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Background Facioscapulohumeral dystrophy (FSHD) is a myopathy characterized by the loss of repressive epigenetic features affecting the D4Z4 locus (4q35). The assessment of DNA methylation at two regions ( DUX4 -PAS and DR1) of D4Z4 locus proved to be an effective method to detect epigenetic signatures compatible with FSHD. The present study aims at validating the employment of this method into clinical practice and improving the protocol by refining the classification thresholds of 4qA/4qA patients. To this purpose, 218 subjects with clinical suspicion of FSHD collected in 2022–2023 were analyzed. Each participant underwent in parallel the traditional FSHD molecular testing ( D4Z4 sizing) and the proposed methylation assay. The results provided by both analyses were compared to evaluate the concordance and calculate the performance metrics of the methylation test. Results Among the 218 subjects, the 4q variant type distribution was 54% 4qA/4qA, 43% 4qA/4qB and 3% 4qB/4qB. The methylation analysis was performed only on carriers of at least one 4qA allele. After refining the classification threshold, the test reached the following performance metrics: sensitivity = 0.90, specificity = 1.00 and accuracy = 0.93. These results confirmed the effectiveness of the methylation assay in identifying patients with genetic signature compatible with FSHD1 and FSHD2 based on their DUX4 -PAS and DR1 profile, respectively. The methylation data were also evaluated with respect to the clinical information. Conclusions The study confirmed the ability of the method to accurately identify methylation profiles compatible with FSHD genetic signatures considering the 4q genotype. Moreover, the test allows the detection of hypomethylated profiles in asymptomatic patients, suggesting its potential application in identifying preclinical conditions in patients with positive family history and FSHD genetic signatures. Furthermore, the present work emphasizes the importance of interpreting methylation profiles considering the patients’ clinical data.

Background Facioscapulohumeral muscular dystrophy (FSHD) is characterized by a typical pattern of muscle involvement, yet it encompasses a wide spectrum of phenotypes, including less common features that remain incompletely defined in the literature. While previous studies have highlighted this clinical variability, no consensus has been reached on how to classify uncommon manifestations, nor have specific predictors been identified. This study aims to describe these uncommon features and explore potential predictors, utilizing data from the French FSHD registry. To this end, we analysed data from 306 FSHD1 patients across nine French neuromuscular referral centres. Descriptive statistics, univariate analyses, and multiple logistic regression models were employed to examine uncommon characteristics and their predictors. Results Uncommon features were observed in 19.6% of cases. The most common was a discrepancy between disease severity and D4Z4 repeat unit (RU) count (41.7%), followed by predominant impairment at proximal lower limb or distal upper limb muscles (21.7%). Three unanticipated features emerged: isolated or predominant axial impairment, anosmia and atopic dermatitis. Univariate analysis revealed that uncommon features were associated with higher RU count (6.5 ± 2.1 vs. 5.8 ± 1.8 in typical patients) and older age of onset (32.0 ± 18.8 years vs. 25.0 ± 15.4 years). Such features were more prevalent in the borderline 8–10 RU range, an association confirmed by multivariate analysis (OR = 2.43, 95% CI 1.21 to 4.87). Later age of onset consistently emerged as a factor across multiple multivariate models. Conclusions This study documents uncommon FSHD features, revealing their association with the 8–10 RU range and later age of onset. These findings further support a complex interplay among genetic and epigenetic modifiers and ageing in shaping the clinical phenotype of FSHD, especially in patients carrying borderline D4Z4 arrays. Differential phenotypes, particularly in relation to RU range and age of onset, points to the importance of harmonized, comprehensive clinical and genetic assessments. Recognizing uncommon features may improve diagnostic accuracy and guide individualized management strategies, highlighting the need for tailored approaches to patient care.

Facioscapulohumeral muscular dystrophy (FSHD) is characterised by progressive skeletal muscle weakness and wasting. FSHD is linked to epigenetic derepression of the subtelomeric D4Z4 macrosatellite at chromosome 4q35. Epigenetic derepression permits the distal‐most D4Z4 unit to transcribe DUX4 , with transcripts stabilised by splicing to a poly(A) signal on permissive 4qA haplotypes. The pioneer transcription factor DUX4 activates target genes that are proposed to drive FSHD pathology. While this toxic gain‐of‐function model is a satisfying “bottom‐up” genotype‐to‐phenotype link, DUX4 is rarely detectable in muscle and DUX4 target gene expression is inconsistent in patients. A reliable biomarker for FSHD is suppression of a target gene score of PAX7, a master regulator of myogenesis. However, it is unclear how this “top‐down” finding links to genomic changes that characterise FSHD and to DUX4. Here, we explore the roles and interactions of DUX4 and PAX7 in FSHD pathology and how the relationship between these two transcription factors deepens understanding via the immune system and muscle regeneration. Considering how FSHD pathomechanisms are represented by “DUX4opathy” models has implications for developing therapies and current clinical trials. Graphical Abstract In this review CRS Banerji and PS Zammit discuss the relationship between transcription factors DUX4 and PAX7 in the pathology of facioscapulohumeral muscular dystrophy.

Emilia Duchnowska,1 Bożena Kosztyła-Hojna,1 Maciej Zdrojkowski,1 Sarah Burton-Jones,2 Wojciech Kułak3 1Department of Clinical Phonoaudiology and Speech Therapy, Medical University of Białystok, Białystok, Poland; 2South West Genomic Laboratory Hub, Bristol, England, UK; 3Department of Paediatric Rehabilitation, Medical University of Białystok, Białystok, PolandCorrespondence: Emilia Duchnowska, Department of Clinical Phonoaudiology and Speech Therapy, Medical University of Białystok, ul. Szpitalna 37, Białystok, 15-270, Poland, Tel +48 603 330 294, Email emilia.duchnowska@umb.edu.plPurpose: The aim of the study was to evaluate hearing, voice, and speech in 10-year-old boy with fascio-scapulo-humeral dystrophy (FSHD).Patients and Methods: Hearing, voice, and speech were assessed in a 10-year-old boy with FSHD due to scarcity of detailed audiophonological assessment in this disorder. Evaluation of muscle tension in upper and lower limb posture, gait, muscle enzyme activity, ECG, USG, bone densitometry, lower limb muscles MRI, handgrip strength were conducted. Hearing was examined using pure-tone, impedance, speech audiometry, and DPOAE. Voice assessment included GRBAS and endoscopic laryngeal examinations. Speech evaluation was conducted using Child Speech Assessment Cards (Karty Oceny Logopedycznej Dziecka, KOLD).Results: Diagnosis of FSHD was genetically confirmed by haplotype testing. Muscle hypotonia and atrophy were observed in limbs and face, along with gait disturbances. The 6-minute walk test (6MWT) result was 570 m, and the upper limb muscle strength was 9.3 kg (right limb) and 11.0 kg (left limb), both limbs: 15.7 kg. Audiological evaluation revealed severe bilateral sensorineural hearing (mean 73 dB HL). Bilateral type As tympanogram was recorded (right ear: 0.27 mL; left ear: 0.18 mL). Stapedial reflex was absent at high frequencies. DPOAE testing revealed sporadic bilateral cochlear responses. Speech audiometry showed reduced speech comprehension. Endoscopic examinations revealed edema of both vocal folds mucosa, preserved mobility. GRBAS scale showed G2R1B3A3S0. Acoustic analysis demonstrated slight reduction in fundamental frequency (F0) and elevated shimmer (10.566%). MPT was slightly shortened to 20 s. Speech evaluation revealed mouth breathing, shortened expiratory phase during phonation, bradylalia, articulation disorders with prolonged pauses between words, high-arched soft palate, shortened lingual frenulum, open bite, reduced tone of facial, lip, and tongue muscles.Conclusion: Genetic testing confirmed the presence of facio-scapulo-humeral muscular dystrophy (FSHD). Bilateral severe sensorineural hearing loss was documented. Speech disorders in FSHD were associated with reduced tension of articulatory muscles.Keywords: genetic diagnostics, FSHD, muscular dystrophy, sensorineural hearing loss, vocal folds edema, articulation disorders

Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common genetically inherited myopathies in adults. It is characterized by incomplete penetrance and variable expressivity. Typically, FSHD patients display asymmetric weakness of facial, scapular, and humeral muscles that may progress to other muscle groups, particularly the abdominal and lower limb muscles. Early-onset patients display more severe muscle weakness and atrophy, resulting in a higher frequency of associated skeletal abnormalities. In these patients, multisystem involvement, including respiratory, ocular, and auditory, is more frequent and severe and may include the central nervous system. Adult-onset FSHD patients may also display some degree of multisystem involvement which mainly remains subclinical. In 95% of cases, FSHD patients carry a pathogenic contraction of the D4Z4 repeat units (RUs) in the subtelomeric region of chromosome 4 (4q35), which leads to the expression of DUX4 retrogene, toxic for muscles (FSHD1). Five percent of patients display the same clinical phenotype in association with a mutation in the SMCHD1 gene located in chromosome 18, inducing epigenetic modifications of the 4q D4Z4 repeated region and expression of DUX4 retrogene. This review highlights the complexities and challenges of diagnosing and managing FSHD, underscoring the importance of standardized approaches for optimal patient outcomes. It emphasizes the critical role of multidisciplinary care in addressing the diverse manifestations of FSHD across different age groups, from skeletal abnormalities in early-onset cases to the often-subclinical multisystem involvement in adults. With no current cure, the focus on alleviating symptoms and slowing disease progression through coordinated care is paramount.

Facioscapulohumeral dystrophy (FSHD) leads to progressive changes in body composition such as loss of muscle mass and increase in adiposity. In healthy subjects, anthropometric parameters are associated with the maximum volume of oxygen consumed per minute (VO2max), which is a health and function indicator in several populations of subjects, both healthy and pathological. Since VO2max can be difficult to test in patients with FSHD due to exercise intolerance, the identification of associated anthropometric parameters could provide new easily obtainable elements for the patients’ clinical stratification. The aim of this study was to evaluate whether anthropometric and body composition parameters are associated with VO2max in patients with FSHD. A total of 22 subjects with a molecular genetics-based diagnosis of FSHD (6 females, 16 males, mean age of 35.18 years) were recruited for the study. VO2max was measured by cardiopulmonary exercise tests (CPETs) on a cycle ergometer, utilizing a step incremental technique (15 Watts (W) every 30 s). Weight (Kg) and height (m) were obtained and utilized to calculate body mass index (BMI). Body composition parameters (fat mass (FM), fat free mass (FFM), and body cell mass (BCM)) were obtained by bioelectrical impedance analysis (BIA). Significant negative associations were found between VO2max and FM (Spearman correlation coefficient (SCC) −0.712), BMI (SCC −0.673), age (SCC −0.480), and weight (SCC −0.634), unlike FFM and BCM. Our results indicate that FM, BMI, age, and body weight are negatively associated with VO2max in patients with FSHD. This evidence may help practitioners to better stratify patients with FSHD.

Muscular dystrophies constitute a group of genetic disorders that cause weakness and progressive loss of skeletal muscle mass. Among them, Miyoshi muscular dystrophy 1 (MMD1), limb girdle muscular dystrophy type R2 (LGMDR2/2B), and LGMDR12 (2L) are characterized by mutation in gene encoding key membrane-repair protein, which leads to severe dysfunctions in sarcolemma repair. Cell membrane disruption is a physiological event induced by mechanical stress, such as muscle contraction and stretching. Like many eukaryotic cells, muscle fibers possess a protein machinery ensuring fast resealing of damaged plasma membrane. Members of the annexins A (ANXA) family belong to this protein machinery. ANXA are small soluble proteins, twelve in number in humans, which share the property of binding to membranes exposing negatively-charged phospholipids in the presence of calcium (Ca2+). Many ANXA have been reported to participate in membrane repair of varied cell types and species, including human skeletal muscle cells in which they may play a collective role in protection and repair of the sarcolemma. Here, we discuss the participation of ANXA in membrane repair of healthy skeletal muscle cells and how dysregulation of ANXA expression may impact the clinical severity of muscular dystrophies.

Purpose Fat free mass (FFM) is considered the metabolically active component of human body and is positively associated with maximal oxygen uptake ( VO 2 max ). 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 VO 2 max compared to healthy subjects (HS). Methods To address this issue, 27 FSHD patients (mean age 37.3; 9 female) and 27 sex and age matched HS, underwent an assessment of VO 2 max by cardiopulmonary exercise tests (CPET) and body composition, with reference to FFM and its subcomponents, by bioimpedance analysis. Results 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’ VO 2 max 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. Conclusion 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 VO 2 max is associated with functional ability in dystrophic patients, BCM, rather than FFM, could be an additional body composition-based clinical stratification factor.

Background Facioscapulohumeral muscular dystrophy (FSHD) is a patchy and slowly progressive disease of skeletal muscle. For MRI to be a useful biomarker in an FSHD clinical trial, it should reliably detect changes over relatively short time-intervals (~ 1 year). We hypothesized that fatty change over the study course would be most likely in muscles already demonstrating disease progression, and that the degree of MRI burden would be correlated with function. Methods We studied 36 patients with FSHD and lower-extremity weakness at baseline. Thirty-two patients returned in our 12-month longitudinal observational study. We analyzed DIXON MRI images of 16 lower-extremity muscles in each patient and compared them to quantitative strength measurement and ambulatory functional outcome measures. Results There was a small shift to higher fat fractions in the summed muscle data for each patient, however individual muscles demonstrated much larger magnitudes of change. The greatest increase in fat fraction was observed in muscles having an intermediate fat replacement at baseline, with minimally (baseline fat fraction < 0.10) or severely (> 0.70) affected muscles less likely to progress. Functional outcome measures did not demonstrate marked change over the interval; however, overall MRI disease burden was correlated with functional outcome measures. Direct comparison of the tibialis anterior (TA) fat fraction and quantitative strength measurement showed a sigmoidal relationship, with steepest drop being when the muscle gets more than ~ 20% fatty replaced. Conclusions Assessing MRI changes in 16 lower-extremity muscles across 1 year demonstrated that those muscles having an intermediate baseline fat fraction were more likely to progress. Ambulatory functional outcome measures are generally related to overall muscle MRI burden but remain unchanged in the short term. Quantitative strength measurement of the TA showed a steep loss of strength when more fatty infiltration is present suggesting that MRI may be preferable for following incremental change or modulation with drug therapy.