Facioscapulohumeral Dystrophy Research Articles

Molecular, Histological, and Functional Changes in Acta1-MCM;FLExDUX4/+ Mice

DUX4 is the major gene responsible for facioscapulohumeral dystrophy (FSHD). Several mouse models expressing DUX4 have been developed, the most commonly used by academic laboratories being ACTA1-MCM/FLExDUX4. In this study, molecular and histological modifications in the tibialis anterior and quadriceps muscles were investigated in this model at different time points. We investigated several changes that could be used as markers of therapeutic efficacy. Our results confirm the progressive muscular dystrophy previously described but also highlight biases associated with tamoxifen injections and the complexity of choosing the genes used to calculate a DUX4-pathway gene composite score. We also developed a comprehensive force test that better reflects the movements made in everyday life. This functional force–velocity–endurance model, which describes the force production capacities at all velocity and fatigue levels, was applied on 12–13-week-old animals without tamoxifen. Our data highlight that previously unsuspected muscle properties are also affected by the expression of DUX4, leading to a weaker muscle with a lower initial muscle force but with preserved power and endurance capacity. Importantly, this force–velocity–endurance approach can be used in humans for clinical evaluations.

Utility of Optical Genome Mapping in Repeat Disorders.

Genomic repeat sequences are patterns of nucleic acids that exist in multiple copies throughout the genome. More than 60 Mendelian disorders are caused by the expansion or contraction of these repeats. Various specific methods for determining tandem repeat variations have been developed. However, these methods are highly specific to the genomic region being studied and sometimes require specialized tools. In this study, we have investigated the use of Optical Genome Mapping (OGM) as a diagnostic tool for detecting repeat disorders. We evaluated 19 patients with a prediagnosis of repeat disorders and explained the molecular etiology of 9 of them with OGM (5 patients with Facioscapulohumeral Muscular Dystrophy (FSHD), 2 patients with Friedreich's Ataxia (FA), 1 patient with Fragile X Syndrome (FXS), and 1 patient with Progressive Myoclonic Epilepsy 1A (EPM1A)). We confirmed OGM results with more widely used fragment analysis techniques. This study highlights the utility of OGM as a diagnostic tool for repeat expansion and contraction diseases such as FA, FXS, EPM1A, and FSHD.

Muscular dystrophy as a cause of unilateral scapular winging.

Shoulder weakness with unilateral scapular winging is a common issue that initially presents to the general physician, sports physician or rheumatologist. Although most of these cases are neurogenic in nature, it is important to consider alternative causes for unilateral scapular winging. Muscular dystrophies can present with marked asymmetry, the most typical being facioscapulohumeral dystrophy (FSHD). We describe a case of FSHD with a summary of the key clinical features to increase the awareness of this condition among physicians.

Deciphering the Complexity of FSHD: A Multimodal Approach as a Model for Rare Disorders

Rare diseases are heterogeneous diseases characterized by various symptoms and signs. Due to the low prevalence of such conditions (less than 1 in 2000 people), medical expertise is limited, knowledge is poor and patients’ care provided by medical centers is inadequate. An accurate diagnosis is frequently challenging and ongoing research is also insufficient, thus complicating the understanding of the natural progression of the rarest disorders. This review aims at presenting the multimodal approach supported by the integration of multiple analyses and disciplines as a valuable solution to clarify complex genotype–phenotype correlations and promote an in-depth examination of rare disorders. Taking into account the literature from large-scale population studies and ongoing technological advancement, this review described some examples to show how a multi-skilled team can improve the complex diagnosis of rare diseases. In this regard, Facio-Scapulo-Humeral muscular Dystrophy (FSHD) represents a valuable example where a multimodal approach is essential for a more accurate and precise diagnosis, as well as for enhancing the management of patients and their families. Given their heterogeneity and complexity, rare diseases call for a distinctive multidisciplinary approach to enable diagnosis and clinical follow-up.

635P Pain impacts quality of life, psychological disorders and exercise in a large international cohort of patients with facioscapulohumeral muscular dystrophy

635P Pain impacts quality of life, psychological disorders and exercise in a large international cohort of patients with facioscapulohumeral muscular dystrophy

623P Characteristics of Japanese patient with facioscapulohumeral muscular dystrophy in the Japanese nationwide registry of muscular dystrophy (Remudy)

623P Characteristics of Japanese patient with facioscapulohumeral muscular dystrophy in the Japanese nationwide registry of muscular dystrophy (Remudy)

294P Identification of disease-specific extracellular vesicle-associated plasma biomarkers for Duchenne muscular dystrophy (DMD) and facioscapulohumeral muscular dystrophy (FSHD)

294P Identification of disease-specific extracellular vesicle-associated plasma biomarkers for Duchenne muscular dystrophy (DMD) and facioscapulohumeral muscular dystrophy (FSHD)

640P Efficacy and safety of EPI-321, an investigational single dose epigenome editing therapy targeting D4Z4 in facioscapulohumeral Muscular Dystrophy (FSHD)

640P Efficacy and safety of EPI-321, an investigational single dose epigenome editing therapy targeting D4Z4 in facioscapulohumeral Muscular Dystrophy (FSHD)

261P Insights into facioscapulohumeral dystrophy in African individuals: clinical and molecular findings from a collaborative study

261P Insights into facioscapulohumeral dystrophy in African individuals: clinical and molecular findings from a collaborative study

622P An unusual case of double trouble of facioscapulohumeral dystrophy (FSHD) and coexisting congenital myopathy uncovered by whole genome sequencing

622P An unusual case of double trouble of facioscapulohumeral dystrophy (FSHD) and coexisting congenital myopathy uncovered by whole genome sequencing

599P The UK Facioscapulohumeral Muscular Dystrophy Patient Registry: a powerful tool to support clinical research and patient voice in the translational research pathway

599P The UK Facioscapulohumeral Muscular Dystrophy Patient Registry: a powerful tool to support clinical research and patient voice in the translational research pathway

636P Longitudinal insights into childhood onset facioscapulohumeral dystrophy: a five-year natural history study

636P Longitudinal insights into childhood onset facioscapulohumeral dystrophy: a five-year natural history study

The other face of facioscapulohumeral muscular dystrophy: Exploring orofacial weakness using muscle ultrasound.

One of the most distinct clinical features of facioscapulohumeral muscular dystrophy (FSHD) is facial weakness. It leads to diminished facial expression and functional impairments. Despite its clinical relevance, little else is known about orofacial muscle involvement. We therefore evaluated orofacial muscle involvement in a sizeable cohort of FSHD participants with muscle ultrasound. Muscle ultrasound images of the following orofacial muscles were scored visually and quantitatively: depressor anguli oris (DAO), orbicularis oris (OO), buccinator, temporalis, masseter, digastric, zygomaticus major and minor bilaterally, and the geniohyoid. Reliability analyses of both visual and quantitative evaluations were performed. Ultrasound results were correlated with other measures: the FSHD clinical score, facial weakness score, and facial function scale. We included 107 FSHD participants (male 54%; age 52 ± 14 years), of whom 92% showed signs of facial weakness. The reliability of visual ultrasound analysis varied widely (κ 0.0-1.0). Quantitative ultrasound reliability was high (intraclass correlation analysis ≥ 0.96). The DAO, buccinator, OO, temporalis, and zygomaticus minor muscles were affected most often (15%-39%). The digastric, geniohyoid, zygomaticus major, and masseter muscles were least often affected (<5%). The ultrasound compound score correlated weakly to moderately with other outcome measures used (ρ = 0.3-0.7). This study adds to the understanding of orofacial weakness in FSHD, confirming the involvement of the muscles of facial expression in FSHD using ultrasound. We showed that orofacial muscle ultrasound is feasible and reliable when quantitatively assessed. Future studies should evaluate orofacial muscle ultrasound longitudinally, alongside clinical and patient-reported facial weakness outcome measures, to assess their potential as outcome measures.

Characterizing Mechanical Changes in the Biceps Brachii Muscle in Mild Facioscapulohumeral Muscular Dystrophy Using Shear Wave Elastography.

There is no general consensus on evaluating disease progression in facioscapulohumeral muscular dystrophy (FSHD). Recently, shear wave elastography (SWE) has been proposed as a noninvasive diagnostic tool to assess muscle stiffness in vivo. Therefore, this study aimed to characterize biceps brachii (BB) muscle mechanics in mild-FSHD patients using SWE. Eight patients with mild FSHD, the BB were assessed using SWE, surface electromyography (sEMG), elbow moment measurements during rest, maximum voluntary contraction (MVC), and isometric ramp contractions at 25%, 50%, and 75% MVC across five elbow positions (60°, 90°, 120°, 150°, and 180° flexion). The mean absolute percentage deviation (MAPD) was analyzed as a measure of force control during ramp contractions. The shear elastic modulus of the BB in FSHD patients increased from flexed to extended elbow positions (e.g., p < 0.001 at 25% MVC) and with increasing contraction intensity (e.g., p < 0.001 at 60°). MAPD was highly variable, indicating significant deviation from target values during ramp contractions. SWE in mild FSHD is influenced by contraction level and joint angle, similar to findings of previous studies in healthy subjects. Moreover, altered force control could relate to the subjective muscle weakness reported by patients with dystrophies.

D4Z4 Hypomethylation in Human Germ Cells.

Expression of the double homeobox 4 (DUX4) transcription factor is highly regulated in early embryogenesis and is subsequently epigenetically silenced. Ectopic expression of DUX4 due to hypomethylation of the D4Z4 repeat array on permissive chromosome 4q35 alleles is associated with facioscapulohumeral muscular dystrophy (FSHD). In peripheral blood samples from 188 healthy individuals, D4Z4 methylation was highly variable, ranging from 19% to 76%, and was not affected by age. In 48 FSHD2 patients, D4Z4 methylation varied from 3% to 30%. Given that DUX4 is one of the earliest transcribed genes after fertilization, the D4Z4 array is expected to be unmethylated in mature germ cells. Deep bisulfite sequencing of 188 mainly normozoospermic sperm samples revealed an average methylation of 2.5% (range 0.3-22%). Overall, the vast majority (78%) of individual sperm cells displayed no methylation at all. In contrast, only 19 (17.5%) of 109 individual germinal vesicle (GV) oocytes displayed D4Z4 methylation <2.5%. However, it is not unexpected that immature GV oocytes which are not usable for assisted reproduction are endowed with D4Z4 (up to 74%) hypermethylation and/or abnormal (PEG3 and GTL2) imprints. Although not significant, it is interesting to note that the pregnancy rate after assisted reproduction was higher for donors of sperm samples and oocytes with <2.5% methylation.

Clinical and genetic evaluation of hereditary myopathies in an adult Saudi cohort

BackgroundDiagnosis of hereditary myopathy is often challenging owing to overlapping clinical phenotypes and muscle histopathological findings. This retrospective study aimed to identify the phenotypic and genotypic spectra of hereditary myopathies at a tertiary hospital in Riyadh, Saudi Arabia.MethodsWe reviewed the medical records of patients with hereditary myopathy who were evaluated between January 2018 and December 2022.ResultsEighty-seven patients (78 families) were included, two-thirds were men with a mean age of 35 (SD 14.2) years. Limb-girdle muscular dystrophy (LGMD) was the most prevalent clinical diagnosis (25 cases; 29%), of whom, a genetic diagnosis was achieved in 15 of 22 patients tested (68%). In genetically confirmed LGMD, the most prevalent disorders were dysferlinopathy (27%) followed by fukutin-related protein (FKRP) - related limb girdle muscular dystrophy (20%), sarcoglycanopathy (20%), lamin A/C related myopathy (13%), and calpain-3 myopathy (13%). In 26 patients with pathogenic/likely pathogenic variants, the genetic testing method was whole exome sequencing (WES) (42%), Next generation sequencing (NGS) (31%), and targeted single gene analysis (27%). The sensitivity of each genetic testing method was as follows: 100% for targeted single-gene analysis, 100% for targeted analysis of D4Z4 repeat array units, 88% for myotonic dystrophy protein kinase (DMPK) repeat expansion analysis, 42% for NGS-neuromuscular panel, and 46% for WES.ConclusionThe prevalent types of hereditary myopathies were consistent with those reported locally and internationally. This study highlights the diagnostic yield of various molecular genetic tests for the diagnosis of hereditary myopathy in an adult cohort and the need for improved access to advanced molecular testing in cases suspected to have facioscapulohumeral muscular dystrophy (FSHD) or mitochondrial myopathies.

Oligonucleotide Therapies for Facioscapulohumeral Muscular Dystrophy: Current Preclinical Landscape.

Facioscapulohumeral muscular dystrophy (FSHD) is an inherited myopathy, characterized by progressive and asymmetric muscle atrophy, primarily affecting muscles of the face, shoulder girdle, and upper arms before affecting muscles of the lower extremities with age and greater disease severity. FSHD is a disabling condition, and patients may also present with various extramuscular symptoms. FSHD is caused by the aberrant expression of double homeobox 4 (DUX4) in skeletal muscle, arising from compromised epigenetic repression of the D4Z4 array. DUX4 encodes the DUX4 protein, a transcription factor that activates myotoxic gene programs to produce the FSHD pathology. Therefore, sequence-specific oligonucleotides aimed at reducing DUX4 levels in patients is a compelling therapeutic approach, and one that has received considerable research interest over the last decade. This review aims to describe the current preclinical landscape of oligonucleotide therapies for FSHD. This includes outlining the mechanism of action of each therapy and summarizing the preclinical results obtained regarding their efficacy in cellular and/or murine disease models. The scope of this review is limited to oligonucleotide-based therapies that inhibit the DUX4 gene, mRNA, or protein in a way that does not involve gene editing.

Bioimpedance analysis of fat free mass and its subcomponents and relative associations with maximal oxygen consumption in facioscapulohumeral dystrophy.

Fat free mass (FFM) is considered the metabolically active component of human body and is positively associated with maximal oxygen uptake ( ). However, FFM is composed of metabolically active and inactive subcomponents whose proportion can vary depending on body composition and clinical condition, possibly affecting such association. Although it is known that in facioscapulohumeral dystrophy (FSHD) peculiar changes in body composition occur, it is unclear whether there are alterations in FFM composition and, if so, whether such alterations affect the association towards compared to healthy subjects (HS). To address this issue, 27 FSHD patients (mean age 37.3; 9 female) and 27 sex and age matched HS, underwent an assessment of by cardiopulmonary exercise tests (CPET) and body composition, with reference to FFM and its subcomponents, by bioimpedance analysis. In between-groups comparison, patients showed lower amounts of body cell mass (BCM) and intracellular water (ICW) which reflect in lower BCM/FFM ratio and higher extracellular to intracellular water ratio (ECW/ICW). Patients' was lower than HS and, even if with lower associative values than HS, correlated with FFM and BCM, while BCM/FFM and ECW/ICW ratios associations were observed only in HS. FSHD patients showed lower amount of BCM and ICW. BCM resulted as the parameter with the highest associative value with VO2max in both groups. Since is associated with functional ability in dystrophic patients, BCM, rather than FFM, could be an additional body composition-based clinical stratification factor.

Progesterone may be a regulator and B12 could be an indicator of the proximal D4Z4 repeat methylation status on 4q35ter.

Facioscapulohumeral dystrophy (FSHD) has a hypomethylation-related epigenetic background and exhibits a different course in male and female patients. The differences between males and females have been linked to the levels of sex hormones. This study is the first to investigate the possible effect of these hormones on methylation status. We hypothesized that the levels of sex-related hormones, estradiol, testosterone, progesterone, and prolactin might be associated with the methylation status of the proximal part of the D4Z4. We also investigated the effect of fT3, folic acid, and vitamin B12 levels. We collected blood from 28 FSHD patients and 28 controls. DNA was extracted from each individual for bisulfite methylation analysis and serum was separated for biochemical analysis of estradiol, testosterone, progesterone, prolactin, fT3, folic acid, and B12 analysis. Methylation analysis was specified to the DR1, 5P regions and the proximal region covering both DR1 and 5P. Methylation levels were compared between FSHD patients and controls. The correlation of methylation levels with estradiol, testosterone, progesterone, prolactin, fT3, folic acid, and B12 was investigated. We found that the 5P region and the proximal region were significantly hypomethylated in FSHD patients compared to the controls, but not the DR1 region. Male patients exhibited a significant reduction in DNA methylation compared to male controls. Older FSHD patients exhibited a notable decrease in fT3 levels and hypomethylation of the 5P region. Analyses of each CpG revealed seven hypomethylated positions that were significantly different from the control group. Two of the positions demonstrated a correlation with progesterone in the control group. With the exception of one position, the methylation levels were inversely correlated with vitamin B12 in FSHD patients. The results of our study indicate that the methylation of the proximal D4Z4 region, particularly at specific positions, may be associated with progesterone. In addition, vitamin B12 may be an indicator of hypomethylation. We suggest that examining position-specific methylations may be a useful approach for the development of epigenetic treatment modalities.

Atypical Facio-Scapulo-Humeral Dystrophy with facial sparing: a case report

Facio-Scapulo-Humeral Dystrophy (FSHD) is an autosomal dominant and third most common inherited muscular dystrophy. Typical phenotype of FSHD initially affects the muscles of the face and upper arm. Atypical FSHD refers to genetically confirmed FSHD with phenotypic variations. Scapulo-Humeral Dystrophy (SHD) is the most common atypical form of FSDH characterized by no facial muscle weakness on clinical examination, while other signs remain consistent with FSHD. We report a 31-year-old male who presented with foot drop and had an unexpected presentation as SHD. Provisional diagnosis of SHD was based on careful medical history, physical examination findings, modest rise in muscle enzymes, and needle electromyography findings of myopathy. Muscle biopsy suggested dystrophic changes which supported the diagnosis of FSHD with facial sparing. Rehabilitation plan included patient and family counseling/education, lifestyle modifications, energy conservation strategies, right ankle foot orthosis, and therapeutic exercises with regular follow-up for monitoring of the disease.