Facioscapulohumeral Dystrophy Research Articles

A Systemically Administered Unconjugated Antisense Oligonucleotide Targeting DUX4 Improves Muscular Injury and Motor Function in FSHD Model Mice.

Facioscapulohumeral muscular dystrophy (FSHD), one of the most common muscular dystrophies, is caused by an abnormal expression of the DUX4 gene in skeletal muscles, resulting in muscle weakness. In this study, we investigated MT-DUX4-ASO, a novel gapmer antisense oligonucleotide (ASO). MT-DUX4-ASO decreased the expression of DUX4 and its target genes in FSHD patient-derived myoblasts. For the first time, we demonstrated that a systemically administered ASO, even without a ligand for drug delivery, could significantly improve muscle injury and motor function in the ACTA1-MCM/FLExDUX4 (DUX4-TG) mouse model of FSHD. Tamoxifen (TMX) injection transiently induces skeletal-muscle-specific DUX4 expression in DUX4-TG mice, while the skeletal muscles of TMX-untreated DUX4-TG mice have leaky DUX4 expression in a small subset of myofibers similar to those of FSHD patients. Subcutaneous 10 mg/kg of MT-DUX4-ASO at two-week intervals significantly suppressed muscular DUX4 target gene expression, histological muscle injury, and blood muscle injury marker elevation in TMX-untreated DUX4-TG mice. Notably, MT-DUX4-ASO at 10 mg/kg every other week significantly prevented the TMX-induced declines in treadmill test running speed and muscle force in DUX4-TG mice. Thus, the systemically administered unconjugated MT-DUX4-ASO suppressed disease progression in DUX4-TG mice, extending the potential of unconjugated ASOs as a promising FSHD treatment strategy.

Whole exome sequencing highlights rare variants in CTCF, DNMT1, DNMT3A, EZH2 and SUV39H1 as associated with FSHD.

Introduction: Despite the progress made in the study of Facioscapulohumeral Dystrophy (FSHD), the wide heterogeneity of disease complicates its diagnosis and the genotype-phenotype correlation among patients and within families. In this context, the present work employed Whole Exome Sequencing (WES) to investigate known and unknown genetic contributors that may be involved in FSHD and may represent potential disease modifiers, even in presence of a D4Z4 Reduced Allele (DRA). Methods: A cohort of 126 patients with clinical signs of FSHD were included in the study, which were characterized by D4Z4 sizing, methylation analysis and WES. Specific protocols were employed for D4Z4 sizing and methylation analysis, whereas the Illumina® Next-Seq 550 system was utilized for WES. The study included both patients with a DRA compatible with FSHD diagnosis and patients with longer D4Z4 alleles. In case of patients harboring relevant variants from WES, the molecular analysis was extended to the family members. Results: The WES data analysis highlighted 20 relevant variants, among which 14 were located in known genetic modifiers (SMCHD1, DNMT3B and LRIF1) and 6 in candidate genes (CTCF, DNMT1, DNMT3A, EZH2 and SUV39H1). Most of them were found together with a permissive short (4-7RU) or borderline/long DRA (8-20RU), supporting the possibility that different genes can contribute to disease heterogeneity in presence of a FSHD permissive background. The segregation and methylation analysis among family members, together with clinical findings, provided a more comprehensive picture of patients. Discussion: Our results support FSHD pathomechanism being complex with a multigenic contribution by several known (SMCHD1, DNMT3B, LRIF1) and possibly other candidate genes (CTCF, DNMT1, DNMT3A, EZH2, SUV39H1) to disease penetrance and expressivity. Our results further emphasize the importance of extending the analysis of molecular findings within the proband's family, with the purpose of providing a broader framework for understanding single cases and allowing finer genotype-phenotype correlations in FSHD-affected families.

The FSHD muscle-blood biomarker: a circulating transcriptomic biomarker for clinical severity in facioscapulohumeral muscular dystrophy.

Facioscapulohumeral muscular dystrophy (FSHD) is a prevalent, incurable skeletal myopathy. Clinical trials for FSHD are hindered by heterogeneous biomarkers poorly associated with clinical severity, requiring invasive muscle biopsy. Macroscopically, FSHD presents with slow fatty replacement of muscle, rapidly accelerated by inflammation. Mis-expression of the transcription factor DUX4 is currently accepted to underlie pathogenesis, and mechanisms including PAX7 target gene repression have been proposed. Here, we performed RNA-sequencing on MRI-guided inflamed and isogenic non-inflamed muscle biopsies from the same clinically characterized FSHD patients (n = 24), alongside isogenic peripheral blood mononucleated cells from a subset of patients (n = 13) and unaffected controls (n = 11). Multivariate models were employed to evaluate the clinical associations of five published FSHD transcriptomic biomarkers. We demonstrated that PAX7 target gene repression can discriminate control, inflamed and non-inflamed FSHD muscle independently of age and sex (P < 0.013), while the discriminatory power of DUX4 target genes was limited to distinguishing FSHD muscle from control. Importantly, the level of PAX7 target gene repression in non-inflamed muscle associated with clinical assessments of FSHD severity (P = 0.04). DUX4 target gene biomarkers in FSHD muscle showed associations with lower limb fat fraction and D4Z4 array length but not clinical assessment. Lastly, PAX7 target gene repression in FSHD muscle correlated with the level in isogenic peripheral blood mononucleated cells (P = 0.002). A refined PAX7 target gene biomarker comprising 143/601 PAX7 target genes computed in peripheral blood (the FSHD muscle-blood biomarker) associated with clinical severity in FSHD patients (P < 0.036). Our new circulating biomarker validates as a classifier of clinical severity in an independent data set of 54 FSHD patient and 29 matched control blood samples, with improved power in older patients (P = 0.03). In summary, we present the minimally invasive FSHD muscle-blood biomarker of FSHD clinical severity valid in patient muscle and blood, of potential use in routine disease monitoring and clinical trials.

The upper extremity functional index (UEFI): Italian validation in patients with Facioscapulohumeral muscular dystrophy

Purpose The aim of this study was to adapt the Upper Extremity Functional Index (UEFI) to an Italian population affected by Facioscapulohumeral muscular dystrophy (FSHD) by translating and validating this instrument in an Italian cohort. Materials and methods Five Italian FSHD patients were interviewed regarding the form and content of the translated instrument. Subsequently, fifty-two patients were recruited for the validation purpose by serially completing the UEFI-IT and a battery of clinical assessments and questionnaires. Finally, a subset of thirty-nine patients underwent test-retest reliability. Results The Italian translation of the UEFI was highly relevant to patients, had a level of test-retest reliability from “good” to “excellent” (ICC = 0.90 with 95% confidence interval between 0.82 and 0.95), and a satisfactory internal consistency (Cronbach’s alpha = 0.96). Participants confirmed the usefulness and clearness of the tool in cultural validity. In known group validity, the UEFI-IT was significantly lower in patients unable to walk (24.10 ± 11.33 vs 55.71 ± 13.98, p < .0001; AUC = 0.9631) and in patients with longer disease duration (43.43 ± 17.16 vs 58.14 ± 13.71, p = 0.0034; AUC = 0.7359). Finally, the concurrent validity showed strong associations between the UEFI-IT and motor assessments, pain perception, and quality-of-life evaluations. Conclusions Overall, the UEFI-IT is an appropriate, valid, and reliable outcome measure for Italian-speaking FSHD patients.

Epigenetic profiling of the D4Z4 locus: Optimization of the protocol for studying DNA methylation at single CpG site level.

The alteration of epigenetic modifications, including DNA methylation, can contribute to the etiopathogenesis and progression of many diseases. Among them, facioscapulohumeral dystrophy (FSHD) is a muscular disorder characterized by the loss of repressive epigenetic features affecting the D4Z4 locus (4q35). As a consequence, these alterations are responsible for DNA hypomethylation and a transcriptional-active chromatin conformation change that, in turn, lead to the aberrant expression of DUX4 in muscle cells. In the present study, methylation levels of 29 CpG sites of the DR1 region (within each repeat unit of the D4Z4 macrosatellite) were assessed on 335 subjects by employing primers designed for enhancing the performance of the assay. First, the DR1 original primers were optimized by adding M13 oligonucleotide tails. Moreover, the DR1 reverse primer was replaced with a degenerate one. As a result, the protocol optimization allowed a better sequencing resolution and a more accurate evaluation of DR1 methylation levels. Moreover, the assessment of the repeatability of measurements proved the reliability and robustness of the assay. The optimized protocol emerges as an excellent method to detect methylation levels compatible with FSHD.

Diagnostic strategies for muscular dystrophies: a cross-sectional study

Background: Muscular dystrophies are a wide heterogeneity group of neuromuscular diseases that very often constitutes a challenge for clinicians to perform an adequate diagnosis. Many patients remain underdiagnosed o misdiagnosed consequently affecting their prognosis and quality of life. Therefore, we aimed to establish clinical and molecular characteristics of patients with increased CPK levels and muscular dystrophies in our region to facilitate diagnosis and follow-up on patients with suspected muscular dystrophies. Methods: A cross-sectional study was made using a retrospective search of patients attended in Comfamiliar Risaralda between 2010 and 2021. The study included patients from both genders and all ages who presented with a diagnosis of polymyositis, myoclonus, myopathy, and muscular dystrophy between 2010 and 2022 in Comfamiliar Risaralda. Patients with CPK levels lower than 500 U/L were excluded. Results: A database analysis was carried out from 2010 to 2022 of 5219 patients treated in a fourth-level care institution in the Eje Cafetero region, finding 221 patients filtered by a diagnosis of myopathy, myoclonus, polymyositis, and dystrophy. We found a combined prevalence of all muscular dystrophies of 4.2 per 100.000 habitants, Duchenne muscular dystrophy of 0.6 per 100.000 habitants, limb-girdle muscular dystrophy of 0.6 per 100.000 habitants, facioscapulohumeral dystrophy of 0.5 per 100.000 habitants, Bethem dystrophy, type 2 Emery Dreifuss muscular dystrophy and merosin-deficient muscular dystrophy of 0.1 per 100.000 habitants. A diagnostic sequence was elaborated from clinical and paraclinical features found in our patients. Conclusions: Although muscular dystrophies consist of a heterogeneous group of neuromuscular diseases, there are still clinical and paraclinical features that can help physicians to detect any particular case and perform a good approach and follow-up. Our diagnostic sequence will facilitate physicians to determine any particular muscular dystrophy.

Outcomes of scapulothoracic fusion in patients with facioscapulohumeral dystrophy: a comparison of allograft versus autograft bone grafting.

Scapulothoracic (ST) fusion for facioscapulohumeral muscular dystrophy (FSHD) is an established treatment that corrects scapular instability, although it has high reported complication rates. The purpose of our study was to characterize the outcomes of ST fusion for FSHD in a large patient cohort and compare the outcomes based on bone graft type and fixation technique. Our hypothesis was that union rates would not differ by bone graft type during ST fusion. A retrospective chart review was undertaken to identify patients who underwent ST fusion at multiple institutions performed by a single surgeon between 2013 and 2019 with minimum 2-year follow-up. Patient demographic characteristics, surgical technique, time to union, complications, and clinical outcomes including patient-reported outcome measures were recorded. Univariate and multivariate statistical analyses including regression analyses were performed to compare preoperative and postoperative outcomes. A total of 50 patients with 54 ST fusions (bilateral in 4 patients) and an average follow-up period of 5.8 years (standard deviation, 1.6 years) were included for analysis. Active forward elevation (77° vs. 124°, P<.00001) and abduction (60° vs. 90°, P<.00001) both improved significantly after fusion. Average internal rotation after fusion was at spinal level L3-L4. The visual analog scale pain score (2.6 vs. 1.2, P<.00001), Subjective Shoulder Value score (33 vs. 76, P<.00001), and American Shoulder and Elbow Surgeons (ASES) score (41.8 vs. 76.1, P<.00001) all improved significantly postoperatively. Of the shoulders, 50% (27 of 54) received treatment with cerclage wires and 50% (27 of 54) received treatment with Luque wires. Femoral head allograft was used in 53.7% of shoulders (29 of 54), whereas iliac crest autograft was used in 46.3% (25 of 54). Average radiographic time to healing was 11.1 weeks (standard deviation, 3.2 weeks), with no incidence of nonunion, and did not significantly differ by bone graft type (P=.26) or technique (P=.20). The complication rate was 24.1%, including seroma (n=3), superficial infection (n=2), transient neurologic injury (n=2), hemothorax (n=1), rib fracture (n=1), pneumothorax (n=1), and shortness of breath (n=1), although none requiring reoperation. There was no significant difference in the rate of postoperative complications when compared by surgical technique (P=.81) and bone graft type (P=.93). There were no independently predictive factors influencing the rate of postoperative complications by multivariate regression. Regression analysis showed that the postoperative ASES score was independently associated with the preoperative ASES score (P<.0001), use of iliac crest autograft (P<.011), and presence of complications (P<.043). Patients receiving ST fusion for FSHD demonstrate globally improved active motion and patient-reported outcome measures. Fusion construct or type of bone graft does not affect time to union or complication rates. Surgeons should be aware of a relatively high complication rate in the early postoperative period.

Three-dimensional quantitative muscle ultrasound in patients with facioscapulohumeral dystrophy and myotonic dystrophy.

Ultrasound imaging of muscle tissue conventionally results in two-dimensional sampling of tissue. For heterogeneously affected muscles, a sampling error using two-dimensional (2D) ultrasound can therefore be expected. In this study, we aimed to quantify and extend ultrasound imaging findings in neuromuscular disorders by using three-dimensional quantitative muscle ultrasound (3D QMUS). Patients with facioscapulohumeral dystrophy (n = 31) and myotonic dystrophy type 1 (n = 16) were included in this study. After physical examination, including Medical Research Council (MRC) scores, the tibialis anterior muscle was scanned with automated ultrasound. QMUS parameters were calculated over 15 cm of the length of the tibialis anterior muscle and were compared with a healthy reference data set. With 3D QMUS local deviations from the healthy reference could be detected. Significant Pearson correlations (P < .01) between MRC score and QMUS parameters in male patients (n = 23) included the mean echo intensity (EI) (0.684), the standard deviation of EI (0.737), and the residual attenuation (0.841). In 91% of all patients, mean EI deviated by more than 1 standard deviation from the healthy reference. In general, the proportion of muscle tissue with a Z score >1 was about 50%. In addition to mean EI, multiple QMUS parameters reported in this study are potential biomarkers for pathology. Besides a moderate correlation of mean EI with muscle weakness, two other parameters showed strong correlations: standard deviation of EI and residual attenuation. Local detection of abnormalities makes 3D QMUS a promising method that can be used in research and potentially for clinical evaluation.

The endosomal escape vehicle platform enhances delivery of oligonucleotides in preclinical models of neuromuscular disorders

Biological therapeutic agents are highly targeted and potent but limited in their ability to reach intracellular targets. These limitations often necessitate high therapeutic doses and can be associated with less-than-optimal therapeutic activity. One promising solution for therapeutic agent delivery is use of cell-penetrating peptides. Canonical cell-penetrating peptides, however, are limited by low efficiencies of cellular uptake and endosomal escape, minimal proteolytic stability, and toxicity. To overcome these limitations, we designed a family of proprietary cyclic cell-penetrating peptides that form the core of our endosomal escape vehicle technology capable of delivering therapeutic agent-conjugated cargo intracellularly. We demonstrated the therapeutic potential of this endosomal escape vehicle platform in preclinical models of muscular dystrophy with distinct disease etiology. An endosomal escape vehicle-conjugated, splice-modulating oligonucleotide restored dystrophin protein expression in striated muscles in the mdx mouse, amodel for Duchenne muscular dystrophy. Furthermore, another endosomal escape vehicle-conjugated, sterically blocking oligonucleotide led to knockdown of aberrant transcript expression levels in facioscapulohumeral muscular dystrophy patient-derived skeletal muscle cells. These findings suggest a significant therapeutic potential of our endosomal escape vehicle conjugated oligonucleotides for targeted upregulation and downregulation of gene expression in neuromuscular diseases, with possible broader application of this platform for delivery of intracellular biological agents.

SMCHD1 and LRIF1 converge at the FSHD-associated D4Z4 repeat and LRIF1 promoter yet display different modes of action

Facioscapulohumeral muscular dystrophy (FSHD) is caused by the epigenetic derepression of the 4q-linked D4Z4 macrosatellite repeat resulting in inappropriate expression of the D4Z4 repeat-encoded DUX4 gene in skeletal muscle. In 5% of FSHD cases, D4Z4 chromatin relaxation is due to germline mutations in one of the chromatin modifiers SMCHD1, DNMT3B or LRIF1. The mechanism of SMCHD1- and LRIF1-mediated D4Z4 repression is not clear. We show that somatic loss-of-function of either SMCHD1 or LRIF1 does not result in D4Z4 chromatin changes and that SMCHD1 and LRIF1 form an auxiliary layer of D4Z4 repressive mechanisms. We uncover that SMCHD1, together with the long isoform of LRIF1, binds to the LRIF1 promoter and silences LRIF1 expression. The interdependency of SMCHD1 and LRIF1 binding differs between D4Z4 and the LRIF1 promoter, and both loci show different transcriptional responses to either early developmentally or somatically perturbed chromatin function of SMCHD1 and LRIF1.

Molecular and Phenotypic Changes in FLExDUX4 Mice.

Facioscapulohumeral muscular dystrophy (FSHD) is caused by the aberrant expression of the double homeobox 4 (DUX4) gene. The FLExDUX4 mouse model carries an inverted human DUX4 transgene which has leaky DUX4 transgene expression at a very low level. No overt muscle pathology was reported before 16 weeks. The purpose of this study is to track and characterize the FLExDUX4 phenotypes for a longer period, up to one year old. In addition, transcriptomic changes in the muscles of 2-month-old mice were investigated using RNA-seq. The results showed that male FLExDUX4 mice developed more severe phenotypes and at a younger age in comparison to the female mice. These include lower body and muscle weight, and muscle weakness measured by grip strength measurements. Muscle pathological changes were observed at older ages, including fibrosis, decreased size of type IIa and IIx myofibers, and the development of aggregates containing TDP-43 in type IIb myofibers. Muscle transcriptomic data identified early molecular changes in biological pathways regulating circadian rhythm and adipogenesis. The study suggests a slow progressive change in molecular and muscle phenotypes in response to the low level of DUX4 expression in the FLExDUX4 mice.

Facioscapulohumeral Muscular Dystrophy is Associated With Altered Myoblast Proteome Dynamics

Proteomic studies in facioscapulohumeral muscular dystrophy (FSHD) could offer new insight into disease mechanisms underpinned by post-transcriptional processes. We used stable isotope (deuterium oxide; D2O) labeling and peptide mass spectrometry to investigate the abundance and turnover rates of proteins in cultured muscle cells from two individuals affected by FSHD and their unaffected siblings (UASb). We measured the abundance of 4420 proteins and the turnover rate of 2324 proteins in each (n = 4) myoblast sample. FSHD myoblasts exhibited a greater abundance but slower turnover rate of subunits of mitochondrial respiratory complexes and mitochondrial ribosomal proteins, which may indicate an accumulation of “older” less viable mitochondrial proteins in myoblasts from individuals affected by FSHD. Treatment with a 2′-O-methoxyethyl modified antisense oligonucleotide targeting exon 3 of the double homeobox 4 (DUX4) transcript tended to reverse mitochondrial protein dysregulation in FSHD myoblasts, indicating the effect on mitochondrial proteins may be a DUX4-dependent mechanism. Our results highlight the importance of post-transcriptional processes and protein turnover in FSHD pathology and provide a resource for the FSHD research community to explore this burgeoning aspect of FSHD.

Lean tissue mass measurements by dual-energy X-ray absorptiometry and associations with strength and functional outcome measures in facioscapulohumeral muscular dystrophy

Facioscapulohumeral muscular dystrophy (FSHD) is a slowly progressive disease of skeletal muscle. Dual energy X-ray absorptiometry (DEXA) is a widely available, cost-effective and sensitive technique for measuring whole body and regional lean tissue mass and has been used in prior clinical trials in neuromuscular diseases. The Clinical Trial Readiness to Solve Barriers to Drug Development in FSHD (ReSolve) study is a prospective, longitudinal, observational multisite study. We obtained concurrent DEXA scans and functional outcome measurements in 185 patients with FSHD at the baseline visit. We determined the associations between lean tissue mass in the upper and lower extremities and corresponding clinical outcome measures. There were moderate correlations between upper and lower extremity lean tissue mass and their corresponding strengths and function. Lean tissue mass obtained by DEXA scan may be useful as a biomarker in future clinical trials in FSHD.

In skeletal muscle and neural crest cells, SMCHD1 regulates biological pathways relevant for Bosma syndrome and facioscapulohumeral dystrophy phenotype.

Many genetic syndromes are linked to mutations in genes encoding factors that guide chromatin organization. Among them, several distinct rare genetic diseases are linked to mutations in SMCHD1 that encodes the structural maintenance of chromosomes flexible hinge domain containing 1 chromatin-associated factor. In humans, its function as well as the impact of its mutations remains poorly defined. To fill this gap, we determined the episignature associated with heterozygous SMCHD1 variants in primary cells and cell lineages derived from induced pluripotent stem cells for Bosma arhinia and microphthalmia syndrome (BAMS) and type 2 facioscapulohumeral dystrophy (FSHD2). In human tissues, SMCHD1 regulates the distribution of methylated CpGs, H3K27 trimethylation and CTCF at repressed chromatin but also at euchromatin. Based on the exploration of tissues affected either in FSHD or in BAMS, i.e. skeletal muscle fibers and neural crest stem cells, respectively, our results emphasize multiple functions for SMCHD1, in chromatin compaction, chromatin insulation and gene regulation with variable targets or phenotypical outcomes. We concluded that in rare genetic diseases, SMCHD1 variants impact gene expression in two ways: (i) by changing the chromatin context at a number of euchromatin loci or (ii) by directly regulating some loci encoding master transcription factors required for cell fate determination and tissue differentiation.

Comparison of quantitative muscle ultrasound and whole-body muscle MRI in facioscapulohumeral muscular dystrophy type 1 patients

IntroductionMuscle ultrasound is a fast, non-invasive and cost-effective examination that can identify structural muscular changes by assessing muscle thickness and echointensity (EI) with a quantitative analysis (QMUS). To assess applicability and repeatability of QMUS, we evaluated patients with genetically confirmed facioscapulohumeral muscular dystrophy type 1 (FSHD1), comparing their muscle ultrasound characteristics with healthy controls and with those detected by MRI. We also evaluated relationships between QMUS and demographic and clinical characteristics.Materials and methodsThirteen patients were included in the study. Clinical assessment included MRC sum score, FSHD score and The Comprehensive Clinical Evaluation Form (CCEF). QMUS was performed with a linear transducer scanning bilaterally pectoralis major, deltoid, rectus femoris, tibialis anterior and semimembranosus muscles in patients and healthy subjects. For each muscle, we acquired three images, which were analysed calculating muscle EI by computer-assisted grey-scale analysis. QMUS analysis was compared with semiquantitative 1.5 T muscle MRI scale.ResultsAll muscles in FSHD patients showed a significant increased echogenicity compared to the homologous muscles in healthy subjects. Older subjects and patients with higher FSHD score presented increased muscle EI. Tibialis anterior MRC showed a significant inverse correlation with EI. Higher median EI was found in muscles with more severe MRI fat replacement.ConclusionsQMUS allows quantitative evaluation of muscle echogenicity, displaying a tight correlation with muscular alterations, clinical and MRI data. Although a confirmation on larger sample is needed, our research suggests a possible future application of QMUS in diagnosis and management of muscular disorders.

Finding the Determinants of Disease Severity in FSHD.

Finding the Determinants of Disease Severity in FSHD.

Treatment of Facioscapulohumeral Muscular Dystrophy (FSHD): A Systematic Review.

Facioscapulohumeral muscular dystrophy (FSHD) is the third most common type of muscular dystrophy. This disease presents as a slowly progressive asymmetric muscle weakness that involves the facial, scapular, and upper arm muscles mainly. Currently, there is no established consensus on this disease treatment in terms of medications. We assessed the response to the treatment of the drugs utilized in clinical trials by performing a systematic literature review in English using the preferred reporting items for systematic reviews (PRISMA) and meta-analyses. We only used human clinical trials in patients diagnosed with FSHD that received consistent pharmacological treatment. We included 11 clinical trials that fulfilled our criteria. We concluded that albuterol had statistically significant results in three out of four clinical trials, with improved elbow flexors muscle strength. Vitamin C, vitamin E, zinc gluconate, and selenomethionine showed significant improvement in the maximal voluntary contraction and endurance limit time of quadriceps muscle. At the same time, diltiazem and MYO-029 demonstrate no improvement in function, strength, or muscle mass. Losmapimod, currently in phase I of the ReDUX4 trial, showed promising results. Peradventure, more clinical trials are still needed to address this subject. Nevertheless, this review provides a clear and concise update on the treatment for this disease.

Anesthetic management with remimazolam for laryngectomy in a severely underweight patient with facioscapulohumeral muscular dystrophy.

Anesthetic management with remimazolam for laryngectomy in a severely underweight patient with facioscapulohumeral muscular dystrophy.

Compromised nonsense-mediated RNA decay results in truncated RNA-binding protein production upon DUX4 expression

Nonsense-mediated RNA decay (NMD) degrades transcripts carrying premature termination codons. NMD is thought to prevent the synthesis of toxic truncated proteins. However, whether loss of NMD results in widespread production of truncated proteins is unclear. A human genetic disease, facioscapulohumeral muscular dystrophy (FSHD), features acute inhibition of NMD upon expression of the disease-causing transcription factor, DUX4. Using a cell-based model of FSHD, we show production of truncated proteins from physiological NMD targets and find that RNA-binding proteins are enriched for aberrant truncations. The NMD isoform of one RNA-binding protein, SRSF3, is translated to produce a stable truncated protein, which is detected in FSHD patient-derived myotubes. Ectopic expression of truncated SRSF3 confers toxicity, and its downregulation is cytoprotective. Our results delineate the genome-scale impact of NMD loss. This widespread production of potentially deleterious truncated proteins has implications for FSHD biology as well as other genetic diseases where NMD is therapeutically modulated.

SA7 A Systematic Literature Review to Assess the Level of Evidence in Facioscapulohumeral Muscular Dystrophy

Facioscapulohumeral muscular dystrophy (FSHD) is a rare, debilitating disease for which there are no approved pharmacological interventions. As the disease progresses, patients lose upper limb function and mobility, which results in a decrease in the ability to perform activities of daily living and independence; patients often live with chronic pain. This systematic literature review assessed the existing evidence base regarding clinical, economic and humanistic outcomes in FSHD.