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Facioscapulohumeral muscular dystrophy in the Dutch population
Abstract
Extrapolating the figures from a previous study on FSHD in a province of The Netherlands to the entire Dutch population suggests that at present a nearly complete overview is obtained of all symptomatic kindred. In 139 families, dominant inheritance was observed in 97, a pattern compatible with germline mosaicism in 6, while sporadic cases were found in 36 families. A mutation frequency of 9.6% was calculated. Mental retardation and severe retinal vasculopathy were reported in low frequencies (1%). Early onset was seen more frequently in sporadic cases. Chromosome 4 linkage appeared excluded in 3 of 22 autosomal-dominant families. The clinical pictures in the linked and nonlinked families were identical.
... This is an open access article under the CC BY-NC-ND license (http:// creativecommons.org/licenses/by-nc-nd/4.0/). Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common inherited muscular dystrophies, with an estimated prevalence in the United Kingdom (UK) from 2.9-3.9 per 100,000 in the general population [1][2][3] and affecting approximately 2400 people. 4 The overall prevalence of FSHD internationally is reportedly between 3.2-4.6 ...
... Our clinical experience suggests that exercise is an appropriate modality for upper limb rehabilitation patients with FSHD and that current practice is variable, possibly resulting from a lack of best practice or clinical guidelines. The aims of this study are therefore to identify (1) what exercise modalities people living with FSHD are undertaking in the community and (2) what future research projects would gain the support of patients with FSHD and would be manageable for them. ...
... It is important to identify a safe range of exercise modalities and parameters that can be carried out by people with FSHD. Existing research studies had focused predominantly on the lower limbs 1,4,6,[11][12][13][20][21][22] in which some exercise programs have demonstrated effectiveness for increasing cardiovascular fitness in FSHD 23,24 and other neuromuscular disorders, 20,21 although others have suggested that some exercise intensities can be detrimental. 12,14 There are also other secondary benefits associated with physical activity, such as decreased risk of comorbidities and improved overall well-being. ...
Objective
To identify what exercise modalities people living with Facioscapulohumeral Dystrophy (FSHD) are undertaking in the community as a part of their ongoing rehabilitation and 2) what future research projects would gain the support of people with FSHD.
Design
An online questionnaire comprised of open and closed questions. Conventional content analysis was used for open questions and quantitative analysis was used for closed questions.
Setting
Online questionnaire distributed to a UK FSHD registry.
Participants
232 patients on the UK FSHD registry.
Interventions
None
Main Outcome Measure
None
Results
A response rate of 43.6% was achieved with 232 out of 532 patients completing the survey. Despite 85.8% of patients suffering from shoulder instability which affects daily living, only 44.4% engaged with exercises targeting the upper body. The themes from the data were: Understanding of disease mechanism shaping exercise choice, Lack of understanding about the condition and the benefit of exercise, Support from professionals, Barriers to exercise, and Thoughts about future research. Participants (92.2%) agreed additional research into upper limb exercises is needed and felt a 3-month arm cycling intervention with monthly clinical visits and MRI imaging would be appropriate.
Conclusions
Exercise selection was variable amongst FSHD patients and lack of information, pain, fatigue, availability and access to facilities, cost and time were identified as barriers to exercise. This may account for the limited engagement with upper-limb rehabilitation despite the high percentage of shoulder instability in patients with FSHD. Further research is needed to develop evidence-based exercise interventions and guidance for upper limb exercise prescription in FSHD and patients are supportive of this
... but due to advances in diagnostics and awareness, the most recent estimates lie between 1:15.000 and 1:8.500 in Europe. 1,30,31 FSHD is considered a slowly progressive muscle disorder, with the rate of muscle weakening thought to occur in bursts after longer periods of no apparent functional decline. 31 Prognosis is variable, but roughly correlates with age at onset and D4Z4 repeat size (see genetics of FSHD). ...
... 45 While occasionally observed and postulated to be part of FSHD pathogenesis, cardiac involvement, ptosis, extraocular muscle weakness and extensive contractures are not considered to be FSHD specific. 30,45 2.2 | The genetics of FSHD Linkage studies mapped the FSHD locus to chromosome 4q, which subsequently led to the discovery that FSHD is associated with partial deletions of the D4Z4 repeat. 27 The D4Z4 repeat consists of units of 3.3 kb each, ordered head-to-tail, with the number of units varying from 8 to 100 in the European population ( Figure 1A). ...
... 14,53 FSHD1 is inherited in an autosomal dominant fashion with incomplete penetrance, 27 with 10% to 30% of cases being the result of de novo mutations. 30,34,54 De novo mutations are often mitotic in origin, leading to somatic mosaicism. Depending on D4Z4 repeat size and proportion of affected cells, mosaicism can be found in either the clinically unaffected parent or in the proband. ...
Facioscapulohumeral muscular dystrophy (FSHD), a common hereditary myopathy, is caused either by the contraction of the D4Z4 macrosatellite repeat at the distal end of chromosome 4q to a size of 1 to 10 repeat units (FSHD1) or by mutations in D4Z4 chromatin modifiers such as Structural Maintenance of Chromosomes Hinge Domain Containing 1 (FSHD2). These two genotypes share a phenotype characterized by progressive and often asymmetric muscle weakening and atrophy, and common epigenetic alterations of the D4Z4 repeat. All together, these epigenetic changes converge the two genetic forms into one disease and explain the derepression of the DUX4 gene, which is otherwise kept epigenetically silent in skeletal muscle. DUX4 is consistently transcriptionally upregulated in FSHD1 and FSHD2 skeletal muscle cells where it is believed to exercise a toxic effect. Here we provide a review of the recent literature describing the progress in understanding the complex genetic and epigenetic architecture of FSHD, with a focus on one of the consequences that these epigenetic changes inflict, the DUX4‐induced immune deregulation cascade. Moreover, we review the latest therapeutic strategies, with particular attention to the potential of epigenetic correction of the FSHD locus.
... FSHD is a gain-of-function, autosomal dominant disease with both familial and denovo occurrences (Padberg, 1982;Lunt et al., 1995;Padberg et al., 1995;Zatz et al., 1995;Tawil et al., 1996;Zatz et al., 1998;de Greef et al., 2010;) with the latter often resulting from a post-zygotic mutation that leads to somatic mosaicism Weiffenbach et al., 1993;Upadhyaya et al., 1995;van der Maarel et al., 2000). ...
... Neurological features: Retinal vasculopathies (Fitzsimons et al., 1987) and sensorineural deafness (Kilmer et al., 1995;Padberg et al., 1995) are extra-muscular features often associated with FSHD, with high tone hearing loss described in a number of patients. ...
D4Z4 is a subtelomeric macrosatellite repeat on chromosome 4q that codes for DUX4, a gene that is causal to the muscle wasting disease Facioscapulohumeral muscular dystrophy (FSHD). DUX4 expression is influenced by a number of genetic and epigenetic modifiers, including variation in D4Z4 copy number, single nucleotide polymorphisms (SNPs) on 4q, DNA and histone methylation changes, modifier genes like SMCHD1 and DNMT3B, and telomeres. The overarching goal of the research presented in this dissertation was to demonstrate the feasibility of targeting the disease locus using genome editing tools. To achieve this, we first needed to identify suitable cellular platforms for subsequent genome editing experiments. Through genotyping analysis, we were able to identify a cell line (HCT116) that was well-suited to studies investigating D4Z4/DUX4 expression, given that it harbors a disease-permissive 4qA allele. Using HCT116 and three of its DNA methyltransferase knockouts (1KO, 3BKO and DKO), we probed for factors that influence DUX4 expression in these cell lines. These experiments revealed that H3K9me3 loss and CpG hypomethylation can independently result in DUX4 expression in non-myogenic cell types. HCT116 and its DNMT KOs offer a new platform for studying DUX4 expression, albeit with some caveats. Importantly, we showed existence of D4Z4 transcripts in a variety of adult human tissues in addition to testis, with notably high expression in the thymus. Using these cell lines, we next explored the mechanism by which modifiers of D4Z4, such as SMCHD1 and telomeres might influence DUX4 expression. We generated several independent SMCHD1 knockout clones in HCT116 using TALENs. Characterization of these KOs revealed that despite no detectable changes in H3K9me3 or CpG methylation at D4Z4, SMCHD1 loss causes expression of unspliced DUX4, a phenomenon that was phenocopied by treatment of cells with a chemical inhibitor of telomerase. Spliced and pathogenic DUX4 was only expressed in these KOs upon treatment with 5-Aza-C, which demethylates DNA and lowers H3K9me3 levels at D4Z4. Given these results and the previously known importance of H3K9me3 enrichment in transcription and splicing, we speculate on a model, where SMCHD1 protein and telomeres, may act in coordination to provide an extra layer of transcriptional repression in addition to H3K9me3, at D4Z4. To achieve the main goal of this project, we took four independent approaches aimed at directly or indirectly repressing DUX4. In the first approach, we successfully deleted the array from a 4q permissive allele (in HCT116 and DKO cells), generating recombinants that likely had a shortened 4q chromosomal end and harbored an exogenously provided telomere seeding construct. Although we were unable to isolate clones of D4Z4-deleted cells, these results showed that the entire array can be deleted, also highlighting adverse side-effects of such targeting on cell viability. For our second approach, we used a CRISPR-based effector system to upregulate SMCHD1 transcript levels. Using a dCas9-VP64 activator construct, we were able to affect >2-fold upregulation in SMCHD1 in 293T cells. This avenue can be explored further to assess the effect of such upregulation on DUX4 and its target gene expression, in clinically relevant cell types. A SNP, resulting in a non-canonical polyadenylation (poly-A) sequence in DUX4 exon 3 is believed to stabilize pathogenic DUX4 transcripts in somatic cells. In a novel third approach, we designed pairs of gRNAs flanking the poly-A and deleted it using Cas9 nuclease recruited by these gRNAs. Significant lowering of DUX4 transcription in a mutant clone of HCT116, which contains a deletion of the pathogenic poly-A highlighted the importance of this sequence in transcript stabilization. Additionally, through lentiviral transduction of patient myoblasts, we showed that this approach can not only repress DUX4 expression, but also alleviate misregulation of a subset of its downstream target genes that are also biomarkers of FSHD. For our final approach, we enriched H3K9me3 at D4Z4 using a the dCas9-KRAB repressor system and a suitable gRNA. In both DKO cells and patient myoblasts, targeting repressed DUX4 expression significantly. Additionally, DUX4 target genes were also repressed in myoblasts and we showed that this repression was a consequence of increase and spread of H3K9me3 at D4Z4. Taken together, the results from these studies have generated promising future directions that can help understand the mechanism of how modifiers regulate D4Z4 expression. More importantly, by demonstrating the feasibility of targeting the disease locus in different cell types (including patient myoblasts), we have laid the foundation for development of future cell-based therapies to alleviate patient suffering in FSHD.
... Overview: Fascioscapulohumeral dystrophy (FSHD) is the third most common inherited muscular dystrophy after DMD and myotonic dystrophy [64] with an estimated prevalence of 1 in 14,000 -20,000 individuals [65][66][67][68]. The term "facioscapulohumeral" is derived from the muscle groups that are initially affected by weakness and atrophy, which are the facial, scapular, and humeral muscles [64,69]. ...
... The term "facioscapulohumeral" is derived from the muscle groups that are initially affected by weakness and atrophy, which are the facial, scapular, and humeral muscles [64,69]. FSHD is inherited in autosomal dominant pattern associated with subtelomeric deletion of chromosome 4q with loss of a subset of repeat units in the D4Z4 macrosatellite repeat array [65]. The loss of ten or fewer repeats causes FSHD and in general the lower the number of repeats the more clinically serious the disorder. ...
The role of genetic mutation in the pathogenesis of cardiomyopathies (CM) has been long-established. In contrast, the involvement of familial (hereditary) neuromuscular diseases (NDs) in the development of CM remains under-researched. Little attention has been paid to better characterize and understand myocardial involvement in NDs. There is evidence that early diagnosis may improve therapeutic response in ND patients with CM. However, diagnosis can be easily missed because signs and symptoms of cardiac dysfunction are non-specific or can overlap with that of muscular wasting (reduced physical activity) and respiratory failure due to the underlying ND. Diagnosis can also be delayed because of the late manifestations of the traditional non-invasive imaging markers of cardiac dysfunction particularly left ventricular (LV) systolic function and LV volumes or dimensions on echocardiography and late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (CMRI). For these reasons, a better understanding of longitudinal progress, cardiac complications and long-term cardiac outcomes is warranted. The clinician should also be familiar with the therapeutic options in CM associated with NDs. Thus, this review discusses important clinical and diagnostic features of CM in patients with NDs as well as emerging diagnostic and therapeutic options.
... Fitzsimons et al. performed detailed examinations including fundus angiography inthe eyes of 75 FSHD patients and demonstrated peripheral retinal capillary abnormalities including telangiectasia, leakage and micro aneurysm formation (Fitzsimons et al. 1987). (Padberg et al. 1995) also demonstrated retinal vasculopathy in 49% of patients with FSHD by using retinal angiography. (Padberg et al. 1995)Two exudative retinal detachments due to retinal telangiectasia in FSHD were reported in the literature. ...
... (Padberg et al. 1995) also demonstrated retinal vasculopathy in 49% of patients with FSHD by using retinal angiography. (Padberg et al. 1995)Two exudative retinal detachments due to retinal telangiectasia in FSHD were reported in the literature. (Pauleikhoff et al. 1992) Since retinal detachment is a severe complication of Coats' disease, clinicians should carefully perform eye examination in patients with FSHD to prevent a potential visual loss with laser treatment applied to theinvolved areas of the retina. ...
... Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common neuromuscular disorders (Padberg et al. 1995;Mostacciuolo et al. 2009;Deenen et al. 2014), yet the molecular mechanisms causing FSHD are unclear. FSHD is an autosomal dominant myopathy associated with a variable age of onset (Padberg et al. 1995;Pastorello et al. 2012). ...
... Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common neuromuscular disorders (Padberg et al. 1995;Mostacciuolo et al. 2009;Deenen et al. 2014), yet the molecular mechanisms causing FSHD are unclear. FSHD is an autosomal dominant myopathy associated with a variable age of onset (Padberg et al. 1995;Pastorello et al. 2012). Clinical manifestations are heterogeneous; and in 90%-95% of FSHD cases, the disease onset is linked to contraction of multiple 3.3-kb tandem D4Z4 repeats located in the subtelomeric region of the long arm of Chromosome 4 (FSHD1A; 4q35 locus). ...
DNA is organized into complex three-dimensional chromatin structures but how this special organization regulates gene expression remains a central question. These DNA/chromatin looping structures can range in size from 10-20 kilobases (enhancers/repressors) to many megabases (Mb) during intra- and inter-chromosomal interactions. Recently, the influence of telomere length on chromatin organization prior to senescence has revealed the existence of long distance chromatin loops that dictate the expression of genes located up to 10Mb from the telomeres (Telomere Position Effect-Over Long Distances; TPE-OLD). Here, we demonstrate the existence of a telomere loop at the 4q35 locus involving the Sorbin and SH3 domain-containing protein 2 gene, SORBS2, a skeletal muscle protein using a modification of the chromosome conformation capture method. The loop reveals a cis-acting mechanism modifying SORBS2 transcription. The expression of this gene is altered by TPE-OLD in myoblasts from patients affected with the age-associated genetic disease, facioscapulohumeral muscular dystrophy (FSHD1A, MIM 158900). SORBS2 is expressed in FSHD myoblasts with short telomeres, while not detectable in FSHD myoblasts with long telomeres or in healthy myoblasts regardless of telomere length. This indicates that TPE-OLD may modify the regulation of the 4q35 locus in a pathogenic context. Upon differentiation, both FSHD and healthy myotubes express SORBS2 suggesting that SORBS2 is normally up-regulated by maturation/differentiation of skeletal muscle and is misregulated by TPE-OLD-dependent variegation in FSHD myoblasts. These findings provide additional insights for the complexity and age-related symptoms of FSHD.
... Facioscapulohumeral muscular dystrophy (FSHD), an autosomal dominant disorder, is one of the most common muscular dystrophy in adults in Europe [1][2][3]. It is initially characterized by weakness and atrophy of face and scapular muscles [4]. ...
... The disease is pre- dominantly inherited in an autosomal-dominant pattern. However, 10%-30% of cases are attributed to de novo variants, with a high frequency of somatic mosaicism [1][2][3]. FSHD is caused by aberrant expression of DUX4, which encodes a protein that induces apoptosis by causing immune responses in muscle cells. Each D4Z4 unit on chromosome 4q35 encodes a copy of the DUX4 retrogene [4,5]. ...
Background:
Facioscapulohumeral muscular dystrophy (FSHD) is a common form of muscular dystrophy that mainly affects skeletal muscle. FSHD1 accounts for 95% of all FSHD cases and can be diagnosed based on the pathogenic contraction of the D4Z4-repeat array on chromosome 4q35. Genetic diagnosis of FSHD1 is challenging because of the large size and repetitive nature of the D4Z4 region. We evaluated the clinical applicability of optical genome mapping (OGM) for the genetic diagnosis of FSHD1.
Methods:
We included 25 individuals with clinically confirmed or suspected/probable FSHD and their families. Ultra-high-molecular-weight DNA from peripheral blood was labeled, stained, and imaged using a single-molecule OGM platform (Bionano Genomics Saphyr system). D4Z4 repeat size and haplotype information were analyzed using the manufacturer's dedicated pipeline. We also compared the workflow and test time between Southern blot analysis and OGM.
Results:
We obtained concordant OGM and Southern blot results with 10 samples from patients with clinically confirmed FSHD. The D4Z4 repeat size differed within 1 unit between the Southern blot analysis and OGM. Among nine patients with clinically suspected or probable FSHD, six patients were confirmed to have pathogenic contractions by OGM. In our cohort, one de novo mosaic FSHD1 patient was successfully diagnosed with OGM. Moreover, OGM has a more straightforward and less time-consuming workflow than Southern blot analysis.
Conclusions:
OGM enables accurate and reliable detection of pathogenic contraction of the D4Z4-repeat array and is a valuable tool for the genetic diagnosis of FSHD1.
... Facioscapulohumeral muscular dystrophy (FSHD) is a progressive myopathy that affects women and men of all ages with an estimated worldwide prevalence of ∼1 in 8300-15 000 [1][2][3]. FSHD is caused by aberrant expression of the Double homeobox 4 (DUX4) retrogene in skeletal muscle as a consequence of epigenetic dysregulation of the 4q35 D4Z4 macrosatellite repeat array [4][5][6][7][8]. DUX4 encodes a transcription factor that is expressed at the 4cell stage and plays an important role in the early stages of human embryonic development before becoming epigenetically silenced [9,10]. ...
Facioscapulohumeral muscular dystrophy (FSHD) is a progressive myopathy caused by the aberrant increased expression of the DUX4 retrogene in skeletal muscle cells. The DUX4 gene encodes a transcription factor that functions in zygotic genome activation and then is silenced in most adult somatic tissues. DUX4 expression in FSHD disrupts normal muscle cell function; however, the downstream pathogenic mechanisms are still unclear. Histologically, FSHD affected muscles show a characteristic dystrophic phenotype that is often accompanied by a pronounced immune cell infiltration, but the role of the immune system in FSHD is not understood. Previously, we used ACTA1;FLExDUX4 FSHD-like mouse models varying in severity as discovery tools to identify increased Interleukin 6 and microRNA-206 levels as serum biomarkers for FSHD disease severity. In this study, we use the ACTA1;FLExDUX4 chronic FSHD-like mouse model to provide insight into the immune response to DUX4 expression in skeletal muscles. We demonstrate that these FSHD-like muscles are enriched with the chemoattractant eotaxin and the cytotoxic eosinophil peroxidase, and exhibit muscle eosinophilia. We further identified muscle fibers with positive staining for eosinophil peroxidase in human FSHD muscle. Our data supports that skeletal muscle eosinophilia is a hallmark of FSHD pathology.
... Facioscapulohumeral muscular dystrophy (FSHD) is one of the most prevalent neuromuscular disorders 1 and leads to significant lifetime morbidity, with up to 20% of patients requiring a wheelchair. 2,3 Two genetic forms of FSHD have been reported. FSHD1 (MIM: 158900) accounts for 95% of the cases and is linked to the reduction in copy number of the D4Z4 microsatellite repeat at 4q35 below 10 units. ...
Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common neuromuscular disorders and has no cure. Due to an unknown molecular mechanism, FSHD displays overlapping manifestations with the neurodegenerative disease amyotrophic lateral sclerosis (ALS). FSHD is caused by aberrant gain of expression of the transcription factor double homeobox 4 (DUX4), which triggers a pro-apoptotic transcriptional program resulting in inhibition of myogenic differentiation and muscle wasting. Regulation of DUX4 activity is poorly known. We identify Matrin 3 (MATR3), whose mutation causes ALS and dominant distal myopathy, as a cellular factor controlling DUX4 expression and activity. MATR3 binds to the DUX4 DNA-binding domain and blocks DUX4-mediated gene expression, rescuing cell viability and myogenic differentiation of FSHD muscle cells, without affecting healthy muscle cells. Finally, we characterize a shorter MATR3 fragment that is necessary and sufficient to directly block DUX4-induced toxicity to the same extent as the full-length protein. Collectively, our data suggest MATR3 as a candidate for developing a treatment for FSHD.
... Facioscapulohumeral muscular dystrophy (FSHD) is a disabling inherited muscle disease that affects children and adults. FSHD is one of the most common types of muscular dystrophy, with a prevalence ranging from 3.2 to 4.6 per 100,000 in Europe [1][2][3]. This autosomal dominant disorder is characterized by progressive and asymmetric weakness of facial and scapular muscles [4]. ...
In patients with facioscapulohumeral muscular dystrophy (FSHD), a rare genetic neuromuscular disease, reduced physical performance is associated with lower blood levels of vitamin C, zinc, selenium, and increased oxidative stress markers. Supplementation of vitamin C, vitamin E, zinc, and selenium improves the quadriceps' physical performance. Here, we compared the nutritional status of 74 women and 85 men with FSHD. Calorie intake was lower in women with FSHD than in men. Moreover, we assessed vitamin C, vitamin E, zinc, copper, and selenium intakes in diet and their concentrations in the plasma. Vitamin E, copper, and zinc intake were lower in women with FSHD than in men, whereas plasma vitamin C, copper levels, and copper/zinc ratio were higher in women with FSHD than in men. The dietary intake and plasma concentrations of the studied vitamins and minerals were not correlated in both sexes. A well-balanced and varied diet might not be enough in patients with FSHD to correct the observed vitamin/mineral deficiencies. A low energy intake is a risk factor for suboptimal intake of proteins, vitamins, and minerals that are important for protein synthesis and other metabolic pathways and that might contribute to progressive muscle mass loss. Antioxidant supplementation and higher protein intake seem necessary to confer protection against oxidative stress and skeletal muscle mass loss.
... Commonly, the initial symptom is facial muscle involvement, and it is often overlooked. The expressionless face pattern is often attributed to family traits, and this is thought to be one of the reasons why patients remain undiagnosed in earlier phases (5,6). When the shoulder girdle and periscapular muscles are involved, the scapular winging becomes apparent with patients unable to elevate their arms overhead. ...
Facioscapulohumeral muscular dystrophy (FSHD) is a common hereditary disorder which typically results in scapular winging due to wasting of the periscapular muscles affected by this condition.
Scapulothoracic arthrodesis (STA) is the current surgical treatment for FSHD patients with severe winging and preserved deltoid muscle.
There are several different techniques in the literature such as multifilament cables alone and cable or cerclage wires combined with single or multiple plates. We prefer cables without plates as it provides independent strong fixation points and strongly recommend utilization of autograft.
The functional results of studies report that regardless of the technique used, shoulder elevation and thus quality of life is improved, as shown with outcome scores.
There are several complications associated with STA. Pulmonary complications are common and usually resolve spontaneously. Meticulous surgical technique and effective postoperative analgesia may reduce the incidence. Scapular complications which are associated with the fixation may be encountered in the early or late period, which are related to the learning curve of the surgeon.
In conclusion, STA is a reliable solution to a major problem in FSHD patients that helps them maintain their activities of daily living until a cure for the disease is found. A successful result is strongly dependent on patient selection, and a multidisciplinary team of neurologists, geneticists and orthopaedic surgeons is required to achieve good results.
... It gets its name from the muscles that are affected most often: those of the face (facio-), around the shoulder blades (scapulo-), and in the upper arms (humeral). Although it can eventually affect the legs as well, leaving the patient partially immobilized [368][369][370][371] . Onset usually occurs in the teenage years but can begin in childhood or as late as age 50. ...
Almost half of the human genome derives from transposable elements (TE). Among them, the Long INterspersed Element-1 (LINE-1 or L1) forms the only currently active and autonomous transposable element family in humans. Although hundreds of thousands L1 copies are dispersed in the human genome, only 80-100 of them are still retrotransposition competent, i.e. able to replicate by a “copy-and-paste” mechanism via an RNA intermediate and a reverse transcription step. On the one hand, L1 activity can have deleterious consequences, such as insertional mutagenesis, and is tightly regulated at the transcriptional or post-transcriptional levels. However, specific host factors are necessary for completion of L1 replication cycle. When occurring in the germline or in the early embryo, L1 insertions can be transmitted to the next generation. Somatic retrotransposition has been also described in epithelial tumors and in the brain, both in neural progenitor cells and differentiated neurons. Nevertheless, the extent of L1 expression and mobilization in other somatic tissues remains unclear.Here, we investigated the activity of L1 retrotransposons in human and mouse skeletal muscle cells. We show that the most abundant L1 protein, ORF1p, which is essential to retrotransposition, is undetectable under our experimental conditions, in mouse or human muscle samples, while it is readily detected in cancer cells or in testis. Similarly, it was undetected in immortalized mouse or human myoblasts. However, we found that L1 is capable of retrotransposition in human and mouse myoblasts when expressed from a plasmid or from an integrated copy with a constitutive or inducible promoter, respectively. In conclusion, while L1 expression is under the limit of detection in muscle, myoblasts are permissive to retrotransposition, indicating that these cells express all the cellular factors necessary to achieve this process, and do not express significant restriction factors that would prevent retrotransposition.Altogether, our findings suggest that somatic L1 activity could not be confined to the brain or cancer cells, but could also occur in muscles under environmental or pathological conditions that would unleash L1 expression.
... The proportion of wheelchairdependent FSHD1 at 13.5%, among those patients over 50 years old, which is lower than the previously reported 20%. 21,39,40 During 2001-2020, only two patients died, and those deaths were due to unknown causes. This is consistent with previous opinion that FSHD1 typically progresses relatively slowly and generally does not affect mortality. ...
Background: Facioscapulohumeral muscular dystrophy type 1 (FSHD1) is a rare disease, which is often underdiagnosed due to its heterogeneous presentations and complex molecular genetic basis, leading to a lack of population-based epidemiology data, especially of prevalence and disease progression.
Methods: Fujian Neuromedical Centre (FNMC) is a diagnosis centre for clinical-genetic FSHD in China, and the only one employing pulsed-field gel electrophoresis (PFGE)-based Southern blotting for all FSHD1 genetic tests. Three sources distributed across all six spatial zones in China, were used to obtain information regarding FSHD1 events, namely, FNMC, Genetic and Myopathy Group (branches of the Neurology Society of the Chinese Medical Association), and “FSHD-China” (an organization supported by FSHD patients). During 2001-2020, all genetically-confirmed FSHD1 from China were registered in FNMC. Follow-up was conducted in the 20-year period to obtain data on disease progression, which was mainly described in terms of independent ambulation loss.
Findings: Of the 1,744 FSHD1 genetic tests (total test number 1,802) included in the analysis, 997 (57.2%) patients from 620 families were diagnosed with FSHD1. The estimated prevalence of genetically-confirmed FSHD1 in China is 0.75 per million (95% confidence interval [CI], 0.70-0.79) during 2001-2020, with 0.78 (95% CI, 0.72-0.85) in males and 0.71 (95% CI, 0.65-0.78) in females. The estimated prevalence increased from 0.22 (95% CI, 0.19-0.26) per million in 2001-2015 to 0.53 (95% CI, 0.49-0.57) per million in 2016-2020 (p < 0.001). The prevalence in Fujian province was 7.10 per million, 4.66 per million, and 2.44 per million, during 2001-2020, 2001-2015, and 2016-2020, respectively. Among the 861 symptomatic plus asymptomatic patients of the total 997 patients, the median onset age at first-ever muscle weakness was 16 years of age (range 1-81); the median number of contracted D4Z4 repeats was 5 units (range 1-9); the median 4qA-allele-specific methylation level was 41% (range 14%-69%). Of the 977 symptomatic patients followed-up during 2001-2020, 117 patients (12.0%) lost independent ambulation. The expected duration from onset of first-ever muscle weakness to onset of independent ambulation loss was 40 years. The group with loss of independent ambulation had a smaller number of contracted D4Z4 repeats (p < 0.001) and had an earlier onset age of first-ever muscle weakness (p < 0.001) compared to the group without loss of independent ambulation.
Interpretation: Our research captures the largest genetically-confirmed FSHD1 population worldwide, to calculate its prevalence of 0.75 per million in China from 2001 to 2020. Approximately 12.0% of symptomatic plus asymptomatic patients of FSHD1 will lose independent ambulation in 40 years from onset of first-ever muscle weakness.
Funding: This work has been supported by the grants (U2005201, 81870902, N.W.) and (81974193, 81671237, Z.Q.W.) from the National Natural Science Foundation of China; Joint Funds for the Innovation of Science and Technology of Fujian Province (2018Y9082) (N.W.), and the Key Clinical Specialty Discipline Construction Program of Fujian (N.W.).
... Facioscapulohumeral muscular dystrophy (FSHD) is a progressive myopathy that affects ∼1 in 8300-15,000 people worldwide (Deenen et al., 2014;Orphanet, 2021;Padberg et al., 1995). FSHD affects women and men of all ages; however, it is characterized by high variability in clinical presentation with disease onset, progression and severity differing greatly between individuals and particularly within families (Jones et al., 2012;Mul et al., 2018b;Statland et al., 2015a;Tawil et al., 1996;Tonini et al., 2004;Wang and Tawil, 2016). ...
Facioscapulohumeral muscular dystrophy (FSHD) is caused by misexpression of DUX4 in skeletal myocytes. As DUX4 is the key therapeutic target in FSHD, surrogate biomarkers of DUX4 expression in skeletal muscle are critically needed for clinical trials. Although no natural animal models of FSHD exist, transgenic mice with inducible DUX4 expression in skeletal muscles rapidly develop myopathic phenotypes consistent with FSHD. Here, we established a new, more-accurate FSHD-like mouse model based on chronic DUX4 expression in a small fraction of skeletal myonuclei that develops pathology mimicking key aspects of FSHD across its lifespan. Utilizing this new aged mouse model and DUX4-inducible mouse models, we characterized the DUX4-related microRNA signatures in skeletal muscles, which represent potential biomarkers for FSHD. We found increased expression of miR-31-5p and miR-206 in muscles expressing different levels of DUX4 and displaying varying degrees of pathology. Importantly, miR-206 expression is significantly increased in serum samples from FSHD patients compared with healthy controls. Our data support miR-31-5p and miR-206 as new potential regulators of muscle pathology and miR-206 as a potential circulating biomarker for FSHD.
This article has an associated First Person interview with the first author of the paper.
... Лице-плече-лопаточная миодистрофия Ландузи-Дежерина (МЛД) -наследственная прогрессирующая миопатия, поражающая все возрастные категории. По своей распространенности МЛД занимает третье место среди всех наследственных мышечных дистрофий, согласно литературным данным в различных популяциях её частота находится в пределах от 1:20000 до 1:7000 человек [1][2][3][4]. В принятой в настоящее время молекулярно-генетической модели развития МЛД основная роль отводится эктопичной экспрессии транскрипционного фактора DUX4 в мышечной ткани [5]. Ген DUX4 кодируется макросателлитными повторами D4Z4 хромосомы 4, причем считается, что зрелые РНК-транскрипты образуются только с дистального повтора D4Z4 [6]. ...
Актуальность. Миодистрофия Ландузи-Дежерина (МЛД) является одной из наиболее часто встречающихся мышечных дистрофий. В 95% случаев заболевание связано с частичной делецией массива повторов D4Z4 на одном из аллелей 4-й хромосомы. Существующие диагностические методики гибридизации по Саузерну и молекулярного комбинга являются ресурсо- и времязатратными. В настоящее время в Российской Федерации молекулярно-генетическая диагностика МЛД не проводится. Цель. Поиск новых подходов к диагностике МЛД для использования в молекулярно-генетических лабораториях. Методы. ДНК выделялась в агарозных блоках и подвергалась обработке эндонуклеазой EcoRI. Полученные фрагменты ДНК разделялись методом пульс-электрофореза в агарозном геле, после этого агарозный гель фрагментировался согласно маркеру молекулярного веса и использовался в качестве матрицы для полимеразной цепной реакции (ПЦР). Принадлежность полученных ПЦР-продуктов к последовательностям повторов D4Z4 4-й хромосомы подтверждалась секвенированием по Сэнгеру. Результаты. Протокол пульс-электрофореза оптимизирован таким образом, что после всех этапов ДНК в агарозном геле пригодна для использования в качестве матрицы для ПЦР. Разработана ПЦР-система специфичной амплификации контрольных ДНК-матриц 4-й хромосомы и подтверждена секвенированием принадлежность получаемых ПЦР-продуктов к последовательности повторов D4Z4 4-й хромосомы. Выводы. Показана возможность использования ДНК в агарозном геле после пульс-электрофореза в качестве матрицы для детекции повторов D4Z4 методом ПЦР. Представленная ПЦР-система специфично амплифицирует последовательности D4Z4 4-й хромосомы. Используя данную ПЦР-систему и геномную ДНК пациента с известной длиной массива повторов D4Z4 проведена успешная диагностика МЛД. Таким образом разработан новый подход к диагностике МЛД для использования в молекулярно-генетических лабораториях.
Relevance. Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common muscular dystrophies. In 95% of cases, the disease is associated with partial deletion of the array of the D4Z4 repeats on one of the alleles of the 4th chromosome. The existing diagnostic methods of Southern blotting and molecular combing are quite resource-and time-consuming. At the moment, molecular genetic diagnostic of FSHD is not provided on the territory of the Russian Federation. Aim: to find new approaches for molecular genetic diagnostic of FSHD acceptable for use in standard molecular genetic laboratories Materials and methods: DNA isolated in agarose plugs and treated by the EcoRI restriction enzyme. DNA fragments then were separated by pulse field gel electrophoresis (PFGE) in agarose gel. After PFGE, the agarose gel was fragmented and used as a matrix for PCR. The identity of the obtained PCR products to the sequence of the D4Z4 repeats of the 4th chromosome was confirmed by sequencing by Sanger. Results. The PFGE protocol is optimized in such a way that, after all stages, DNA in agarose gel is suitable for use as a matrix for PCR. We achieve a specific amplification of the control DNA matrices of the 4th chromosome and confirm belonging of the PCR products to the sequence of D4Z4 repeats of the 4th chromosome by the Senger sequencing. Conclusions. This paper shows the possibility of using DNA in agarose gel after PFGE as a matrix for detection of D4Z4 repeats by PCR. The presented PCR system specifically amplify sequence of the 4th chromosome D4Z4 repeats. Using this PCR system and genomic DNA of a patient with a known length of the D4Z4 repeats array, a successful diagnosis of FSHD was performed. Thus, we propose a new approach for FSHD diagnostic, acceptable for use in standard molecular genetic laboratories.
... Facioscapulohumeral muscular dystrophy (FSHD) afflicts females and males of all ages and an estimated 1:8,300-22,000 people worldwide [1][2][3][4]. All forms of FSHD share a common pathogenic mechanism, increased somatic expression of the DUX4 (Double homeobox 4) retrogene caused by the loss of stable epigenetic repression of the chromosome 4q35.2 ...
Background:
All types of facioscapulohumeral muscular dystrophy (FSHD) are caused by the aberrant activation of the somatically silent DUX4 gene, the expression of which initiates a cascade of cellular events ultimately leading to FSHD pathophysiology. Typically, progressive skeletal muscle weakness becomes noticeable in the second or third decade of life, yet there are many individuals who are genetically FSHD but develop symptoms much later in life or remain relatively asymptomatic throughout their lives. Conversely, FSHD may clinically present prior to 5-10 years of age, ultimately manifesting as a severe early-onset form of the disease. These phenotypic differences are thought to be due to the timing and levels of DUX4 misexpression.
Methods:
FSHD is a dominant gain-of-function disease that is amenable to modeling by DUX4 overexpression. We have recently created a line of conditional DUX4 transgenic mice, FLExDUX4, that develop a myopathy upon induction of human DUX4-fl expression in skeletal muscle. Here, we use the FLExDUX4 mouse crossed with the skeletal muscle-specific and tamoxifen-inducible line ACTA1-MerCreMer to generate a highly versatile bi-transgenic mouse model with chronic, low-level DUX4-fl expression and cumulative mild FSHD-like pathology that can be reproducibly induced to develop more severe pathology via tamoxifen induction of DUX4-fl in skeletal muscles.
Results:
We identified conditions to generate FSHD-like models exhibiting reproducibly mild, moderate, or severe DUX4-dependent pathophysiology and characterized progression of pathology. We assayed DUX4-fl mRNA and protein levels, fitness, strength, global gene expression, and histopathology, all of which are consistent with an FSHD-like myopathic phenotype. Importantly, we identified sex-specific and muscle-specific differences that should be considered when using these models for preclinical studies.
Conclusions:
The ACTA1-MCM;FLExDUX4 bi-transgenic mouse model has mild FSHD-like pathology and detectable muscle weakness. The onset and progression of more severe DUX4-dependent pathologies can be controlled via tamoxifen injection to increase the levels of mosaic DUX4-fl expression, providing consistent and readily screenable phenotypes for assessing therapies targeting DUX4-fl mRNA and/or protein and are useful to investigate certain conserved downstream FSHD-like pathophysiology. Overall, this model supports that DUX4 expression levels in skeletal muscle directly correlate with FSHD-like pathology by numerous metrics.
... Facioscapulohumeral muscular dystrophy (FSHD) is one of the most prevalent muscular dystrophies (Padberg et al., 1995;Deenen et al., 2014), yet there is currently no treatment available and few clinical trials of promising therapies are ongoing. Thus, there is a desperate need to identify drug targets to stop or reverse progression of the disease. ...
Facioscapulohumeral muscular dystrophy (FSHD) is characterized by misexpression of the double homeobox 4 (DUX4) developmental transcription factor in mature skeletal muscle, where it is responsible for muscle degeneration. Preventing expression of DUX4 mRNA is a disease-modifying therapeutic strategy with the potential to halt or reverse the course of disease. We previously reported that agonists of the β-2 adrenergic receptor suppress DUX4 expression by activating adenylate cyclase to increase cAMP levels. Efforts to further explore this signaling pathway led to the identification of p38 mitogen-activated protein kinase as a major regulator of DUX4 expression. In vitro experiments demonstrate that clinically advanced p38 inhibitors suppress DUX4 expression in FSHD type 1 and 2 myoblasts and differentiating myocytes in vitro with exquisite potency. Individual small interfering RNA-mediated knockdown of either p38α or p38β suppresses DUX4 expression, demonstrating that each kinase isoform plays a distinct requisite role in activating DUX4 Finally, p38 inhibitors effectively suppress DUX4 expression in a mouse xenograft model of human FSHD gene regulation. These data support the repurposing of existing clinical p38 inhibitors as potential therapeutics for FSHD. The surprise finding that p38α and p38β isoforms each independently contribute to DUX4 expression offers a unique opportunity to explore the utility of p38 isoform-selective inhibitors to balance efficacy and safety in skeletal muscle. We propose p38 inhibition as a disease-modifying therapeutic strategy for FSHD. SIGNIFICANCE STATEMENT: Facioscapulohumeral muscular dystrophy (FSHD) currently has no treatment options. This work provides evidence that repurposing a clinically advanced p38 inhibitor may provide the first disease-modifying drug for FSHD by suppressing toxic DUX4 expression, the root cause of muscle degeneration in this disease.
... In most cases, FSHD is characterized by progression of dystrophic changes in the cranio-caudal direction with asymmetric lesions of facial muscles, shoulder girdle, shoulders and legs. The prevalence of the disease in different populations varies from 1:20′000 to 1:14′000, conceding only to Duchenne muscular dystrophy and myotonic dystrophy [1][2][3][4]. ...
Background
Facial-scapular-humeral myodystrophy Landouzy-Dejerine (FSHD) is an autosomal dominant disease, the basis of its pathogenesis is ectopic expression of the transcription factor DUX4 in skeletal muscle. There are two types of the disease: FSHD1 (MIM:158900) and FSHD2 (MIM: 158901), which have different genetic causes but are phenotypically indistinguishable. In FSHD1, partial deletion of the D4Z4 repeats on the 4th chromosome affects the expression of DUX4, whereas FSHD2 is caused by the mutations in the protein regulating the methylation status of chromatin - SMCHD1. High variability of clinical picture, both intra - and inter-family indicates a large number of factors influencing clinical picture. There are key genetic, epigenetic and gender factors that influence the expressivity and penetrance of the disease. Using only one of these factors allows just a rough prediction of the course of the disease, which indicates the combined effect of all of the factors on the DUX4 expression and on the clinical picture.
Results
In this paper, we analyzed the impact of genetic, epigenetic and gender differences on phenotype and the possibility of using them for disease prognosis and family counselling.
Conclusions
Key pathogenesis factors have been identified for FSHD. However, the pronounced intra - and inter-family polymorphism of manifestations indicates a large number of modifiers of the pathological process, many of which remain unknown.
... Intriguingly, there are key examples indicating that the regulation of gene expression via TPE is critical for preventing diseases associated with telomere maintenance defects. Facioscapulohumeral muscular dystrophy, or FSHD, is a myopathy characterized by facial, scapular, and arm muscle atrophy and shows a late onset associated with telomere attrition [119]. The etiology of FSHD has been linked to the upregulation of the gene DUX4 in a subset of patients, particularly in the presence of short telomeres [120]. ...
Telomeres, the nucleoprotein structures at the ends of eukaryotic chromosomes, play an integral role in protecting linear DNA from degradation. Dysregulation of telomeres can result in genomic instability and has been implicated in increased rates of cellular senescence and many diseases, including cancer. The integrity of telomeres is maintained by a coordinated network of proteins and RNAs, such as the telomerase holoenzyme and protective proteins that prevent the recognition of the telomere ends as a DNA double-strand breaks. The structure of chromatin at telomeres and within adjacent subtelomeres has been implicated in telomere maintenance pathways in model systems and humans. Specific post-translational modifications of histones, including methylation, acetylation, and ubiquitination, have been shown to be necessary for maintaining a chromatin environment that promotes telomere integrity. Here we review the current knowledge regarding the role of histone modifications in maintaining telomeric and subtelomeric chromatin, discuss the implications of histone modification marks as they relate to human disease, and highlight key areas for future research.
... Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant neuromuscular disease with an estimated prevalence ranging from 1:14,000 to 1:20,000 (109,276,298,305,390). Clinically, FSHD shows asymmetric regional muscle weakness in the face, shoulders, and upper arms. ...
Muscular dystrophies represent a large group of genetic disorders that significantly impair quality of life and often progress to premature death. There is no effective treatment for these debilitating diseases. Most therapies, developed to date, focus on alleviating the symptoms or targeting the secondary effects, while the underlying gene mutation is still present in the human genome. The discovery and application of programmable nucleases for site-specific DNA double-stranded breaks provides a powerful tool for precise genome engineering. In particular, the CRISPR/Cas system has revolutionized the genome editing field and is providing a new path for disease treatment by targeting the disease-causing genetic mutations. In this review, we provide a historical overview of genome-editing technologies, summarize the most recent advances, and discuss potential strategies and challenges for permanently correcting genetic mutations that cause muscular dystrophies.
... The prevalence of FSHD is estimated at between 1:15,000 and 1:20,000, making it the third most common form of muscular dystrophy after Duchenne dystrophy and myotonic dystrophy (Padberg et al., 1995b;Flanigan et al., 2001). A recent evaluation of the prevalence of FSHD in the Netherlands suggests a significantly higher prevalence of 2.4/20,000; confirmation of this new figure would make the prevalence of FSHD nearly identical to that of myotonic dystrophy (Deenen et al., 2014). ...
Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common forms of muscular dystrophy with a distinctive pattern of skeletal muscle weakness and a wide spectrum of disease severity. The pathophysiologic consequences of the genetic lesion, the loss of a critical number of macrosatellite repeats (D4Z4) in the subtelomeric region of chromosome 4q35, remained unexplained for almost two decades. Recent studies demonstrate that contraction in the number of D4Z4 repeats results in chromatin relaxation and transcriptional de-repression of DUX4, a gene normally expressed only in the germline. In about 5% of individuals with phenotypic FSHD, there is no contraction in the D4Z4 repeats and yet similar chromatin changes are present, resulting in the inappropriate expression of the DUX4 gene. The chromatin changes in this form of FSHD (FSHD2) are the result, in most cases, of mutations in SMCHD1, a gene on chromosome 18 involved in chromatin regulation. The recent identification of aberrant activation of DUX4 transcription in FSHD as the root cause of FSHD now allows for a targeted approach to therapeutic development.
... Landouzy-Dejerine facioscapulohumeral muscular dystrophy (FSHD) is one of the most common diseases in the group of hereditary progressive muscular dystrophies, which is the third most frequent after Duchenne muscular dystrophy and myotonic dystrophy. The disease incidence in different populations varies from 1 : 20000 to 1 : 14000 [1][2][3][4]. To date, two genetic variants of FSHD have been described; they are similar in clinical manifestations and are designated as types 1 and 2. Autosomal dominant inheritance is typical of FSHD1; about 25% of cases are caused by de novo mutations [5,6]. ...
Landouzy–Dejerine facioscapulohumeral muscular dystrophy (FSHD) is one of the most common hereditary myodystrophies. A study of the genetic nature of the disease, which has an autosomal dominant mode of inheritance, is extremely interesting and revealing. A unique structure of D4Z4 macrosatellite repeats found in the 4q35 region was originally characterized by a decrease in the number of repeats in patients with Landouzy–Dejerine muscular dystrophy, which resulted in the activation of neighboring genes, in particular, the DUX4 transcription factor. Later, it was found that the epigenetic mechanisms responsible for the chromatin condensation of this region underlie the activation. To date, additional participants leading to pathogenesis of the disease, such as SMCHD1 methylation regulator and DBE-T regulatory long noncoding RNA, have been identified. The revealed complexity of the disease mechanisms is in good agreement with the observed pattern of the disease inheritance. The study of the Landouzy–Dejerine muscular dystrophy pathogenesis is a good example of how monogenic diseases can possess a more complex nature of inheritance.
... Around 1% of individuals with FSHD experience restrictive respiratory disease which requires an intervention; however, this is typically seen in those FSHD patients with severe muscle weakness [7]. Patients can also present with additional symptoms such as severe muscular inflammation, subclinical hearing loss, and abnormalities of the peripheral retinal capillary [8][9][10][11][12]. Research has also suggested that FSHD can result in changes to the central nervous system. ...
Facioscapulohumeral muscular dystrophy (FSHD) is an inherited myopathy affecting approximately 1 in 7500 individuals worldwide. It is a progressive disease characterised by skeletal muscle weakness and wasting. A genetic mutation on the 4q35 chromosome results in the expression of the double homeobox 4 gene (DUX4) which drives oxidative stress, inflammation, toxicity, and atrophy within the skeletal muscle. FSHD is characterised by oxidative stress, and there is currently no cure and a lack of therapies for the disease. Antioxidants have been researched for many years, with investigators aiming to use antioxidants therapeutically for oxidative stress-associated diseases. This has included both natural and synthetic antioxidants. The use of antioxidants in preclinical or clinical models has been largely successful with a plethora of research reporting positive results. However, when translated to clinical trials, the use of antioxidants as a therapeutic intervention for a variety of disease has been largely unsuccessful. Moreover, specifically focusing on FSHD, limited research has been conducted on the use of antioxidants as a therapy in either preclinical or clinical models. This review summarises the current state of antioxidant use in the treatment of FSHD and discusses their potential avenue for therapeutic use for FSHD patients.
... One of the most common muscular dystrophies [18], facioscapulohumeral muscular dystrophy (FSHD), is characterized by a slowly progressive muscle weakness that may lead to wheelchair-dependency [19], and currently has no efficient treatment [20]. Generally, it is an autosomal dominant disease [21] that is caused by gain-of-function mutations that allow the production of the full-length DUX4 gene product [22][23][24]. Therefore, the reduction of DUX4 gene expression might be a promising treatment strategy for FSHD [25]. ...
Many muscular dystrophies, including lethal Duchenne muscular dystrophy, are incurable and require the sustained application of drugs that have only minor treatment effects and serious negative side effects. The mechanism of siRNA-mediated transcriptional gene regulation (TGR) appears to have a long-lasting effect and may be a viable solution to treat muscle disorders because single or at least rarely repeated therapies would be used. For the best results, siRNA should be delivered to all disease affected muscles, and systemic delivery of siRNA through blood vessels is probably the only applicable choice to achieve this goal. Unfortunately, there are many challenges to overcome such as siRNA degradation in blood, renal clearance, blood–muscle barrier, cell entry and endosomal escape. By exploiting and considering the unique features of muscles and the mechanism of TGR, we will discuss the possible ways to induce TGR in muscles by using non-viral systemic siRNA delivery methods.
... Facioscapulohumeral muscular dystrophy (FSHD) is autosomal dominant, characterised by descending, often asymmetric, skeletal muscle weakness and wasting, starting with facial, shoulder and proximal upper limb muscles (Tawil and Van Der Maarel, 2006). FSHD has an incidence of ∼1:15,000 (Flanigan et al., 2001) and prevalence of 1 in 8333 to 1 in 20,000 (Deenen et al., 2014;Padberg et al., 1995). ...
Skeletal muscle wasting in facioscapulohumeral muscular dystrophy (FSHD) results in substantial morbidity. On a disease-permissive chromosome 4qA haplotype, genomic and/or epigenetic changes at the D4Z4 macrosatellite repeat allows transcription of the DUX4 retrogene. Analysing transgenic mice carrying a human D4Z4 genomic locus from an FSHD-affected individual showed that DUX4 was transiently induced in myoblasts during skeletal muscle regeneration. Centromeric to the D4Z4 repeats is an inverted D4Z4 unit encoding DUX4c. Expression of DUX4, DUX4c and DUX4 constructs, including constitutively active, dominant-negative and truncated versions, revealed that DUX4 activates target genes to inhibit proliferation and differentiation of satellite cells, but that it also downregulates target genes to suppress myogenic differentiation. These transcriptional changes elicited by DUX4 in mouse have significant overlap with genes regulated by DUX4 in man. Comparison of DUX4 and DUX4c transcriptional perturbations revealed that DUX4 regulates genes involved in cell proliferation, whereas DUX4c regulates genes engaged in angiogenesis and muscle development, with both DUX4 and DUX4c modifing genes involved in urogenital development. Transcriptomic analysis showed that DUX4 operates through both target gene activation and repression to orchestrate a transcriptome characteristic of a less-differentiated cell state.
... Facioscapulohumeral dystrophy (FSHD) is an autosomal dominant, slowly progressive type of muscular dystrophy, with an estimated prevalence of 1:21 000. [1,2] FSHD is, thus, one of the most common inherited muscular dystrophies with the first signs of weakness occurring in the muscles of the face and shoulder girdle. [3] Fatty infiltration with loss of muscle fibres gradually results in weakness of nearly all skeletal muscles. ...
Purpose To investigate the upper extremity (UE) at the level of impairments and related activity limitations and participation restrictions in people with facioscapulohumeral muscular dystrophy (FSHD). Methods The study was conducted using web-based questionnaires that were distributed amongst people with FSHD in the Netherlands. Eighty-eight respondents started the survey, and 71 completed it. The questionnaires covered the following dimensions: Function, Activity and Participation of the International Classification of Functioning Disability and Health. Results More than 40% of the respondents experienced pain in one arm or both the arms. Increased pain and stiffness scores and longer disease duration were associated with increased limitation scores. For basic activities, lifting the arm above shoulder-level was most frequently reported as most limited, coherent with the clinical picture of FSHD. Among the respondents, 50% indicated restrictions at school, 78% indicated restrictions at work and more than 80% indicated restrictions whilst participating in sports, hobbies, household activities and romantic relationships. Conclusions This study has shown that alongside the well-known problem of lifting the arms above shoulder-level, UE activities below shoulder height during vocational and occupational activities are also problematic in patients with FSHD. Alongside disease duration, pain and stiffness are associated with UE activity limitations.
• Implications for Rehabilitation
• Attention is needed for pain and experienced stiffness in the upper extremity as it is frequently present in patients with FSHD.
• Rehabilitation professionals need to be aware that patients with FSHD not only experience problems with activities above shoulder height, but also with activities below shoulder height.
• At least 50% of the patients with FSHD experience restrictions in participation as a result of limitations in their UE.
... There are reports that suggest that several factors may affect the prognosis and clinical severity of FSHD. Women appear to be less affected compared to men, 1,11,13 although this was not noted in patients with FSHD2. 7 Severely affected cases also seem to originate more often through new mutations or more commonly transmitted through maternal than through paternal lines. ...
Facioscapulohumeral muscular dystrophy (FSHD) is the third most common type of muscular dystrophy after dystrophinopathies and myotonic dystrophy. The classic form of FSHD is characterized by asymmetric weakness of the face, scapulae, abdomen, and upper and lower extremities. The clinical spectrum of FSHD is wide and can range from asymptomatic individuals to individuals who are wheelchair dependent and have significant motor disabilities. Extramuscular complications such as hearing loss, retinal vascular disease, pain, cognitive impairment, and seizures are associated with FSHD patients, particularly in those with an infantile onset. Several phenotypes other than the classical constellation of signs typical of FSHD are also described. Management is primarily supportive, with surveillance and interventions targeting FSHD specific complications.
... Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant inherited muscular dystrophy and affects about 1 in 20,000 people worldwide [1]. Symptoms may develop in early childhood but generally appear after adolescence. ...
... FSHD is a dominantly inherited disease in its most common form, with a prevalence estimate ranging from 1:8000 to 1:20,000 [4][5][6]. A generally slowly progressive disease, FSHD causes significant lifetime morbidity, with up to 20% of those above age 50 requiring full time wheelchair use. ...
... Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant myopathy with a prevalence of 1 in 20000 [1,2]. FSHD is characterized by a highly selective and slowly progressive muscle involvement [3]. ...
Background:
Facioscapulohumeral muscular dystrophy type 1 (FSHD1) is the third most common inherited muscular dystrophy. Considering the highly variable clinical expression and the slow disease progression, sensitive outcome measures would be of interest.
Methods and findings:
Using muscle MRI, we assessed muscular fatty infiltration in the lower limbs of 35 FSHD1 patients and 22 healthy volunteers by two methods: a quantitative imaging (qMRI) combined with a dedicated automated segmentation method performed on both thighs and a standard T1-weighted four-point visual scale (visual score) on thighs and legs. Each patient had a clinical evaluation including manual muscular testing, Clinical Severity Score (CSS) scale and MFM scale. The intramuscular fat fraction measured using qMRI in the thighs was significantly higher in patients (21.9 ± 20.4%) than in volunteers (3.6 ± 2.8%) (p<0.001). In patients, the intramuscular fat fraction was significantly correlated with the muscular fatty infiltration in the thighs evaluated by the mean visual score (p<0.001). However, we observed a ceiling effect of the visual score for patients with a severe fatty infiltration clearly indicating the larger accuracy of the qMRI approach. Mean intramuscular fat fraction was significantly correlated with CSS scale (p≤0.01) and was inversely correlated with MMT score, MFM subscore D1 (p≤0.01) further illustrating the sensitivity of the qMRI approach. Overall, a clustering analysis disclosed three different imaging patterns of muscle involvement for the thighs and the legs which could be related to different stages of the disease and put forth muscles which could be of interest for a subtle investigation of the disease progression and/or the efficiency of any therapeutic strategy.
Conclusion:
The qMRI provides a sensitive measurement of fat fraction which should also be of high interest to assess disease progression and any therapeutic strategy in FSHD1 patients.
... Facioscapulohumeral Muscular Dystrophy (FSHD) is one of the most common progressive muscular dystrophies (prevalence 1:15000) [1,2]. Recent studies have suggested that both Facioscapulohumeral muscular dystrophy (FSHD) types 1 and 2 operate through a common downstream genetic mechanism of de-repression of a retrogene DUX4, not normally expressed in somatic muscle tissue [3,4]. ...
Background:
Posited pathological mechanisms in Facioscapulohumeral Muscular Dystrophy (FSHD) include activation in somatic tissue of normally silenced genes, increased susceptibility to oxidative stress, and induction of apoptosis.
Objective:
To determine the histopathological changes in FSHD muscle biopsies and compare to possible pathological mechanisms of disease.
Methods:
We performed a cross-sectional study on quadriceps muscle biopsies from 32 genetically confirmed FSHD participants, compared to healthy volunteers and myotonic dystrophy type 1 as disease controls. Biopsies were divided into groups to evaluate apoptosis rates, capillary density, myonuclear and satellite cell counts.
Results:
Apoptosis rates were increased in FSHD (n=10, 0.74%) compared to myotonic dystrophy type 1 (n=10, 0.14%, P=0.003) and healthy volunteers (n=14, 0.13%, P=0.002). Apoptosis was higher in FSHD patients with the smallest residual D4Z4 fragments. Capillary density was decreased in FSHD1 (n=10, 316 capillaries/mm(2)) compared to healthy volunteers (n=15, 448 capillaries/mm(2), P=0.001). No differences were seen in myonuclear or satellite cell counts.
Conclusions:
Preliminary evidence for increased apoptosis rates and reduced capillary density may reflect histopathological correlates of disease activity in FSHD. The molecular-pathological correlates to these changes warrants further investigation.
... Facioscapulohumeral muscular dystrophy is one of the most prevalent muscular dystrophies (prevalence 1:15,000-1:20,000), with a typically descending pattern of weakness, starting in the face and shoulders, followed later by the distal and proximal lower extremities [1][2][3][4][5]. The current genetic model proposes both FSHD types 1 and 2 are caused by de-repression of DUX4 expression, a retrogene believed to cause disease in toxic gain of function manner [6]. ...
Objective
Facioscapulohumeral muscular dystrophy type 1 (FSHD1) is one of the most common forms of autosomal-dominant muscular dystrophies characterized by variable disease penetrance due to shortened D4Z4 repeat units on 4q35. The molecular diagnosis of FSHD1 is usually made by Southern blotting, which is complex, time-consuming, and lacks clinical practicality. Therefore, in this study, optical genome mapping (OGM) is employed for the genetic diagnosis of FSHD1. Furthermore, epigenetic heterogeneity is determined from methylation analysis.
Methods
Genomic DNA samples from four members of the same family were subjected to whole-exome sequencing. OGM was used to identify structural variations in D4Z4, while sodium bisulfite sequencing helped identify the methylation levels of CpG sites in a region located distally to the D4Z4 array. A multidisciplinary team collected the clinical data, and comprehensive family analyses aided in the assessment of phenotypes and genotypes.
Results
Whole-exome sequencing did not reveal variants related to clinical phenotypes in the patients. OGM showed that the proband was a compound heterozygote for the 4qA allele with four and eight D4Z4 repeat units, whereas the affected younger brother had only one 4qA allele with four D4Z4 repeat units. Both the proband and her younger brother were found to display asymmetric weakness predominantly involving the facial, shoulder girdle, and upper arm muscles, whereas the younger brother had more severe clinical symptoms. The proband's father, who was found to be normal after a neurological examination, also carried the 4qA allele with eight D4Z4 repeat units. The unaffected mother exhibited 49 D4Z4 repeat units of the 4qA allele and a minor mosaic pattern with four D4Z4 repeat units of the 4qA allele. Consequently, the presence of the 4qA allele in the four D4Z4 repeat units strongly pointed to the occurrence of maternal germline mosaicism. The CpG6 methylation levels were lower in symptomatic patients compared to those in the asymptomatic parents. The older sister had lower clinical scores and ACSS and higher CpG6 methylation levels than that of her younger brother.
Conclusions
In this study, two siblings with FSHD1 with phenotypically normal parents were identified by OGM. Our findings suggest that the 4qA allele of four D4Z4 repeats was inherited through maternal germline mosaicism. The clinical phenotype heterogeneity is influenced by the CpG6 methylation levels. The results of this study greatly aid in the molecular diagnosis of FSHD1 and in also understanding the clinical phenotypic variability underlying the disease.
Facioscapulohumeral muscular dystrophy (FSHD) is an exclusively human neuromuscular disease. In the last decades the cause of FSHD was identified: the loss of epigenetic repression of the D4Z4 repeat on chromosome 4q35 resulting in inappropriate transcription of DUX4. This is a consequence of a reduction of the array below 11 units (FSHD1) or of a mutation in methylating enzymes (FSHD2). Both require the presence of a 4qA allele and a specific centromeric SSLP haplotype. Muscles become involved in a rostro-caudally order with an extremely variable progression rate. Mild disease and non-penetrance in families with affected individuals is common. Furthermore, 2% of the Caucasian population carries the pathological haplotype without clinical features of FSHD. In order to explain the various features of FSHD we applied Ockham’s Razor to all possible scenarios and removed unnecessary complexities. We postulate that early in embryogenesis a few cells escape epigenetic silencing of the D4Z4 repeat. Their number is assumed to be roughly inversely related to the residual D4Z4 repeat size. By asymmetric cell division, they produce a rostro-caudal and medio-lateral decreasing gradient of weakly D4Z4-repressed mesenchymal stem cells. The gradient tapers towards an end as each cell-division allows renewed epigenetic silencing. Over time, this spatial gradient translates into a temporal gradient based on a decreasing number of weakly silenced stem cells. These cells contribute to a mildly abnormal myofibrillar structure of the fetal muscles. They also form a downward tapering gradient of epigenetically weakly repressed satellite cells. When activated by mechanical trauma, these satellite cells de-differentiate and express DUX4. When fused to myofibrils they contribute to muscle cell death in various ways. Over time and dependent on how far the gradient reaches the FSHD phenotype becomes progressively manifest. We thus hypothesize FSHD to be a myodevelopmental disease with a lifelong attempt to restore DUX4 repression.
With several therapeutic strategies for facioscapulohumeral muscular dystrophy (FSHD) entering clinical testing, outcome measures are becoming increasingly important. Considering the spatiotemporal nature of FSHD disease activity, clinical trials would benefit from non-invasive imaging-based biomarkers that can predict FSHD-associated transcriptome changes. This study investigated two FSHD-associated transcriptome signatures (DUX4 and PAX7 signatures) in FSHD skeletal muscle biopsies, and tested their correlation with a variety of disease-associated factors, including Ricci clinical severity score, disease duration, D4Z4 repeat size, muscle pathology scorings and functional outcome measures. It establishes that DUX4 and PAX7 signatures both show a sporadic expression pattern in FSHD-affected biopsies, possibly marking different stages of disease. This study analyzed two imaging-based biomarkers—Turbo Inversion Recovery Magnitude (TIRM) hyperintensity and fat fraction—and provides insights into their predictive power as non-invasive biomarkers for FSHD signature detection in clinical trials. Further insights in the heterogeneity of—and correlation between—imaging biomarkers and molecular biomarkers, as provided in this study, will provide important guidance to clinical trial design in FSHD. Finally, this study investigated the role of infiltrating non-muscle cell types in FSHD signature expression and detected potential distinct roles for two fibro-adipogenic progenitor subtypes in FSHD.
Riassunto
La distrofia muscolare facio-scapolo-omerale (DMFSO) è una malattia muscolare rara di origine genetica, autosomica dominante a penetranza incompleta e a espressività variabile. È caratterizzata dal coinvolgimento dei muscoli del viso e del cingolo scapolare, con una progressione ai muscoli omerali, addominali e delle logge anteroesterne delle gambe. I deficit, spesso bilaterali, possono anche comparire ed evolvere in modo asimmetrico. La malattia, di solito, si manifesta prima dei 20 anni con un’evoluzione lentamente progressiva e una gravità molto variabile. Le forme infantili restano le più gravi. Quasi il 20% dei pazienti necessita di una sedia a rotelle. Sul piano genetico, la DMFSO di tipo 1 è associata alla delezione eterozigote di unità ripetute di 3,3 kb, D4Z4, situate nella regione subtelomerica del cromosoma 4q35, che porterebbe a un rilassamento della cromatina e all’espressione ectopica del retrogene DUX4, normalmente represso. Questa riattivazione di DUX4 causerebbe una cascata di attivazione di geni tossici per i muscoli. La gravità della malattia dipenderebbe sia dal numero di unità ripetute D4Z4 sia da fattori epigenetici associati. Tuttavia, la grande variabilità interindividuale e intrafamiliare rende difficile stabilire correlazioni genotipo-fenotipo. La DMFSO di tipo 2, clinicamente identica al tipo 1, non è legata a una delezione di D4Z4, ma, nella maggior parte dei casi, a una variante patogena del gene SMCHD1, la cui perdita di funzione porterebbe all’ipometilazione di D4Z4 e all’espressione di DUX4. Nessun trattamento terapeutico ha dimostrato la sua efficacia fino a oggi, per cui la gestione della DMFSO è sintomatica e multidisciplinare. Ha lo scopo di mantenere o, anche, di rallentare le lesioni muscolari e di garantire un certo livello di comfort di vita. Tuttavia, sono allo studio molte prospettive, sia in termini di definizione di biomarcatori più affidabili che di identificazione di farmaci candidati.
Facioscapulohumeral muscular dystrophy (FSHD) is one of the most prevalent muscular dystrophies characterized by considerable variability in severity, rates of progression and functional outcomes. Few studies follow FSHD cohorts long enough to understand predictors of disease progression and functional outcomes, creating gaps in our understanding which impacts clinical care and the design of clinical trials. Efforts to identify molecularly targeted therapies create a need to better understand disease characteristics with predictive value to help refine clinical trial strategies and understand trial outcomes.
Here we analyzed a prospective cohort from a large, longitudinally-followed registry of patients with FSHD in the United States to determine predictors of outcomes such as need for wheelchair use. This study analyzed de-identified data from 578 individuals with confirmed FSHD type 1 enrolled in the United States National Registry for FSHD Patients and Family members. Data were collected from January 2002 to September 2019 and included an average of nine years (range 0 to 18) of follow up surveys. Data were analyzed using descriptive epidemiological techniques, and risk of wheelchair use was determined using cox proportional hazards models. Supervised machine learning analysis was completed using Random Forest modeling and included all 189 unique features collected from registry questionnaires. A separate medications-only model was created that included 359 unique medications reported by participants.
Here we show that smaller allele sizes were predictive of earlier age at onset, diagnosis and likelihood of wheelchair use. Additionally, we show that women were more likely overall to progress to wheelchair use and at a faster rate as compared to men, independent of genetics. Use of machine learning models that included all reported clinical features showed that the effect of allele size on progression to wheelchair use is small compared to disease duration, which may be important to consider in trial design. Medical comorbidities and medication use add to the risk for need for wheelchair dependence, raising the possibility for better medical management impacting outcomes in FSHD.
The findings in this study will require further validation in additional, larger datasets but could have implications for clinical care, and inclusion criteria for future clinical trials in FSHD.
Facioscapulohumeral muscular dystrophy (FSHD) is one of the most prevalent muscular dystrophies; and while not life limiting can cause considerable lifetime morbidity with individuals losing the ability to walk or maintain a job. Common presentations include weakness of muscles of facial expression, shoulder girdle, core muscles, and distal muscles in the leg. Advances to our molecular understanding of FSHD have identified a target for therapy, derepression of a transcription factor, DUX4, which cause the disease through a toxic gain-of-function. Necessary for disease includes decreased methylation in the D4Z4 region of chromosome 4, and a permissive polymorphism that provides a polyadenylation sequence stabilizing DUX4 mRNA. Many of the same chemistries and approaches used for other neuromuscular diseases, including antisense oligonucleotide therapies or RNA interference, may be important for FSHD, which is at a transition point, with advances being made in our molecular genetic understanding, implementation of standards of care, and molecularly targeted therapeutics.
Purpose
Facioscapulohumeral muscular dystrophy (FSHD) is a common adult muscular dystrophy. Over 95% of FSHD cases are associated with contraction of the D4Z4 tandem repeat (~3.3 kb per unit) at 4q35 with a specific genomic configuration (haplotype) called 4qA. Molecular diagnosis of FSHD typically requires pulsed-field gel electrophoresis with Southern blotting. We aim to develop novel genomic and computational methods for characterising D4Z4 repeat numbers in FSHD.
Methods
We leveraged a single-molecule optical mapping platform that maps locations of restriction enzyme sites on high molecular weight (>150 kb) DNA molecules. We developed bioinformatics methods to address several challenges, including the differentiation of 4qA with 4qB alleles, the differentiation of 4q35 and 10q26 segmental duplications, the quantification of repeat numbers with different enzymes that may or may not have recognition sites within D4Z4 repeats. We evaluated the method on 25 human subjects (13 patients, 3 individual control subjects, 9 control subjects from 3 families) labelled by the Nb.BssSI and/or Nt.BspQI enzymes.
Results
We demonstrated that the method gave a direct quantitative measurement of repeat numbers on D4Z4 repeats with 4qA allelic configuration and the levels of postzygotic mosaicism. Our method had high concordance with Southern blots from several cohorts on two platforms (Bionano Saphyr and Bionano Irys), but with improved quantification of repeat numbers.
Conclusion
While the study is limited by small sample size, our results demonstrated that single-molecule optical mapping is a viable approach for more refined analysis on genotype-phenotype relationships in FSHD, especially when postzygotic mosaicism is present.
Objective:
An observational cross-sectional study was conducted in a national facioscapulohumeral muscular dystrophy (FSHD) expertise center to estimate the penetrance of FSHD1 and to evaluate phenotype-genotype correlations.
Methods:
Ten FSHD1 probands carrying 4-9 D4Z4 unit alleles and 140 relatives were examined. All 150 participants were genetically characterized, including D4Z4 methylation levels in the mutation carriers. Mutation carriers were classified as (1) symptomatic: with symptoms of muscle weakness on history and muscle FSHD signs on examination; (2) asymptomatic: without symptoms of muscle weakness but with muscle FSHD signs on examination; and (3) nonpenetrant: without symptoms of muscle weakness on history and without muscle FSHD signs on examination. We assessed the relationship between age-corrected clinical severity score and repeat size, sex, and D4Z4 methylation levels.
Results:
The maximum likelihood estimates of symptomatic and those of symptomatic plus asymptomatic FSHD showed that penetrance depends on repeat size and increases until late adulthood. We observed many asymptomatic carriers with subtle facial weakness with or without mild shoulder girdle weakness (25% [17/69]). Nonpenetrance was observed less frequently than in recent population studies (17% [12/69]), and most asymptomatic patients reported some shoulder pain. D4Z4 methylation tended to be lower in moderately to severely affected mutation carriers with 7 or 9 repeats.
Discussion:
This family-based study detected a lower overall nonpenetrance than previously observed, probably due to many asymptomatic mutation carriers identified by careful examination of facial and shoulder muscles. The recognition of asymptomatic mutation carriers is essential for selection of participants for future trials, and the likelihood estimates are helpful in counseling.
Facioscapulohumeral muscular dystrophy (FSHD) is among the most prevalent of the adult-onset muscular dystrophies. FSHD causes a loss of muscle mass and function, resulting in severe debilitation and reduction in quality of life. Currently only the symptoms of FSHD can be treated and with minimal benefit. The available options are not curative and none of the treatments address the underlying cause of FSHD. The genetic, epigenetic, and molecular mechanisms triggering FSHD are now quite well understood, and it has been shown that expression of the transcriptional regulator double homeobox 4 (DUX4) is necessary for disease onset and is largely thought to be the causative factor in FSHD. Therefore, we sought to identify compounds suppressing DUX4 expression in a phenotypic screen using FSHD patient-derived muscle cells, a zinc finger and SCAN domain-containing 4 (ZSCAN4)-based reporter gene assay for measuring DUX4 activity, and ~3000 small molecules. This effort identified molecules that reduce DUX4 gene expression and hence DUX4 activity. Among those, β-2 adrenergic receptor agonists and phosphodiesterase inhibitors, both leading to increased cellular cAMP, effectively decreased DUX4 expression by > 75% in cells from individuals with FSHD. Of note, we found that cAMP production reduces DUX4 expression through a protein kinase A-dependent mode of action in FSHD patient myotubes. These findings increase our understanding of how DUX4 expression is regulated in FSHD and point to potential areas of therapeutic intervention.
Facioscapulohumeral muscular dystrophy (FSHD), a prevalent inherited human myopathy, develops following a complex interplay of genetic and epigenetic events. FSHD1, the more frequent genetic form, is associated with: (1) deletion of an integral number of 3.3 Kb (D4Z4) repeated elements at the chromosomal region 4q35, (2) a specific 4q35 subtelomeric haplotype denominated 4qA, and (3) decreased methylation of cytosines at the 4q35-linked D4Z4 units. FSHD2 is most often caused by mutations at the SMCHD1 (Structural Maintenance of Chromosomes Hinge Domain 1) gene, on chromosome 18p11.32. FSHD2 individuals also carry the 4qA haplotype and decreased methylation of D4Z4 cytosines. Each D4Z4 unit contains a copy of the retrotransposed gene DUX4 (double homeobox containing protein 4). DUX4 gene functionality was questioned in the past because of its pseudogene-like structure, its location on repetitive telomeric DNA sequences (i.e. junk DNA), and the elusive nature of both the DUX4 transcript and the encoded protein, DUX4. It is now known that DUX4 is a nuclear-located transcription factor, which is normally expressed in germinal tissues. Aberrant DUX4 expression triggers a deregulation cascade inhibiting muscle differentiation, sensitizing cells to oxidative stress, and inducing muscle atrophy. A unifying pathogenic model for FSHD emerged with the recognition that the FSHD-permissive 4qA haplotype corresponds to a polyadenylation signal that stabilizes the DUX4 mRNA, allowing the toxic protein DUX4 to be expressed. This working hypothesis for FSHD pathogenesis highlights the intrinsic epigenetic nature of the molecular mechanism underlying FSHD as well as the pathogenic pathway connecting FSHD1 and FSHD2. Pharmacological control of either DUX4 gene expression or the activity of the DUX4 protein constitutes current potential rational therapeutic approaches to treat FSHD.
Die Muskeldystrophien bilden eine heterogene Untergruppe der primären Myopathien. Ihr Name verweist auf das „dystrophe“ histologische Bild mit gestörter Gewebearchitektur und mesenchymaler Proliferation (Duchenne 1868, Erb 1884). Zur Klassifizierung der Muskeldystrophien wurden phänotypische Merkmale wie charakteristische Lokalisation, Krankheitsverlauf und Erbgang herangezogen. Als häufigste und dramatischste Form erlangte die Muskeldystrophie vom Typ Duchenne (DMD) paradigmatische Bedeutung. Daher gehen auch wir in den folgenden Abschnitten insbesondere auf die DMD ein und lassen uns von dort aus über bestehende Verbindungen oder offensichtliche Unterschiede zu den anderen Formen der Muskeldystrophie führen.
Le terme de myopathie — qui pourrait aussi bien s’appliquer à toute maladie musculaire — est utilisé ici dans le sens restrictif souvent usité de maladie musculaire primitive ou secondaire.
Les myopathies primitives ou dystrophies musculaires habituellement génétiques se séparent des myopathies secondaires (ou se retrouvent notamment diverses formes métaboliques ou inflammatoires précédemment signalées).
Ainsi ce chapitre concerne d’abord le cadre des myopathies génétiques primitives encore dites dystrophies musculaires progressives. Ces formes entrent dans le cadre des amyotrophies systématisées, c’est-à-dire à localisations préférentielles et évocatrices. Cette répartition les oppose aux atteintes diffuses non sélectives des myopathies secondaires de causes variées.
Scapulothoracic motion relies upon the coordinated contraction of surrounding musculature to adequately position the glenoid in three-dimensional space, thus maximizing glenohumeral contact and stability throughout the entire range of motion. When glenohumeral motion is initiated, the periscapular musculature must tilt, rotate, protract, and/or retract the scapula to minimize abnormal humeral head translations during shoulder motion. There are many possible causes of abnormal scapular motion that are important to recognize in order to both prevent and relieve symptoms. Physical examination of the scapula should focus on an evaluation of resting scapular position and scapulothoracic motion in three dimensions with arm elevation. The purpose of this chapter is to provide clinicians with the tools necessary to accurately and efficiently evaluate scapulothoracic motion.
Facioscapulohumeral muscular dystrophy (FSHD) is an inherited and progressive muscle disorder. Although its name suggests otherwise, it comprises weakness of the facial, shoulder and upper arm muscles, and also of the trunk and leg muscles. Its severity and disease course vary greatly and mild or early FSHD can be difficult to recognise. Knowledge of its subtle signs and symptoms can lead directly to the correct diagnosis without diagnostic delay and without needing multiple diagnostic procedures. We give an overview of the signs and symptoms of FSHD in severe as well as in mild cases, to facilitate correct and instant recognition of this relatively common muscle disorder.
Introduction:
We determined the reliability and validity of electrical impedance myography (EIM) in facioscapulohumeral muscular dystrophy (FSHD).
Methods:
We performed a prospective study of EIM on 16 bilateral limb and trunk muscles in 35 genetically defined and clinically affected FSHD patients (reliability testing on n=18). Summary scores based on body region were derived. Reactance and phase (50 and 100 kHz) were compared to measures of strength, FSHD disease severity, and functional outcomes.
Results:
Participants were mostly men, mean age 53.0 years, and included a full range of severity. Limb and trunk muscles showed good to excellent reliability [intraclass correlation coefficients (ICC) 0.72-0.99]. Summary scores for the arm, leg, and trunk showed excellent reliability (ICC 0.89-0.98). Reactance was the most sensitive EIM parameter to a broad range of FSHD disease metrics.
Discussion:
EIM is a reliable measure of muscle composition in FSHD which offers the possibility to serially evaluate affected muscles. This article is protected by copyright. All rights reserved.
Objectives Facioscapulohumeral muscular dystrophy type 1 (FSHD1) has been genetically linked to reduced numbers (≤8) of D4Z4 repeats at 4q35. Particularly severe FSHD cases, characterised by an infantile onset and presence of additional extra-muscular features, have been associated with the shortest D4Z4 reduced alleles with 1–3 repeats (1–3 DRA). We searched for signs of perinatal onset and evaluated disease outcome through the systematic collection of clinical and anamnestic records of de novo and familial index cases and their relatives, carrying 1–3 DRA.
Setting Italy.
Participants 66 index cases and 33 relatives carrying 1–3 DRA.
Outcomes The clinical examination was performed using the standardised FSHD evaluation form with validated inter-rater reliability. To investigate the earliest signs of disease, we designed the Infantile Anamnestic Questionnaire (IAQ). Comparison of age at onset was performed using the non-parametric Wilcoxon rank-sum or Kruskal-Wallis test. Comparison of the FSHD score was performed using a general linear model and Wald test. Kaplan-Meier survival analysis was used to estimate the age-specific cumulative motor impairment risk.
Results No patients had perinatal onset. Among index cases, 36 (54.5%) showed the first signs by 10 years of age. The large majority of patients with early disease onset (26 out of 36, 72.2%) were de novo; whereas the majority of patients with disease onset after 10 years of age were familial (16, 53.3%). Comparison of the disease severity outcome between index cases with age at onset before and over 10 years of age, failed to detect statistical significance (Wald test p value=0.064). Of 61 index cases, only 17 (27.9%) presented extra-muscular conditions. Relatives carrying 1–3 DRA showed a large clinical variability ranging from healthy subjects, to patients with severe motor impairment.
Conclusions The size of the D4Z4 allele is not always predictive of severe clinical outcome. The high degree of clinical variability suggests that additional factors contribute to the phenotype complexity.
Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal-dominant disorder localized to 4q35. Neither the gene nor the gene product has been identified. There is presently no established treatment for FSHD. Prospective data on the natural history of this disorder are essential for the effective design of therapeutic trials. We systematically followed 81 well defined FSHD patients for up to 3 years using a standardized protocol that included manual muscle testing (MMT), maximum voluntary isometric contraction testing (MVICT), and functional testing. Muscle strength was strongly associated with measures of muscle mass, age at onset, and duration of disease. Decline in strength over time was slow but detectable with both MVICT and MMT. The magnitude of decline was not associated with either age, gender, age at onset, or duration of disease. This study establishes reliable and valid measures of disease state and progression for use as outcome variables in clinical trials in FSHD, and also provides guidelines for determining sample size and duration of follow-up. A two-armed clinical trial involving 160 patients per group and 1 year of follow-up would provide 80% power to detect complete arrest of the progression of the disease. Trials with fewer patients would thus have adequate power to detect only improvements in strength, unless follow-up duration were extended well beyond 1 year.
Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant neuromuscular disorder which maps to chromosome 4qter, distal to the D4S139 locus. The cosmid clone 13E, isolated in a search for homeobox genes, was subsequently mapped to 4q35, also distal to D4S139. A subclone, p13E-11, detects in normal individuals a polymorphic EcoRI fragment usually larger than 28 kilobases (kb). Surprisingly, using the same probe we detected de novo DNA rearrangements, characterized by shorter EcoRI fragments (14-28 kb), in 5 out of 6 new FSHD cases. In 10 Dutch families analysed, a specific shorter fragment between 14-28 kb cosegregates with FSHD. Both observations indicate that FSHD is caused by independent de novo DNA rearrangements in the EcoRI fragment detected by p13E-11.
We have recently assigned the facioscapulohumeral muscular dystrophy (FSHD) gene to chromosome 4 by linkage to the microsatellite marker Mfd 22 (locus D4S171). We now report that D4S139, a VNTR locus, is much more closely linked to FSHD. Two-point linkage analysis between FSHD and D4S139 in nine informative families showed a maximum combined lod score (Zmax) of 17.28 at a recombination fraction θ of 0.027. Multipoint linkage analysis between FSHD and the loci D4S139 and D4S171 resulted in a peak lod score of 20.21 at 2.7 cM from D4S139. Due to the small number of recombinants found with D4S139, the position of the FSHD gene relative to that of D4S139 could not be established with certainty. D4S139 was mapped to chromosome 4q35-qter by in situ hybridization, thus firmly establishing the location of the FSHD gene in the subtelomeric region of chromosome 4q. One small family yielded a negative lod score for D4S139. In the other families no significant evidence for genetic heterogeneity was obtained. Studies of additional markers and new families will improve the map of the FSHD region, reveal possible genetic heterogeneity, and allow better diagnostic reliability.
The autosomal dominant disorder facioscapulohumeral muscular dystrophy (FSHD) is the last of the major progressive muscular dystrophies in which the gene had not been located. In linkage analysis on ten Dutch families with this disorder a lod score of 6.34 at a recombination fraction of 0.13 was obtained with the microsatellite marker Mfd 22 (D4S171). This maps the FSHD gene to chromosome 4. Only one family was uninformative for this marker. We found no evidence of genetic heterogeneity.
We have recently assigned the facioscapulohumeral muscular dystrophy (FSHD) gene to chromome 4 by linkage to the microsatellite marker Mfd 22 (locus D4S171). We now report that D4S139, a VNTR locus, is much more closely linked to FSHD. Two-point linkage analysis between FSHD and D4S139 in nine informative families showed a maximum combined lod score (Zmax) of 17.28 at a recombination fraction theta of 0.027. Multipoint linkage analysis between FSHD and the loci D4S139 and D4S171 resulted in a peak lod score of 20.21 at 2.7 cM from D4S139. Due to the small number of recombinants found with D4S139, the position of the FSHD gene relative to that of D4S139 could not be established with certainty. D4S139 was mapped to chromosome 4q35-qter by in situ hybridization, thus firmly establishing the location of the FSHD gene in the subtelomeric region of chromosome 4q. One small family yielded a negative lod score for D4S139. In the other families no significant evidence for genetic heterogeneity was obtained. Studies of additional markers and new families will improve the map of the FSHD region, reveal possible genetic heterogeneity, and allow better diagnostic reliability.
We have performed retinal fluorescein angiography and audiometry in 32 familial and 7 sporadic cases of facioscapulohumeral muscular dystrophy. A mild to moderate retinal vasculopathy, consisting of retinal teleangiectasis and microaneurysms, was present in 18 of 37 evaluable angiograms (49%); 5 patients had minimal changes and 14 angiograms (38%) were normal. High frequency hearing loss was found in 25 (64%) out of 39 patients. Retinal changes were absent in 5 of 18 families (6 cases examined), and after correction for age and sex, hearing function was normal in 5 of 19 families (7 cases examined). Age and severity of the myopathy did not have a clear relationship with the retinal vasculopathy or the hearing loss. There were no differences between families in which the myopathy was linked to chromosome 4q35 and families in which linkage could not be proven. Minimal retinal vascular changes and high tone hearing loss can be observed occasionally in the normal population. Therefore, although retinal vasculopathy and hearing loss are part of the clinical picture of FSHD, these signs cannot be accepted as decisive criteria for FSHD in clinically equivocal cases.
We report 10 patients (5 familial, 5 sporadic) with facioscapulohumeral muscular dystrophy (FSHD) with onset of facial and shoulder girdle weakness in early infancy. They showed the same broad range of clinical signs and symptoms as can be seen normally in FSHD. In 7 patients Southern blotting with p13E-11 was performed which showed an abnormal EcoRI fragment (13-22 kb) in 6 of them. We conclude that early onset FSHD does not differ from regular FSHD clinically or genetically. However, the precise mechanisms involved in the extensive clinical variability of the disease are still unknown.
Recently, probe p13E-11 (D4F104S1) was shown to identify de novo DNA rearrangements, which are associated with the development of facioscapulohumeral muscular dystrophy (FSHD). These rearrangements are likely to become instrumental in cloning the FSHD gene itself. Analysis by pulsed-field gel electrophoresis demonstrates that p13E-11 recognizes two highly polymorphic loci, with HindIII restriction fragments ranging in size from about 30 to 320 kb. Haplotype analysis unambiguously assigned one of the two loci to chromosome 4q35. The detection of identical NotI or NruI fragments with both CEB8 (D4F35S1) and p13E-11 demonstrated that the DNA rearrangements are deletions that are restricted to the HindIII fragments detectable by p13E-11. In two cases, the sizes of the deletion could be established and were found to be 25 and 85 kb in length, respectively. So far, we have been able to define the parental origin of the mutation in seven different patients and have found that in five cases the maternal allele was involved.
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