical literature. We report eight additional cases with dual diagnoses of two genetic conditions. All cases had a phenotype atypical for their primary diagnosis, leading to the search for a second genetic diagnosis. These cases highlight the importance of the history, physical examination and continued work-up if the phenotype of the patient falls drastically outside what has been reported with their primary diagnosis. Some of the diagnoses of the patients presented here (e.g., Myotonic Dystrophy Type 1, fascioscapulohumeral muscular dystrophy) would not have been identified by genetic testing done on a next generation sequencing backbone (e.g., panel or exome sequencing). When the clinical picture is atypical or more severe than expected the possibility of a dual diagnosis (double trouble) should be considered. Identification of a second genetic condition can impact management and genetic counseling.

Deficits in plasma membrane repair have been identified in dysferlinopathy and Duchenne Muscular Dystrophy, and contribute to progressive myopathy. Although Facioscapulohumeral Muscular Dystrophy (FSHD) shares clinicopathological features with these muscular dystrophies, it is unknown if FSHD is characterized by plasma membrane repair deficits. Therefore, we exposed immortalized human FSHD myoblasts, immortalized myoblasts from unaffected siblings, and myofibers from a murine model of FSHD (FLExDUX4) to focal, pulsed laser ablation of the sarcolemma. Repair kinetics and success were determined from the accumulation of intracellular FM1-43 dye post-injury. We subsequently treated FSHD myoblasts with a DUX4-targeting antisense oligonucleotide (AON) to reduce DUX4 expression, and with the antioxidant Trolox to determine the role of DUX4 expression and oxidative stress in membrane repair. Compared to unaffected myoblasts, FSHD myoblasts demonstrate poor repair and a greater percentage of cells that failed to repair, which was mitigated by AON and Trolox treatments. Similar repair deficits were identified in FLExDUX4 myofibers. This is the first study to identify plasma membrane repair deficits in myoblasts from individuals with FSHD, and in myofibers from a murine model of FSHD. Our results suggest that DUX4 expression and oxidative stress may be important targets for future membrane-repair therapies.

In this article we address the relevance of rare diseases and their peculiarities with respect to pain therapy. Towards this end, four rare diseases (hemophilia, Morbus Fabry, dermatomyositis, and facioscapulohumeral dystrophy (FSHD)) will be presented and fundamental aspects of their pain therapies described. The diseases were chosen to showcase a pain therapy based on the WHO-step-by-step plan (hemophilia), a complex but established pain therapy (M. Fabry), and two less well established, individually adapted pain therapies (dermatomyositis, FSHD).

Facioscapulohumeral muscular dystrophy (FSHD) is an inherited muscle disease caused by misexpression of the DUX4 gene in skeletal muscle. DUX4 is a transcription factor, which is normally expressed in the cleavage-stage embryo and regulates gene expression involved in early embryonic development. Recent studies revealed that DUX4 also activates the transcription of repetitive elements such as endogenous retroviruses (ERVs), mammalian apparent long terminal repeat (LTR)-retrotransposons and pericentromeric satellite repeats (Human Satellite II). DUX4-bound ERV sequences also create alternative promoters for genes or long non-coding RNAs, producing fusion transcripts. To further understand transcriptional regulation by DUX4, we performed nanopore long-read direct RNA sequencing (dRNA-seq) of human muscle cells induced by DUX4, because long reads show whole isoforms with greater confidence. We successfully detected differential expression of known DUX4-induced genes and discovered 61 differentially expressed repeat loci, which are near DUX4–ChIP peaks. We also identified 247 gene–ERV fusion transcripts, of which 216 were not reported previously. In addition, long-read dRNA-seq clearly shows that RNA splicing is a common event in DUX4-activated ERV transcripts. Long-read analysis showed non-LTR transposons including Alu elements are also transcribed from LTRs. Our findings revealed further complexity of DUX4-induced ERV transcripts. This catalogue of DUX4-activated repetitive elements may provide useful information to elucidate the pathology of FSHD. Also, our results indicate that nanopore dRNA-seq has complementary strengths to conventional short-read complementary DNA sequencing.

Facioscapulohumeral muscular dystrophy (FSHD), characterized by progressive muscle weakness and deterioration, is genetically linked to aberrant expression of

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A 35-year-old right-handed man was referred with gradually progressive bilateral shoulder weakness, first noticed at age 16 when he was unable to fully lift his arms above his head. On examination, he had bilateral severe wasting of trapezius muscles, associated marked scapular winging and some

Facioscapulohumeral muscular dystrophy (FSHD) is the third most common form of muscular dystrophy. The disease is named by the initial pattern of weakness, with patients developing facial weakness, scapular winging, and foot drop. As the disorder progresses, other muscles, particularly truncal muscles, are affected and may lead to loss of ambulation. The genetic mechanism has been more clearly elucidated in the past decade. It is clear that the central pathogenic mechanism is epigenetic derepression. A downstream consequence of depression of the D4Z4 units on the long arm of chromosome 4 is expression of DUX4 , which is known to only be naturally expressed early in embryogenesis. In FSHD, expression of DUX4 is the key and leads to muscle damage and fibrosis. The most common mechanism resulting in DUX4 derepression is a deletion of multiple integral copies of the D4Z4 repetitive element on chromosome 4.1 What has been evolving is the discovery of other less common causes of the epigenetic derepression, including those in other genes that have a role in chromatin repression ( SMCHD1 and DNMT3B ).2,3

Purpose Quantitative MRI (qMRI) plays a crucial role for assessing disease progression and treatment response in neuromuscular disorders, but the required MRI sequences are not routinely available in every center. The aim of this study was to predict qMRI values of water T2 (wT2) and fat fraction (FF) from conventional MRI, using texture analysis and machine learning. Method Fourteen patients affected by Facioscapulohumeral muscular dystrophy were imaged at both thighs using conventional and quantitative MR sequences. Muscle FF and wT2 were calculated for each muscle of the thighs. Forty-seven texture features were extracted for each muscle on the images obtained with conventional MRI. Multiple machine learning regressors were trained to predict qMRI values from the texture analysis dataset. Results Eight machine learning methods (linear, ridge and lasso regression, tree, random forest (RF), generalized additive model (GAM), k-nearest-neighbor (kNN) and support vector machine (SVM) provided mean absolute errors ranging from 0.110 to 0.133 for FF and 0.068 to 0.115 for wT2. The most accurate methods were RF, SVM and kNN to predict FF, and tree, RF and kNN to predict wT2. Conclusion This study demonstrates that it is possible to estimate with good accuracy qMRI parameters starting from texture analysis of conventional MRI.

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.

Key Points Question What are the phenotypes expressed among patients with facioscapulohumeral muscular dystrophy (FHSD) who are carriers of D4Z4 reduced allele with 7 to 8 repeat units? Findings In this cross-sectional study of 187 probands and 235 relatives who carry a D4Z4 reduced allele with 7 to 8 repeat units, 47.1% of probands did not have the classic FSHD phenotype, and 52.8% of the carrier relatives were nonpenetrant. In 106 families, 18.9% had a member with autosomal dominant FSHD, whereas in 34.9%, the proband was the only participant expressing a myopathic phenotype. Meaning The findings of this study suggest that knowledge of phenotypic variation in the expression of D4Z4 reduced allele with 7 to 8 repeat units in individuals with FSHD could be informative for clinical management and genetic counseling., This cross-sectional study investigates the clinical expression of facioscapulohumeral muscular dystrophy (FSHD) in the genetic subgroup of carriers of D4Z4 reduced allele with 7 to 8 repeat units., Importance Facioscapulohumeral muscular dystrophy (FSHD) is considered an autosomal dominant disorder, associated with the deletion of tandemly arrayed D4Z4 repetitive elements. The extensive use of molecular analysis of the D4Z4 locus for FSHD diagnosis has revealed wide clinical variability, suggesting that subgroups of patients exist among carriers of the D4Z4 reduced allele (DRA). Objective To investigate the clinical expression of FSHD in the genetic subgroup of carriers of a DRA with 7 to 8 repeat units (RUs). Design, Setting, and Participants This multicenter cross-sectional study included 422 carriers of DRA with 7 to 8 RUs (187 unrelated probands and 235 relatives) from a consecutive sample of 280 probands and 306 relatives from the Italian National Registry for FSHD collected between 2008 and 2016. Participants were evaluated by the Italian Clinical Network for FSHD, and all clinical and molecular data were collected in the Italian National Registry for FSHD database. Data analysis was conducted from January 2017 to June 2018. Main Outcomes and Measures The phenotypic classification of probands and relatives was obtained by applying the Comprehensive Clinical Evaluation Form which classifies patients in the 4 following categories: (1) participants presenting facial and scapular girdle muscle weakness typical of FSHD (category A, subcategories A1-A3), (2) participants with muscle weakness limited to scapular girdle or facial muscles (category B, subcategories B1 and B2), (3) asymptomatic or healthy participants (category C, subcategories C1 and C2), and (4) participants with myopathic phenotypes presenting clinical features not consistent with FSHD canonical phenotype (category D, subcategories D1 and D2). Results A total of 187 probands (mean [SD] age at last neurological examination, 53.5 [15.2] years; 103 [55.1%] men) and 235 relatives (mean [SD] age at last neurologic examination, 45.1 [17.0] years; 104 [44.7%] men) with a DRA with 7 to 8 RUs and a molecular diagnosis of FSHD were evaluated. Of 187 probands, 99 (52.9%; 95% CI, 45.7%-60.1%) displayed the classic FSHD phenotype, whereas 86 (47.1%; 95% CI, 39.8%-54.3%) presented incomplete or atypical phenotypes. Of 235 carrier relatives from 106 unrelated families, 124 (52.8%; 95% CI, 46.4%-59.7%) had no motor impairment, whereas a small number (38 [16.2%; 95% CI, 9.8%-23.1%]) displayed the classic FSHD phenotype, and 73 (31.0%; 95% CI, 24.7%-38.0%) presented with incomplete or atypical phenotypes. In 37 of 106 families (34.9%; 95% CI, 25.9%-44.8%), the proband was the only participant presenting with a myopathic phenotype, while only 20 families (18.9%; 95% CI, 11.9%-27.6%) had a member with autosomal dominant FSHD. Conclusions and Relevance This study found large phenotypic variability associated with individuals carrying a DRA with 7 to 8 RUs, in contrast to the indication that a positive molecular test is the only determining aspect for FSHD diagnosis. These findings suggest that carriers of a DRA with 7 to 8 RUs constitute a genetic subgroup different from classic FSHD. Based on these results, it is recommended that clinicians use the Comprehensive Clinical Evaluation Form for clinical classification and, whenever possible, study the extended family to provide the most adequate clinical management and genetic counseling.

To explore the clinical course of patients presenting with facioscapulohumeral dystrophy type 1 (FSHD1) in childhood, with a view to identifying areas where they differed from older patients and where extra support or monitoring might be required.A retrospective case-notes review of children with FSHD1 seen at a tertiary paediatric neuromuscular centre between 2002 and 2016 was performed. Data collected included age at and nature of presentation, path to diagnosis, genetic testing results, motor function, and occurrence of extramuscular features and complications.Eighteen children (11 females, seven males; mean [SD] age at latest review 13y 10mo [3y 9mo], range 8-19y) from 16 families were identified. Age at onset of FSHD1 correlated with the size of deletion (r=0.81) and most presentations were in children either younger than 5 years or older than 10 years. Children with onset before 5 years were more likely to present with non-muscular symptoms and to develop extramuscular pathology, including developmental and psychiatric issues, hearing or visual impairments, and problems involving respiratory function and nutrition. No cases of epilepsy or cardiac arrhythmia were identified but two children died.The complexity and severity of FSHD1 presenting in early childhood underlines the importance of a multidisciplinary approach to the disorder.Young children often present with non-muscular pathology in facioscapulohumeral dystrophy type 1 (FSHD1), especially hearing loss. Age at onset in paediatric FSHD1 appears bimodal: under 5 years or in adolescence. Prolonged delays to diagnosis are common. Children with very early-onset FSHD1 may require nutritional and/or respiratory support. Developmental and psychiatric comorbidities are common.CARACTERÍSTICAS CLÍNICAS DE LA DISTROFIA FASCIOESCAPULOHUMERAL 1 EN LA NIÑEZ: OBJETIVO: Explorar el curso clínico de los pacientes que presentan distrofina fascioescapulohumeral tipo 1 (FSHD1) en la niñez; con un enfoque que identifique las áreas que difieren de otros pacientes mayores; y, que tipo de soporte extra o monitorización podrían requerir. MÉTODO: Estudio retrospectivo de revisión de casos de niños con FSHD1, que fueron seguidos en un centro neuromuscular pediátrico terciario entre los años 2002 y 2016. La información recogida incluye edad y forma de presentación, algoritmo diagnóstico, resultados de los estudios genéticos, función motriz y aparición de síntomas extra-musculares y complicaciones. RESULTADOS: Dieciocho niños (11 niñas y siete varones; media [desviación standard] edad de la última revisión 13 años 10 meses [3 años 9 meses] rango 8-19 años) de 16 familias fueron identificados. La edad de aparición de del FSHD1 se correlacionó con el tamaño de la deleción (r = 0.81) y la mayor parte de los debuts fueron en niños menores de 5 años o mayores de 10. Aquellos niños cuyo inicio fue antes de los 5 años, mayormente se presentaban con síntomas no-musculares y desarrollaron patología extra-muscular que incluían afectación del desarrollo y psiquiátrica, pérdida auditiva o visual, y, problemas que concernían a la función respiratoria o la nutrición. No se detectaron casos de arritmia o epilepsia, sin embargo, dos niños fallecieron. INTERPRETACIÓN: La complejidad y severidad de la presentación de la FSHD1 en la infancia temprana, resalta la importancia de un abordaje multidisciplinar de esta condición de salud.ASPECTOS CLÍNICOS DA DISTROFIA MUSCULAR FACIO-ESCAPULO-UMERAL 1 NA INFÂNCIA.: OBJETIVO: Explorar o curso clínico de pacientes apresentando distrofia muscular facio-escapulo-tipo 1 (DFEU1) na infância, com vistas a identificar áreas em que eles diferem de pacientes mais velhos, e onde suporte ou monitoramento adicionais podem ser necessários. MÉTODO: Uma revisão retrospectiva de casos de crianças com DFEU1 atendidas em um centro pediátrico neuromuscular terciário entre 2002 e 2016 foi realizada. Os dados coletados incluíram idade e natureza da apresentação, caminho até o diagnóstico, resultados de testes genéticos, função motora, e ocorrência de aspectos extramusculares e complicações. RESULTADOS: Dezoito crianças (11 do sexo feminino, sete do sexo masculino; média [desvio padrão] da idade na última visita 13a10m [3a 9m], variação 8-19a) de 16 famílias foram identificadas. A idade no início da DFEU1 correlacionou com o tamanho da deleção (r = 0,81) e a maior parte das apresentações foram em crianças ou com menos de 5 anos ou com mais de 10 anos. Crianças com início antes de 5 anos tinham maior probabilidade de apresentar sintomas não-musculares e de desenvolver patologia extra-muscular, incluindo questões desenvolvimentais e psiquiátricas, deficiência auditiva ou visual, e problemas envolvendo função respiratória e nutrição. Nenhum caso de epilepsia ou arritmia cardiac foi identificado, mas duas crianças foram a óbito. INTERPRETAÇÃO: A complexidade e severidade da DFEU1 com apresentação precoce na infância realça a importância de abordagem multidisciplinar para esta desordem.

We analyzed the registration data of inpatients with facioscapulohumeral muscular dystrophy (FSHD) receiving care at 27 specialized institutions for muscular dystrophy in Japan from 1999 to 2013 using data from October 1 of each year. The number of inpatients of each year ranged from 63 to 72 (67.1 ± 3.3) throughout the study period. Those aged over 50 years gradually increased during the study period, while the oldest inpatient was 82.8 years old. Most could not walk. The rate of respirator dependency increased from 21.0% in 1999 to 71.0% in 2013, while the rate of patients receiving oral nutrition was 98.4% in 1999 and then reduced to 75.4% in 2013. There were 36 death cases reported in the database, including 15 patients with respiratory failure and 4 with heart failure. Our findings indicate that FSHD patients in a severe condition are impacted by respiratory and nutritional problems and their prognosis for survival is related to respiratory failure.

Background and aim Facioscapulohumeral muscular dystrophy (FSHD) is a common muscular disorder. At present, treatments for FSHD have limited effects on the muscle function of patients. A famous Chinese medicine formula, Buzhong Yiqi (BZYQ), has shown promising effects on several muscular diseases, but evidence regarding its effect on FSHD is lacking. This study aimed to examine the effect of BZYQ on FSHD. Case presentation A 15-year-old girl suffered from progressive muscle weakness, with a genetically confirmed diagnosis of FSHD. Except for routine FSHD management, the patient received BZQY every day. The muscle strength of the patient remarkably increased after discharge. Conclusions This study was novel in reporting a significant improvement in muscle function in a patient with FSHD treated with an integrated approach of BZYQ and routine management. Therefore, BZYQ might be a potential treatment for FSHD, requiring further investigations.

Facioscapulohumeral muscular dystrophy (FSHD) is caused by loss of repression of the DUX4 gene; however, the DUX4 protein is rare and difficult to detect in human muscle biopsies, and pathological mechanisms are obscure. FSHD is also a chronic disease that progresses slowly over decades. We used the sporadic, low-level, muscle-specific expression of DUX4 enabled by the iDUX4pA-HSA mouse to develop a chronic long-term muscle disease model. After 6 months of extremely low sporadic DUX4 expression, dystrophic muscle presented hallmarks of FSHD histopathology, including muscle degeneration, capillary loss, fibrosis, and atrophy. We investigated the transcriptional profile of whole muscle as well as endothelial cells and fibroadiopogenic progenitors (FAPs). Strikingly, differential gene expression profiles of both whole muscle and, to a lesser extent, FAPs, showed significant overlap with transcriptional profiles of MRI-guided human FSHD muscle biopsies. These results demonstrate a pathophysiological similarity between disease in muscles of iDUX4pA-HSA mice and humans with FSHD, solidifying the value of chronic rare DUX4 expression in mice for modeling pathological mechanisms in FSHD and highlighting the importance FAPs in this disease.

International audience; Facioscapulohumeral muscular dystrophy (FSHD) is characterized by incomplete penetrance and intra-familial clinical variability. The disease has been associated with the genetic and epigenetic features of the D4Z4 repetitive elements at 4q35. Recently, D4Z4 hypomethylation has been proposed as a reliable marker in the FSHD diagnosis. We exploited the Italian Registry for FSHD, in which FSHD families are classified using the Clinical Comprehensive Evaluation Form (CCEF). A total of 122 index cases showing a classical FSHD phenotype (CCEF, category A) and 110 relatives were selected to test with the receiver operating characteristic (ROC) curve, the diagnostic and predictive value of D4Z4 methylation. Moreover, we performed DNA methylation analysis in selected large families with reduced penetrance characterized by the co-presence of subjects carriers of one D4Z4 reduced allele with no signs of disease or presenting the classic FSHD clinical phenotype. We observed a wide variability in the D4Z4 methylation levels among index cases revealing no association with clinical manifestation or disease severity. By extending the analysis to family members, we revealed the low predictive value of D4Z4 methylation in detecting the affected condition. In view of the variability in D4Z4 methylation profiles observed in our large cohort, we conclude that D4Z4 methylation does not mirror the clinical expression of FSHD. We recommend that measurement of this epigenetic mark must be interpreted with caution in clinical practice.

The emergence of CRISPR-Cas9 gene-editing technologies and genome-wide CRISPR-Cas9 libraries enables efficient unbiased genetic screening that can accelerate the process of therapeutic discovery for genetic disorders. Here, we demonstrate the utility of a genome-wide CRISPR-Cas9 loss-of-function library to identify therapeutic targets for facioscapulohumeral muscular dystrophy (FSHD), a genetically complex type of muscular dystrophy for which there is currently no treatment. In FSHD, both genetic and epigenetic changes lead to misexpression of DUX4, the FSHD causal gene that encodes the highly cytotoxic DUX4 protein. We performed a genome-wide CRISPR-Cas9 screen to identify genes whose loss-of-function conferred survival when DUX4 was expressed in muscle cells. Genes emerging from our screen illuminated a pathogenic link to the cellular hypoxia response, which was revealed to be the main driver of DUX4-induced cell death. Application of hypoxia signaling inhibitors resulted in increased DUX4 protein turnover and subsequent reduction of the cellular hypoxia response and cell death. In addition, these compounds proved successful in reducing FSHD disease biomarkers in patient myogenic lines, as well as improving structural and functional properties in two zebrafish models of FSHD. Our genome-wide perturbation of pathways affecting DUX4 expression has provided insight into key drivers of DUX4-induced pathogenesis and has identified existing compounds with potential therapeutic benefit for FSHD. Our experimental approach presents an accelerated paradigm towards mechanistic understanding and therapeutic discovery of a complex genetic disease, which may be translatable to other diseases with well-established phenotypic selection assays.

ObjectiveTo investigate single muscle fiber contractile performance in muscle biopsies from patients with facioscapulohumeral muscular dystrophy (FSHD), one of the most common hereditary muscle disorders.MethodsWe 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.ResultsSingle 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.ConclusionMuscle 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.

International audience; Facioscapulohumeral muscular dystrophy (FSHD) has been associated with the genetic and epigenetic molecular features of the CpG-rich D4Z4 repeat tandem array at 4q35. Reduced DNA methylation of D4Z4 repeats is considered part of the FSHD mechanism and has been proposed as a reliable marker in the FSHD diagnostic procedure. We considered the assessment of D4Z4 DNA methylation status conducted on distinct cohorts using different methodologies. On the basis of the reported results we conclude that the percentage of DNA methylation detected at D4Z4 does not correlate with the disease status. Overall, data suggest that in the case of FSHD1, D4Z4 hypomethylation is a consequence of the chromatin structure present in the contracted allele, rather than a proxy of its function. Besides, CpG methylation at D4Z4 DNA is reduced in patients presenting diseases unrelated to muscle progressive wasting, like Bosma Arhinia and Microphthalmia syndrome, a developmental disorder, as well as ICF syndrome. Consistent with these observations, the analysis of epigenetic reprogramming at the D4Z4 locus in human embryonic and induced pluripotent stem cells indicate that other mechanisms, independent from the repeat number, are involved in the control of the epigenetic structure at D4Z4.

Molecular defects in type 1 facioscapulohumeral muscular dystrophy (FSHD) are caused by a heterozygous contraction of the D4Z4 repeat array from 1 to 10 repeat units (RUs) on 4q35. This study compared (1) the phenotype and severity of FSHD1 between patients carrying 6&ndash, 8 vs. 9&ndash, 10 RUs, (2) the amount of methylation in different D4Z4 regions between patients with FSHD1 with different clinical severity scores (CSS). This cross-sectional multicenter study was conducted to measure functional scales and for genetic analysis. Patients were classified into two categories according to RUs: Group 1, 6&ndash, 8, Group 2, 9&ndash, 10. Methylation analysis was performed in 27 patients. A total of 99 carriers of a contracted D4Z4 array were examined. No significant correlations between RUs and CSS (r = 0.04, p = 0.73) and any of the clinical outcome scales were observed between the two groups. Hypomethylation was significantly more pronounced in patients with high CSS (&gt, 3.5) than those with low CSS (&lt, 1.5) (in DR1 and 5P), indicating that the extent of hypomethylation might modulate disease severity. In Group 1, the disease severity is not strongly correlated with the allele size and is mostly correlated with the methylation of D4Z4 regions.

Double homeobox 4 (DUX4) is an early embryonic transcription factor whose expression in the skeletal muscle causes facioscapulohumeral muscular dystrophy (FSHD). Despite decades of research, our knowledge of FSHD and DUX4 biology is incomplete, and the disease has currently no cures or targeted therapies. The unusual evolutionary origin of DUX4, its extensive epigenetic and post-transcriptional gene regulation, and various feedback regulatory loops that control its expression and function all contribute to the highly complex nature of FSHD pathogenesis. In this minireview, I synthesize the current state of knowledge in DUX4 and FSHD biology to highlight key areas where further research is needed to better understand DUX4 regulation. I also emphasize post-transcriptional regulation of and by DUX4 via changes in RNA and protein stability that might underlie key features of FSHD pathophysiology. Finally, I discuss the various feedback loops involved in DUX4 regulation and the context-specific consequences of its expression, which could be key to developing novel therapeutic approaches to combat FSHD.

ObjectiveTo assess the relation between age at onset and disease severity in facioscapulohumeral muscular dystrophy (FSHD).MethodsIn this prospective cross-sectional study, we matched adult patients with FSHD with an early disease onset with 2 sex-matched FSHD control groups with a classic onset; the first group was age matched, and the second group was disease duration matched. Genetic characteristics, muscle performance, respiratory functioning, hearing loss, vision loss, epilepsy, educational level, and work status were compared with the 2 control groups.ResultsTwenty-eight patients with early-onset FSHD were age (n = 28) or duration (n = 27) matched with classic-onset patients. Patients with early-onset FSHD had more severe muscle weakness (mean FSHD clinical score 11 vs 5 in the age-matched and 9 in the duration-matched group, p < 0.05) and a higher frequency of wheelchair dependency (57%, 0%, and 30%, respectively, p < 0.05). In addition, systemic features were more frequent in early-onset FSHD, most important, hearing loss, decreased respiratory function and spinal deformities. There was no difference in work status. Genetically, the shortest D4Z4 repeat arrays (2–3 units) were found exclusively in the early-onset group, and the largest repeat arrays (8–9 units) were found only in the classic-onset groups. De novo mutations were more frequent in early-onset patients (46% vs 4%).ConclusionsPatients with early-onset FSHD more often have severe muscle weakness and systemic features. The disease severity is greater than in patients with classic-onset FSHD who are matched for disease duration, suggesting that the progression is faster in early-onset patients.

Facioscapulohumeral muscular dystrophy (FSHD) is a common, dominantly inherited disease caused by the epigenetic de-repression of the DUX4 gene, a transcription factor normally repressed in skeletal muscle. As targeted therapies are now possible in FSHD, a better understanding of the relationship between DUX4 activity, muscle pathology and muscle magnetic resonance imaging (MRI) changes is crucial both to understand disease mechanisms and for the design of future clinical trials. Here, we performed MRIs of the lower extremities in 36 individuals with FSHD, followed by needle muscle biopsies in safely accessible muscles. We examined the correlation between MRI characteristics, muscle pathology and expression of DUX4 target genes. Results show that the presence of elevated MRI short tau inversion recovery signal has substantial predictive value in identifying muscles with active disease as determined by histopathology and DUX4 target gene expression. In addition, DUX4 target gene expression was detected only in FSHD-affected muscles and not in control muscles. These results support the use of MRI to identify FSHD muscles most likely to have active disease and higher levels of DUX4 target gene expression and might be useful in early phase therapeutic trials to demonstrate target engagement in therapies aiming to suppress DUX4 expression.

Facioscapulohumeral dystrophy type 1 (FSHD-1) is the most common autosomal dominant form of muscular dystrophy with a prevalence of ∼1 in 8000 individuals. It is considered a late-onset form of muscular dystrophy and leads to asymmetric muscle weakness in the facial, scapular, trunk and lower extremities. The prevalent hypothesis on disease pathogenesis is explained by misexpression of a germ line, primate-specific transcription factor DUX4-fl (double homeobox 4, full-length isoform) linked to the chromosome 4q35. In vitro and in vivo studies have demonstrated that very low levels of DUX4-fl expression are sufficient to induce an apoptotic and/or lethal phenotype, and therefore modeling of the disease has proved challenging. In this study, we expand upon our previously established injection model of DUX4 misexpression in zebrafish and describe a DUX4-inducible transgenic zebrafish model that better recapitulates the expression pattern and late onset phenotype characteristic of FSHD patients. We show that an induced burst of DUX4 expression during early development results in the onset of FSHD-like phenotypes in adulthood, even when DUX4 is no longer detectable. We also utilize our injection model to study long-term consequences of DUX4 expression in those that fail to show a developmental phenotype. Herein, we introduce a hypothesis that DUX4 expression during developmental stages is sufficient to induce FSHD-like phenotypes in later adulthood. Our findings point to a developmental role of DUX4 misexpression in the pathogenesis of FSHD and should be factored into the design of future therapies.

To determine how much of the clinical variability in facioscapulohumeral muscular dystrophy type 1 (FSHD1) can be explained by the D4Z4 repeat array size, D4Z4 methylation and familial factors, we included 152 carriers of an FSHD1 allele (23 single cases, 129 familial cases from 37 families) and performed state-of-the-art genetic testing, extensive clinical evaluation and quantitative muscle MRI. Familial factors accounted for 50% of the variance in disease severity (FSHD clinical score). The explained variance by the D4Z4 repeat array size for disease severity was limited (approximately 10%), and varied per body region (facial muscles, upper and lower extremities approximately 30%, 15% and 3%, respectively). Unaffected gene carriers had longer repeat array sizes compared to symptomatic individuals (7.3 vs 6.0 units, P = 0.000) and slightly higher Delta1 methylation levels (D4Z4 methylation corrected for repeat size, 0.96 vs -2.46, P = 0.048). The D4Z4 repeat array size and D4Z4 methylation contribute to variability in disease severity and penetrance, but other disease modifying factors must be involved as well. The larger effect of the D4Z4 repeat array on facial muscle involvement suggests that these muscles are more sensitive to the influence of the FSHD1 locus itself, whereas leg muscle involvement seems highly dependent on modifying factors.

Background SMCHD1 is a disease modifier and a causative gene for facioscapulohumeral muscular dystrophy (FSHD) type 1 and type 2, respectively. A large variety of different mutations in SMCHD1 have been identified as causing FSHD2. In many cases, it is unclear how these mutations disrupt the normal function of SMCHD1. Methods We made and analyzed lenti-viral vectors that express Flag-tagged full-length or different mutant SMCHD1 proteins to better understand the functional domains of SMCHD1 in muscle cells. Results We identified regions necessary for nuclear localization, dimerization, and cleavage sites. Moreover, we confirmed that some mutants increased DUX4 expression in FSHD1 myoblasts. Conclusions These findings provide an additional basis for understanding the molecular consequences of SMCHD1 mutations. Electronic supplementary material The online version of this article (10.1186/s13395-018-0172-z) contains supplementary material, which is available to authorized users.

Double homeobox 4 (DUX4), the causative gene of facioscapulohumeral muscular dystrophy (FSHD), is ectopically expressed in the skeletal muscle cells of FSHD patients because of chromatin relaxation at 4q35. The diminished heterochromatic state at 4q35 is caused by either large genome contractions [FSHD type 1 (FSHD1)] or mutations in genes encoding chromatin regulators, such as SMCHD1 [FSHD type 2 (FSHD2)]. However, the mechanism by which DUX4 expression is regulated remains largely unknown. Here, using a myocyte model developed from patient-derived induced pluripotent stem cells, we determined that DUX4 expression was increased by oxidative stress (OS), a common environmental stress in skeletal muscle, in both FSHD1 and FSHD2 myocytes. We generated FSHD2-derived isogenic control clones with SMCHD1 mutation corrected by clustered regularly interspaced short palindromic repeats (CRISPR)/ CRISPR associated 9 (Cas9) and homologous recombination and found in the myocytes obtained from these clones that DUX4 basal expression and the OS-induced upregulation were markedly suppressed due to an increase in the heterochromatic state at 4q35. We further found that DNA damage response (DDR) was involved in OS-induced DUX4 increase and identified ataxia-telangiectasia mutated, a DDR regulator, as a mediator of this effect. Our results suggest that the relaxed chromatin state in FSHD muscle cells permits aberrant access of OS-induced DDR signaling, thus increasing DUX4 expression. These results suggest OS could represent an environmental risk factor that promotes FSHD progression., 酸化ストレスが顔面肩甲上腕型筋ジストロフィーの 原因遺伝子DUX4を増加させることを発見しました. 京都大学プレスリリース. 2018-09-07.

Aims The present study aimed to investigate the long-term functional results of scapulothoracic fusion using multifilament cables in patients with facioscapulohumeral dystrophy (FSHD) to identify if the early improvement from this intervention is maintained. Patients and Methods We retrospectively investigated the long-term outcomes of 13 patients with FSHD (18 shoulders) in whom scapulothoracic fusion using multifilament cables was performed between 2004 and 2007. These patients have previously been reported at a mean of 35.5 months (24 to 87). There were eight men and five women with a mean age of 26 years. Their mean length of follow-up of our current study was 128 months (94 to 185). To evaluate long-term functional results, the range of shoulder flexion and abduction, Quick Disabilities of the Arm, Shoulder and Hand (QuickDASH) scores were analyzed with a comparison of preoperatively, interim and at the final outcomes. The fusion was examined radiographically in all. Results The complication rate was 33% (six of 18 scapulothoracic fusions) in 13 patients, which comprised failure of fusion in four shoulders (four patients) all occurring within the first year postoperatively. In two shoulders (one patient) wound problems arose due to attribution from the cables which required shortening but the fusion developed satisfactorily. At the final examination, the mean QuickDASH score and range of movement significantly improved in all but one patient (p < 0.001, p < 0.001 and p < 0.001). In the comparison of 13 patients’ mid- and long-term results, the mean QuickDASH score decreased from 9.8 (sd 6.7; 3 to 26) in the third year to 9.1 (sd 5.6; 3 to 22) in the tenth year (p = 0.7); the mean range of shoulder flexion and abduction decreased from 129° (sd 22°; 90° to 160°) and 124° (sd 12; 100° to 150°) at the mid-term to 103° (sd 12°; 80° to 120°) and 101° (sd 8°; 80° to 120°) at the long-term, respectively (p = 0.78 and p = 0.65). Conclusion Scapulothoracic fusion using a multiple cabling method can confer a considerable improvement in clinical and functional outcomes for most patients with FSHD after a long follow-up period. The technique requires careful execution to avoid complications. Cite this article: Bone Joint J 2018;100-B:953–6.

Facioscapulohumeral muscular dystrophy, known in genetic forms FSHD1 and FSHD2, is associated with D4Z4 repeat array chromatin relaxation and somatic derepression of DUX4 located in D4Z4. A complete copy of DUX4 is present on 4qA chromosomes, but not on the D4Z4-like repeats of chromosomes 4qB or 10. Normally, the D4Z4 repeat varies between 8 and 100 units, while in FSHD1 it is only 1-10 units. In the rare genetic form FSHD2, a combination of a 4qA allele with a D4Z4 repeat size of 8-20 units and heterozygous pathogenic variants in the chromatin modifier SMCHD1 causes DUX4 derepression and disease. In this study, we identified 11/79 (14%) FSHD2 patients with unusually large 4qA alleles of 21-70 D4Z4 units. By a combination of Southern blotting and molecular combing, we show that 8/11 (73%) of these unusually large 4qA alleles represent duplication alleles in which the long D4Z4 repeat arrays are followed by a small FSHD-sized D4Z4 repeat array duplication. We also show that these duplication alleles are associated with DUX4 expression. This duplication allele frequency is significantly higher than in controls (2.9%), FSHD1 patients (1.4%) and in FSHD2 patients with typical 4qA alleles of 8-20 D4Z4 units (1.5%). Segregation analysis shows that, similar to typical 8-20 units FSHD2 alleles, duplication alleles only cause FSHD in combination with a pathogenic variant in SMCHD1. We conclude that cis duplications of D4Z4 repeats explain DUX4 expression and disease presentation in FSHD2 families with unusual long D4Z4 repeats on 4qA chromosomes.

Muscular dystrophies represent a complex, varied, and important subset of neuromuscular disorders likely to require the care of a pulmonologist. The spectrum of conditions encapsulated by this subset ranges from severe and fatal congenital muscular dystrophies with onset in infancy to mild forms of limb and girdle weakness with onset in adulthood and minimal respiratory compromise. The list and classification of muscular dystrophies are undergoing near-constant revision, based largely on new insights from genetics and molecular medicine. The authors present an overview of the muscular dystrophies, including their basic features, common clinical phenotypes, and important facets of management.

Facioscapulohumeral muscular dystrophy (FSHD) is caused by insufficient epigenetic repression of D4Z4 macrosatellite repeat where DUX4, an FSHD causing gene is embedded. There are two forms of FSHD, FSHD1 with contraction of D4Z4 repeat and FSHD2 with chromatin compaction defects mostly due to SMCHD1 mutation. Previous reports showed DUX4-induced gene expression changes as well as changes in microRNA expression in FSHD muscle cells. However, a genome wide analysis of small noncoding RNAs that might be regulated by DUX4 or by mutations in SMCHD1 has not been reported yet. Here, we identified several types of small noncoding RNAs including known microRNAs that are differentially expressed in FSHD2 muscle cells compared to control. Although fewer small RNAs were differentially expressed during muscle differentiation in FSHD2 cells compared to controls, most of the known myogenic microRNAs, such as miR1, miR133a and miR206 were induced in both FSHD2 and control muscle cells during differentiation. Our small RNA sequencing data analysis also revealed both DUX4- and SMCHD1-specific changes in FSHD2 muscle cells. Six FSHD2 microRNAs were affected by DUX4 overexpression in control myoblasts, whereas increased expression of tRNAs and 5S rRNAs in FSHD2 muscle cells was largely recapitulated in SMCHD1-depleted control myoblasts. Altogether, our studies suggest that the small noncoding RNA transcriptome changes in FSHD2 might be different from those in FSHD1 and that these differences may provide new diagnostic and therapeutic tools specific to FSHD2.

Item does not contain fulltext INTRODUCTION: Electrical impedance myography (EIM) is a noninvasive technique for measuring muscle composition and a potential physiological biomarker for facioscapulohumeral muscular dystrophy (FSHD). METHODS: Thirty-two participants with genetically confirmed and clinically affected FSHD underwent EIM in 7 muscles bilaterally. Correlations between EIM and baseline clinical measures were used to select EIM variables of interest in FSHD, and EIM and clinical measures were followed for 1 year. RESULTS: There were no significant changes in the EIM variables. Although 50-kHZ reactance correlated the strongest with clinical measures at baseline, the 50-211-kHZ phase ratio demonstrated lower within-subject 12-month variability, potentially offering sample size savings for FSHD clinical trial planning. DISCUSSION: EIM did not identify significant disease progression over 12 months. It is currently unclear whether this is because of limitations of the technology or the slow rate of disease progression in this cohort of FSHD patients over this period of time. Muscle Nerve 58: 213-218, 2018.

ObjectivesTo investigate motor function associations with age, sex, and D4Z4 repeats among participants with early-onset facioscapulohumeral muscular dystrophy (FSHD) type 1 as defined by weakness onset before 10 years of age.MethodsWe collected standardized motor assessments, including manual muscle testing (MMT), quantitative muscle testing, functional motor evaluations, and clinical severity scores (CSSs), at 12 Cooperative International Neuromuscular Research Group centers. To measure associations, we used linear regression models adjusted for sex, evaluation age, age at onset of weakness, and D4Z4 repeats.ResultsAmong 52 participants (60% female, mean age 22.9 ± 14.7 years), weakness was most pronounced in the shoulder and abdominal musculature. Older enrollment age was associated with greater CSSs (p = 0.003). When adjusted for enrollment age, sex, and D4Z4 repeats, younger age at onset of facial weakness was associated with greater CSSs, slower velocities in timed function tests, and lower MMT scores (p < 0.05).ConclusionSignificant clinical variability was observed in early-onset FSHD. Earlier age at onset of facial weakness was associated with greater disease severity. Longitudinal assessments are needed to determine the rate of disease progression in this population.

Charles Edward Beevor (1854–1908) was a prominent English neurologist who served in a variety of positions at the National Hospital for the Paralysed and Epileptic, Queen Square, from 1883 until his sudden death due to coronary artery disease in 1908. Staunchly committed to the meticulous study of neuroanatomy and physiology and education of his fellow physicians, Beevor was an accomplished clinician-scientist. He is most well known for describing the Beevor sign (commonly known as “Beevor's sign”), which is the upward movement of the umbilicus with truncal flexion from a supine position, used to indicate a spinal cord lesion between the levels of T10 and T12. His sign has also been reported to be suggestive of facioscapulohumeral muscular dystrophy. While the initial description of the Beevor sign has traditionally been attributed to his 1903 Croonian Lectures, he actually first described his sign in his 1898 textbook Diseases of the Nervous System: A Handbook for Students and Practitioners. In addition to his eponymous sign, Beevor also made significant contributions to the understanding of the representation of motor movements in the cerebral cortex, and, of more importance, utilized a novel method to identify cerebral vascular territory maps that are still utilized by neurologists today.