Facioscapulohumeral Dystrophy Research Articles

VP.61 An AAV-shRNA DUX4-based therapy to treat facioscapulohumeral muscular dystrophy (FSHD)

Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common muscular dystrophies in adult and so far there is no curative or preventive treatment. FSHD is characterized by the aberrant expression of the <i>DUX4</i> transcription factor in muscle. DUX4 is a toxic protein, which has been implicated in myofiber death, increased sensitivity in oxidative stress, defects in myogenesis, muscle atrophy etc, ultimately leading to myofiber death. Here, we designed an AAV vector carrying a ShRNA directed against <i>DUX4</i> (AAV-shDUX4) to knock down <i>DUX4</i> expression in FSHD muscle cells and in the cre-inducible <i>DUX4</i> bi-transgenic mouse model (ACTA1-MCM/FLExDUX4). In this model, DUX4 is expressed upon Cre-mediated translocation in the nucleus, which occurs after tamoxifen injection. ACTA1-MCM/FLExDUX4 mice were injected with either an AVV-shScrambled or an AAV-shDUX4. After 4 weeks, we observed that all pathological signs of the <i>DUX4</i> expression were reduced in the AAV-shDUX4 animals compared to the AAV-shScrambled animals including: a dramatic derease in the expression of the genes downstream of <i>DUX4</i>, a decrease of the number of fibers with centrally located nuclei, a reduced inflammation etc. Our data suggest that AAV-shDUX4 based therapy is promising therapeutic strategy for FSHD.

P.138 Annualized rates of change from a phase 2, randomized, double-blind, placebo-controlled, 48-week study of losmapimod in subjects with FSHD: ReDUX4

Evaluate annualized clinical outcome changes in subjects with facioscapulohumeral muscular dystrophy (FSHD) treated with losmapimod compared with placebo. FSHD is a relentless, variably progressive disease leading to accumulation of disability over decades. Fulcrum is developing losmapimod, a small molecule p38 α/β MAPK inhibitor, to treat FSHD. An annualized analysis provides data on the slope of disease progression and the potential for treatment with losmapimod to change that slope over time. Subjects aged 18-65 years with FSHD1, CSS 2-4, and MRI-eligible muscles for biopsy were randomized 1:1; losmapimod (15 mg BID): placebo. Assessments included for analysis: MRI assessments of muscle health, reachable workspace (RWS), dynamometry and TUG. Annualized rate of change (%/yr) was calculated using a linear mixed-effects model to estimate slope and percent change per year. Annualized analysis of RWS (measured in Reachable Surface Area, RSA) was prespecified; all other analyses are post-hoc. Eighty subjects (N=40/group), mean age 45.7 (±12.5) years, Ricci score 3.2 were enrolled. Annualized rate of change (%/yr) in total RSA for losmapimod vs. placebo dominant arm: -0.44 vs. -8.42; p=0.07; non-dominant arm: 4.88 vs. -4.02; p=0.01. This slowing or improvement is supported by structural measures via MRI and functional outcomes (dynamometry and TUG). MRI annualized rates of change for losmapimod vs. placebo were 0.31 vs 3.82 for MFI, 4.42 vs 5.96 for MFF, and -7.15 vs -4.50 for LMV. Maximum dynamometry in the shoulder abductors showed variability in annualized rate of change for losmapimod vs. placebo (L -1.98 vs 13.62; R -14.39 vs -8.49) and in hand grip (L -8.30 vs -13.44; R -13.95 vs -15.27). In TUG, the annualized rate of change was -0.93 vs 2.23% in the losmapimod vs placebo group. Annualized rates of change in clinical outcomes support disease slowing or improvement in losmapimod treated subjects compared to placebo.

VP.62 DUX4 expression turn on the myogenic program in MSC

Muscle tissue degeneration is accompanied by fibrosis in patients with the facioscapulohumeral dystrophy (FSHD). In skeletal muscles, MSCs are present and they can participate in muscles regeneration. When a muscle is injured, MSCs can migrate towards damaged site from blood circulation and neighboring intact tissues and participate in the recovery process also. Since FSHD is a genetic disease associated with aberrant <i>DUX4</i> expression, we hypothesized that MSC involved in the regeneration process may also have overexpressed level of <i>DUX4</i>, and created a model of MSC with inducible <i>DUX4</i> expression (MSC-DUX4) using the Jagannathan's approach and construct pCW57.1-DUX4-WT from Addgen. MSCs were obtained from the Cell culture collection of the IDB RAS. <i>DUX4</i> expression was confirmed in MSC-DUX4 cells by immunofluorescent staining. We conducted a comparative analysis of the differentiation potencies of MSCs and MSCs with inducible <i>DUX4</i> expression (MSCs were from the same donor). It was shown that MSCs with induced <i>DUX4</i> expression have an increased potential for myogenic differentiation, which is not characteristic of normal MSCs. These cells can fuse and form mature myotubes expressing the main markers of late myogenesis (Troponin T, MF20). At the same time, MSCs with induced expression of <i>DUX4</i> have reduced potencies for main MSC differentiations - adipogenic and osteogenic, that was shown using biochemical, immunocytochemical and RT-PCR assays. Thus, upon induction of DUX4 expression, MSCs turn on the myogenic program, while losing the capacity for their main differentiations. This does not seem so counterintuitive, since the genes involved in myogenesis are <i>DUX4</i>-downstream target genes. However, the real contribution of MSC-DUX4 to the regeneration of muscles affected by FSHD remains to be analyzed.

P.15 Symptomatic DMD carrier as a differential diagnosis in patients presenting asymmetrical limb weakness

Duchenne/Becker muscular dystrophy (DMD) is one of the most common myopathies, characterized by an X-linked recessive disease. Asymmetrical limb weakness is rarely present in patients with muscle diseases such as ANO5-related myopathy, facioscapulohumeral muscular dystrophy, and sporadic inclusion body myositis. We report two cases of symptomatic DMD carriers presenting with asymmetrical limb weakness. A 50-year-old woman visited the department of neurology presenting with slowly progressive weakness of the limbs since childhood. A neurological examination revealed a weakness of the right arm and both legs, which were graded 4 as MRC system. Muscle MRI showed asymmetric fatty infiltration of the limbs, markedly affected by right biceps brachii, latissimus dorsi, and gastrocnemius. Immunohistochemistry (IHC) of the C-terminal region of the dystrophin gene presented several scattered stain-negative fibers. Genetic analysis revealed c.6703delG (p.Ser2235Ilefs*12, NM_004006.2) mimicking single exon 46 deletion in MLPA. A 29-year-old female presented with an elevated level of serum creatine kinase without subjective weakness. Neurologic examination showed the subtle motor weakness of the right arm, graded 4+. Muscle MRI revealed high T1 signal change on the right biceps femoris, which was not affected clinically, in addition to right biceps brachii and latissimus dorsi. IHC showed dystrophic changes and a mosaic pattern of dystrophin expression. The diagnosis was confirmed by MLPA, revealing heterozygous deletion of exon 44 in the DMD gene. Asymmetrical limb weakness can be a remark for the diagnosis of symptomatic DMD carrier. Furthermore, muscle MRI is more sensitive in detecting pathologic changes than routine neurologic examination. And single-base point mutation can mimick the exon deletion in MLPA, which needs sequencing analysis in a case of single exon deletion in DMD. Therefore, a multidisciplinary approach is mandatory for final diagnosis and a better understanding of symptomatic DMD carriers.

P.141 Manoeuvre study design: A study of GYM329 (RO7204239) in patients with facioscapulohumeral muscular dystrophy (FSHD)

P.141 Manoeuvre study design: A study of GYM329 (RO7204239) in patients with facioscapulohumeral muscular dystrophy (FSHD)

Trajectory of left ventricular ejection fraction in response to therapies in patients with muscular dystrophy.

Patients with muscular dystrophy (MD) are at elevated risk of serious cardiac complications and clinical assessment is limited due to inherent physical limitations. We assessed the utility of left ventricular ejection fraction (LVEF) derived from transthoracic echocardiogram (TTE) as a prognostic marker for major adverse cardiac events (MACE) in a mixed adult MD cohort. One hundred and sixty-five MD patients (median age: 36 (interquartile range [IQR]: 23.0-49.0) years; 65 [39.4%] females) were enrolled in our prospective cohort study. Diagnoses included dystrophinopathies (n=42), limb-girdle MD (n=31), type 1 myotonic dystrophy (n=71), and facioscapulohumeral MD (n=21). Left ventricular ejection fraction, ventricular dimensions at end-diastole and end-systole, and serial measures (n=124; follow-up period: 2.19 [IQR: 1.05-3.32] years) stratified patients for MACE risk. Cardiomyopathy was diagnosed in 60 (36.4%) patients of the broader cohort (median LVEF: 45.0 [IQR: 35.0-50.0] %). Ninety-eight MACE occurred over the 7-year study period. At baseline, patients with a LVEF&lt;55.0% had a high risk of MACE (adjusted odds ratio: 8.30; 95% confidence interval [CI]: 3.18-21.7), concordant with the analysis of LV dimensions. Forty-one percent of these patients showed an improvement in LVEF with the optimization of medical and device therapies. Relative to patients with preserved LVEF, patients with reduced LVEF were at an elevated risk of MACE (adjusted hazard ratio [aHR]: 7.21; 95% CI: 1.99-26.1), and improved LVEF resulted in comparable outcomes (aHR: 1.84; 95% CI: .49-6.91) associated with optimization of medical and device therapies. Reduction in QRS duration by CRT therapy was associated with an improvement in LVEF (average improvement: 12.8 [±2.30] %; p =.04). Reduction in LVEF indicates an increased risk of cardiovascular events in patients with MD. Baseline and serial LVEF obtained by TTE can prognosticate patients for MACE and guide clinical management.

P.140 Understanding the patients' journey pre- and post-diagnosis of facioscapulohumeral muscular dystrophy (FSHD): A real-world retrospective data analysis

P.140 Understanding the patients' journey pre- and post-diagnosis of facioscapulohumeral muscular dystrophy (FSHD): A real-world retrospective data analysis

P.139 A cross sectional study of genetically confirmed cohort of facioscapulohumeral muscular dystrophy (FSHD) in the Indian population

P.139 A cross sectional study of genetically confirmed cohort of facioscapulohumeral muscular dystrophy (FSHD) in the Indian population

Non-myogenic mesenchymal cells contribute to muscle degeneration in facioscapulohumeral muscular dystrophy patients

Muscle-resident non-myogenic mesenchymal cells play key roles that drive successful tissue regeneration within the skeletal muscle stem cell niche. These cells have recently emerged as remarkable therapeutic targets for neuromuscular disorders, although to date they have been poorly investigated in facioscapulohumeral muscular dystrophy (FSHD). In this study, we characterised the non-myogenic mesenchymal stromal cell population in FSHD patients’ muscles with signs of disease activity, identified by muscle magnetic resonance imaging (MRI), and compared them with those obtained from apparently normal muscles of FSHD patients and from muscles of healthy, age-matched controls. Our results showed that patient-derived cells displayed a distinctive expression pattern of mesenchymal markers, along with an impaired capacity to differentiate towards mature adipocytes in vitro, compared with control cells. We also demonstrated a significant expansion of non-myogenic mesenchymal cells (identified as CD201- or PDGFRA-expressing cells) in FSHD muscles with signs of disease activity, which correlated with the extent of intramuscular fibrosis. In addition, the accumulation of non-myogenic mesenchymal cells was higher in FSHD muscles that deteriorate more rapidly. Our results prompt a direct association between an accumulation, as well as an altered differentiation, of non-myogenic mesenchymal cells with muscle degeneration in FSHD patients. Elucidating the mechanisms and cellular interactions that are altered in the affected muscles of FSHD patients could be instrumental to clarify disease pathogenesis and identifying reliable novel therapeutic targets.

Methylation of the 4q35 D4Z4 repeat defines disease status in facioscapulohumeral muscular dystrophy.

Genetic diagnosis of facioscapulohumeral muscular dystrophy (FSHD) remains a challenge in clinical practice as it cannot be detected by standard sequencing methods despite being the third most common muscular dystrophy. The conventional diagnostic strategy addresses the known genetic parameters of FSHD: the required presence of a permissive haplotype, a size reduction of the D4Z4 repeat of chromosome 4q35 (defining FSHD1) or a pathogenic variant in an epigenetic suppressor gene (consistent with FSHD2). Incomplete penetrance and epistatic effects of the underlying genetic parameters as well as epigenetic parameters (D4Z4 methylation) pose challenges to diagnostic accuracy and hinder prediction of clinical severity. In order to circumvent the known limitations of conventional diagnostics and to complement genetic parameters with epigenetic ones, we developed and validated a multistage diagnostic workflow that consists of a haplotype analysis and a high-throughput methylation profile analysis (FSHD-MPA). FSHD-MPA determines the average global methylation level of the D4Z4 repeat array as well as the regional methylation of the most distal repeat unit by combining bisulphite conversion with next-generation sequencing and a bioinformatics pipeline and uses these as diagnostic parameters. We applied the diagnostic workflow to a cohort of 148 patients and compared the epigenetic parameters based on FSHD-MPA to genetic parameters of conventional genetic testing. In addition, we studied the correlation of repeat length and methylation level within the most distal repeat unit with age-corrected clinical severity and age at disease onset in FSHD patients. The results of our study show that FSHD-MPA is a powerful tool to accurately determine the epigenetic parameters of FSHD, allowing discrimination between FSHD patients and healthy individuals, while simultaneously distinguishing FSHD1 and FSHD2. The strong correlation between methylation level and clinical severity indicates that the methylation level determined by FSHD-MPA accounts for differences in disease severity among individuals with similar genetic parameters. Thus, our findings further confirm that epigenetic parameters rather than genetic parameters represent FSHD disease status and may serve as a valuable biomarker for disease status.

Objective Monitoring of Facioscapulohumeral Dystrophy During Clinical Trials Using a Smartphone App and Wearables: Observational Study.

BackgroundFacioscapulohumeral dystrophy (FSHD) is a progressive muscle dystrophy disorder leading to significant disability. Currently, FSHD symptom severity is assessed by clinical assessments such as the FSHD clinical score and the Timed Up-and-Go test. These assessments are limited in their ability to capture changes continuously and the full impact of the disease on patients’ quality of life. Real-world data related to physical activity, sleep, and social behavior could potentially provide additional insight into the impact of the disease and might be useful in assessing treatment effects on aspects that are important contributors to the functioning and well-being of patients with FSHD.ObjectiveThis study investigated the feasibility of using smartphones and wearables to capture symptoms related to FSHD based on a continuous collection of multiple features, such as the number of steps, sleep, and app use. We also identified features that can be used to differentiate between patients with FSHD and non-FSHD controls.MethodsIn this exploratory noninterventional study, 58 participants (n=38, 66%, patients with FSHD and n=20, 34%, non-FSHD controls) were monitored using a smartphone monitoring app for 6 weeks. On the first and last day of the study period, clinicians assessed the participants’ FSHD clinical score and Timed Up-and-Go test time. Participants installed the app on their Android smartphones, were given a smartwatch, and were instructed to measure their weight and blood pressure on a weekly basis using a scale and blood pressure monitor. The user experience and perceived burden of the app on participants’ smartphones were assessed at 6 weeks using a questionnaire. With the data collected, we sought to identify the behavioral features that were most salient in distinguishing the 2 groups (patients with FSHD and non-FSHD controls) and the optimal time window to perform the classification.ResultsOverall, the participants stated that the app was well tolerated, but 67% (39/58) noticed a difference in battery life using all 6 weeks of data, we classified patients with FSHD and non-FSHD controls with 93% accuracy, 100% sensitivity, and 80% specificity. We found that the optimal time window for the classification is the first day of data collection and the first week of data collection, which yielded an accuracy, sensitivity, and specificity of 95.8%, 100%, and 94.4%, respectively. Features relating to smartphone acceleration, app use, location, physical activity, sleep, and call behavior were the most salient features for the classification.ConclusionsRemotely monitored data collection allowed for the collection of daily activity data in patients with FSHD and non-FSHD controls for 6 weeks. We demonstrated the initial ability to detect differences in features in patients with FSHD and non-FSHD controls using smartphones and wearables, mainly based on data related to physical and social activity.Trial RegistrationClinicalTrials.gov NCT04999735; https://www.clinicaltrials.gov/ct2/show/NCT04999735

Antagonism Between DUX4 and DUX4c Highlights a Pathomechanism Operating Through β-Catenin in Facioscapulohumeral Muscular Dystrophy.

Aberrant expression of the transcription factor DUX4 from D4Z4 macrosatellite repeats on chromosome 4q35, and its transcriptome, associate with pathogenesis in facioscapulohumeral muscular dystrophy (FSHD). Forced DUX4 expression halts skeletal muscle cell proliferation and induces cell death. DUX4 binds DNA via two homeodomains that are identical in sequence to those of DUX4c (DUX4L9): a closely related transcriptional regulator encoded by a single, inverted, mutated D4Z4 unit located centromeric to the D4Z4 macrosatellite array on chromosome 4. However, the function and contribution of DUX4c to FSHD pathogenesis are unclear. To explore interplay between DUX4, DUX4c, and the DUX4-induced phenotype, we investigated whether DUX4c interferes with DUX4 function in human myogenesis. Constitutive expression of DUX4c rescued the DUX4-induced inhibition of proliferation and reduced cell death in human myoblasts. Functionally, DUX4 promotes nuclear translocation of β-CATENIN and increases canonical WNT signalling. Concomitant constitutive expression of DUX4c prevents β-CATENIN nuclear accumulation and the downstream transcriptional program. DUX4 reduces endogenous DUX4c levels, whereas constitutive expression of DUX4c robustly suppresses expression of DUX4 target genes, suggesting molecular antagonism. In line, DUX4 expression in FSHD myoblasts correlates with reduced DUX4c levels. Addressing the mechanism, we identified a subset of genes involved in the WNT/β-CATENIN pathway that are differentially regulated between DUX4 and DUX4c, whose expression pattern can separate muscle biopsies from severely affected FSHD patients from healthy. Finally, blockade of WNT/β-CATENIN signalling rescues viability of FSHD myoblasts. Together, our study highlights an antagonistic interplay whereby DUX4 alters cell viability via β-CATENIN signalling and DUX4c counteracts aspects of DUX4-mediated toxicity in human muscle cells, potentially acting as a gene modifier for FSHD severity. Importantly, direct DUX4 regulation of the WNT/β-CATENIN pathway informs future therapeutic interventions to ameliorate FSHD pathology.

On the Role of Delays to Diagnosis of Facioscapulohumeral Muscular Dystrophy

Facioscapulohumeral muscular dystrophy (FSHD) is a rare genetic muscle disease that predominantly affects the facial, scapular, and humeral musculature. Scapular winging is the most common initial finding in patients with FSHD. FSHD can substantially impact a patient’s daily life, ranging from discomfort during work to athletic disadvantages. Another aspect of FSHD that is essential for obtaining successful patient outcomes is timely diagnosis, which can be challenging, possibly due to the heterogeneity of presenting features as well as the rarity of the condition. Some of the methods for increasing the ability to diagnose FSHD should include increased education regarding the disease, as well as other muscular dystrophies, specifically in underserved communities that may have less access to healthcare. Although there is currently no effective pharmacologic intervention for FSHD, recommendations of the American Academy of Neurology and the Practice Issues Review Panel of the American Association of Neuromuscular &amp; Electrodiagnostic Medicine (2015) provide helpful guidance.

Transplantation of PSC-derived myogenic progenitors counteracts disease phenotypes in FSHD mice

Facioscapulohumeral muscular dystrophy (FSHD) is a genetically dominant progressive myopathy caused by improper silencing of the DUX4 gene, leading to fibrosis, muscle atrophy, and fatty replacement. Approaches focused on muscle regeneration through the delivery of stem cells represent an attractive therapeutic option for muscular dystrophies. To investigate the potential for cell transplantation in FSHD, we have used the doxycycline-regulated iDUX4pA-HSA mouse model in which low-level DUX4 can be induced in skeletal muscle. We find that mouse pluripotent stem cell (PSC)-derived myogenic progenitors engraft in muscle actively undergoing DUX4-mediated degeneration. Donor-derived muscle tissue displayed reduced fibrosis and importantly, engrafted muscles showed improved contractile specific force compared to non-transplanted controls. These data demonstrate the feasibility of replacement of diseased muscle with PSC-derived myogenic progenitors in a mouse model for FSHD, and highlight the potential for the clinical benefit of such a cell therapy approach.

Longitudinal Analysis Of Mobile Smartphone Application For The Assessment Of Facioscapulohumeral Muscular Dystrophy (FSHD) Gait

Facioscapulohumeral muscular dystrophy (FSHD) can be categorized as having a loss of muscular function in the torso, pelvic girdle, and legs. FSHD patient’s gait may decline over time, which could be used as a marker of disease progression. If so, this may be beneficial for potential clinical trials. PURPOSE: Evaluate gait velocity and cadence across three gait tasks using a novel smartphone application among individuals with FSHD over 6 months. METHODS: 2 (male = 1, female = 1; avg. age = 65 years) genetically confirmed FSHD1 patients completed three gait trials that required them to walk on a level surface at home 5 out of 7 days a week at two time points, 6 months apart. Patients used a custom smartphone application (FSHD Gait), installed on a smartphone (LG KG40) and secured on the lower back using a running belt, while walking. FSHD Gait application was used to take pictures of their shoes and walking environment. The first task (T1) involved walking 10 meters 12 times once each day. The second task (T2) was to walk 10 meters 6 times, with 6 trials being performed in the morning and 6 in the afternoon with a minimum of 4 hours between sessions. In the final week (T3), participants were instructed to walk for 6 minutes without any breaks. One-way ANOVAs compared the two time points while controlling for shoe type and walking surface. RESULTS: Over the course of 6 months, neither participant expressed a significant decline in gait velocity. There was no difference in gait velocity between time point one and two for T1 (PRE = 0.93 ± 0.24 m/s, POST = 0.85 ± .04 m/s; Cohen’s d = 0.27; p = 0.75), T2 (PRE = 0.93 ± 0.15 m/s, POST = 0.88 ± 0.07 m/s; Cohen’s d = 0.50, p = 0.54) or T3 (PRE = 0.94 ± 0.21 m/s, POST = 1.00 ± .09 m/s; Cohen’s d = 0.47; p = 0.63). Similarly, over the course of 6 months, neither participant expressed decline in cadence between time point one and two for T1 (PRE = 94.07 ± 4.78 steps/min, POST = 99.66 ± 6.44 steps/min; Cohen’s d = 3.36; p = 0.13), T2 (PRE = 103.71 ± 5.17 steps/min, POST = 0.85 ± 0.04 steps/min; Cohen’s d = 0.44; 0.64) or T3 (PRE = 98.74 ± .25 steps/min, POST = 86.88 ± 11.30 steps/min; Cohen’s d = 1.03; p = 0.35). CONCLUSION: FSHD Gait application can successfully collect and analyze gait for FSHD patient assessments over a 6-month period. While cadence nor velocity significantly changed, overall both metrics declined in both participants during T1 and T2.

Update on the Molecular Aspects and Methods Underlying the Complex Architecture of FSHD.

Despite the knowledge of the main mechanisms involved in facioscapulohumeral muscular dystrophy (FSHD), the high heterogeneity and variable penetrance of the disease complicate the diagnosis, characterization and genotype–phenotype correlation of patients and families, raising the need for further research and data. Thus, the present review provides an update of the main molecular aspects underlying the complex architecture of FSHD, including the genetic factors (related to D4Z4 repeated units and FSHD-associated genes), epigenetic elements (D4Z4 methylation status, non-coding RNAs and high-order chromatin interactions) and gene expression profiles (FSHD transcriptome signatures both at bulk tissue and single-cell level). In addition, the review will also describe the methods currently available for investigating the above-mentioned features and how the resulting data may be combined with artificial-intelligence-based pipelines, with the purpose of developing a multifunctional tool tailored to enhancing the knowledge of disease pathophysiology and progression and fostering the research for novel treatment strategies, as well as clinically useful biomarkers. In conclusion, the present review highlights how FSHD should be regarded as a disease characterized by a molecular spectrum of genetic and epigenetic factors, whose alteration plays a differential role in DUX4 repression and, subsequently, contributes to determining the FSHD phenotype.

Spotlight on the August 30 Issue

![Graphic][1]</img>#### Notable in Neurology This Week This issue features an article that examines the association between sex, menopause, and white matter hyperintensities; another determines optimal surveillance strategies for unruptured intracranial aneurysm growth. A featured article examines the association of healthy lifestyles with risk of Alzheimer disease and related dementias in low-income Black and White Americans. ### Quantitative Muscle Analysis in FSHD Using Whole-Body Fat-Referenced MRI: Composite Scores for Longitudinal and Cross-sectional Analysis This prospective, observational, multicenter study in patients with facioscapulohumeral muscular dystrophy (FSHD) type 1 demonstrated … [1]: /embed/inline-graphic-1.gif

Retinal Vascular Disease in Limb-Girdle Muscular Dystrophy.

To report bilateral retinal vascular occlusive disease in limb-girdle muscular dystrophy. Case report. A 34-year-old Asian woman was referred for evaluation and management of central retinal vein occlusion. Ultra-wide-field fluorescein angiography showed resolving initial peripheral retinal vein occlusion in one eye and peripheral venular segmental staining in the fellow asymmetric eye. Genetic testing established the diagnosis of limb-girdle muscular dystrophy (LGMD). Similar to other forms of muscular dystrophy, LGMD is caused by genetic abnormalities in sarcolemma proteins, a key structural component that connects the intracellular cytoskeleton of a myofiber to the extracellular matrix. Like other muscular dystrophies, LGMD may be associated with retinal vascular abnormalities noted. In this case, retinal vascular smooth muscle dysfunction was seen in LGMD, analogous to reported vascular abnormalities in other muscular dystrophies such as facioscapulohumeral dystrophy and Duchenne muscular dystrophy.

ANT1 overexpression models: Some similarities with facioscapulohumeral muscular dystrophy

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disorder characterized by progressive muscle weakness. Adenine nucleotide translocator 1 (ANT1), the only 4q35 gene involved in mitochondrial function, is strongly expressed in FSHD skeletal muscle biopsies. However, its role in FSHD is unclear. In this study, we evaluated ANT1 overexpression effects in primary myoblasts from healthy controls and during Xenopus laevis organogenesis. We also compared ANT1 overexpression effects with the phenotype of FSHD muscle cells and biopsies.Here, we report that the ANT1 overexpression-induced phenotype presents some similarities with FSHD muscle cells and biopsies. ANT1-overexpressing muscle cells showed disorganized morphology, altered cytoskeletal arrangement, enhanced mitochondrial respiration/glycolysis, ROS production, oxidative stress, mitochondrial fragmentation and ultrastructure alteration, as observed in FSHD muscle cells. ANT1 overexpression in Xenopus laevis embryos affected skeletal muscle development, impaired skeletal muscle, altered mitochondrial ultrastructure and led to oxidative stress as observed in FSHD muscle biopsies. Moreover, ANT1 overexpression in X. laevis embryos affected heart structure and mitochondrial ultrastructure leading to cardiac arrhythmia, as described in some patients with FSHD.Overall our data suggest that ANT1 could contribute to mitochondria dysfunction and oxidative stress in FSHD muscle cells by modifying their bioenergetic profile associated with ROS production. Such interplay between energy metabolism and ROS production in FSHD will be of significant interest for future prospects.

Self-reported reduced sleep quality and excessive daytime sleepiness in facioscapulohumeral muscular dystrophy.

Facioscapulohumeral muscular dystrophy (FSHD) causes weakness and secondary associations, such as respiratory complications and pain, that can be linked to abnormal sleep patterns. Limited studies have focused on sleep in FSHD. The purpose of this study was to identify the prevalence of, and clinical features associated with, self-reported lowered sleep quality (SQ) and excessive daytime sleepiness (DS) in a large group of participants with FSHD. We conducted a prospective survey of individuals with self-reported FSHD enrolled in the FSHD Society Registry. The survey consisted of demographic and clinical characteristics, the Pittsburgh Sleep Quality Index (PSQI), and the Epworth Sleepiness Scale. Descriptive statistics were evaluated, and associations between clinical characteristics and SQ and DS were explored using one-way analysis of variance tests. Small effect size was identified as 0.01 ≥ η2 > 0.06, medium was 0.06 ≥ η2 > 0.14, and large was 0.14 ≥ η2 . Six hundred ninety individuals responded to the survey, equally distributed between men and women, and spanning the age range from under 12 to 74 years of age or older. Sixty-six percent of the respondents showed reduced SQ (PSQI > 5) (n=392; 95% confidence interval [CI], 62.4-70.0), and 15% showed excessive DS (>10) (n=89; 95% CI, 12.2-17.9). There was a significant association between SQ and DS. Nocturnal pain had a large significant effect on lowering SQ (P < .001, η2 =0.192). Factors including age and gender had minor effects on SQ. Physicians should monitor sleep quality of patients with FSHD as a routine part of care, with special attention to potentially modifiable factors. Future research should address the physiological effects of pain in sleep.