1,499 results match your criteria Facioscapulohumeral Dystrophy

p38 MAPKs - roles in skeletal muscle physiology, disease mechanisms, and as potential therapeutic targets.

JCI Insight 2021 Jun 22;6(12). Epub 2021 Jun 22.

Rare Disease Research Unit, Pfizer Inc., Cambridge, Massachusetts, USA.

p38 MAPKs play a central role in orchestrating the cellular response to stress and inflammation and in the regulation of myogenesis. Potent inhibitors of p38 MAPKs have been pursued as potential therapies for several disease indications due to their antiinflammatory properties, although none have been approved to date. Here, we provide a brief overview of p38 MAPKs, including their role in regulating myogenesis and their association with disease progression. Read More

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Pathomechanisms and biomarkers in facioscapulohumeral muscular dystrophy: roles of DUX4 and PAX7.

EMBO Mol Med 2021 Jun 21:e13695. Epub 2021 Jun 21.

Randall Centre for Cell and Molecular Biophysics, King's College London, London, UK.

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. Read More

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SMCHD1's ubiquitin-like domain is required for N-terminal dimerization and chromatin localization.

Biochem J 2021 Jun 10. Epub 2021 Jun 10.

Walter and Eliza Hall Institute of Medical Research, Parkville, Australia.

Structural Maintenance of Chromosomes flexible Hinge Domain-containing 1 (SMCHD1) is an epigenetic regulator that mediates gene expression silencing at targeted sites across the genome. Our current understanding of SMCHD1's molecular mechanism, and how substitutions within SMCHD1 lead to the diseases, facioscapulohumeral muscular dystrophy (FSHD) and Bosma arhinia microphthalmia syndrome (BAMS), are only emerging. Recent structural studies of its two component domains - the N-terminal ATPase and C-terminal SMC hinge - suggest that dimerization of each domain plays a central role in SMCHD1 function. Read More

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Cardiac Involvement in Facioscapulohumeral Muscular Dystrophy (FSHD).

Front Neurol 2021 24;12:668180. Epub 2021 May 24.

Department of Neurology, Mayo Clinic, Rochester, MN, United States.

Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common muscular dystrophies and predominantly affects facial and shoulder girdle muscles. Previous case reports and cohort studies identified minor cardiac abnormalities in FSHD patients, but their nature and frequency remain incompletely characterized. We reviewed cardiac, neurological and genetic findings of 104 patients with genetically confirmed FSHD. Read More

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A Patient-Focused Survey to Assess the Effects of the COVID-19 Pandemic and Social Guidelines on People with Muscular Dystrophy.

Muscle Nerve 2021 Jun 8. Epub 2021 Jun 8.

Department of Neurology, University of Kansas Medical Center, Kansas City, Kansas.

Introduction: In this study, we examined the social and health impacts of the coronavirus disease 2019 (COVID-19) pandemic and social guidelines on people with muscular dystrophies.

Methods: A prospective de-identified electronic survey was distributed to adults with self-reported facioscapulohumeral muscular dystrophy (FSHD), myotonic dystrophy (DM), and limb-girdle muscular dystrophy (LGMD) enrolled in national registries or with patient advocacy groups. The COVID-19 Impact Survey was developed by muscular dystrophy experts in association with patient collaborators and advocacy groups. Read More

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FSHD1 Diagnosis in a Russian Population Using a qPCR-Based Approach.

Diagnostics (Basel) 2021 May 28;11(6). Epub 2021 May 28.

Research Centre for Medical Genetics, Laboratory of Functional Genomics, 1, Moskvorechie Str., 115478 Moscow, Russia.

Facioscapulohumeral dystrophy (FSHD) is an autosomal dominant myodystrophy. Approximately 95% of cases of FSHD are caused by partial deletion of the D4Z4 macrosatellite tandem repeats on chromosome 4q35. The existing FSHD1 diagnostic methods are laborious and not widely used. Read More

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The "wrench-head" appearance of thigh muscle CT in infantile facioscapulohumeral muscular dystrophy.

Acta Neurol Belg 2021 May 29. Epub 2021 May 29.

Department of Pediatrics, Kaohsiung Medical University Hospital, Kaohsiung Medical University, No. 100, Tzyou 1st Road, Kaohsiung, 80708, Taiwan.

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The socioeconomic burden of facioscapulohumeral muscular dystrophy.

J Neurol 2021 May 27. Epub 2021 May 27.

Donders Institute for Brain, Cognition and Behaviour, Department of Rehabilitation, Radboud university medical center, Nijmegen, The Netherlands.

Background: Promising genetic therapies are being investigated in facioscapulohumeral muscular dystrophy (FSHD). However, the current cost of illness is largely unknown.

Objective: This study aimed at determining the socioeconomic burden of FSHD. Read More

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Analysis of genes regulated by DUX4 via oxidative stress reveals potential therapeutic targets for treatment of facioscapulohumeral dystrophy.

Redox Biol 2021 Jul 13;43:102008. Epub 2021 May 13.

CNRS UMR9018, Université Paris-Saclay, Institut Gustave Roussy, 94805, Villejuif, France; Koltzov Institute of Developmental Biology, 117334, Moscow, Russia. Electronic address:

Muscles of patients with facioscapulohumeral dystrophy (FSHD) are characterized by sporadic DUX4 expression and oxidative stress which is at least partially induced by DUX4 protein. Nevertheless, targeting oxidative stress with antioxidants has a limited impact on FSHD patients, and the exact role of oxidative stress in the pathology of FSHD, as well as its interplay with the DUX4 expression, remain unclear. Here we set up a screen for genes that are upregulated by DUX4 via oxidative stress with the aim to target these genes rather than the oxidative stress itself. Read More

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Profiling Serum Antibodies Against Muscle Antigens in Facioscapulohumeral Muscular Dystrophy Finds No Disease-Specific Autoantibodies.

J Neuromuscul Dis 2021 May 15. Epub 2021 May 15.

Department of Biomolecular Chemistry, Institute for Molecules and Materials, Radboud University, Nijmegen, The Netherlands.

Background: FSHD is caused by specific genetic mutations resulting in activation of the Double Homeobox 4 gene (DUX4). DUX4 targets hundreds of downstream genes eventually leading to muscle atrophy, oxidative stress, abnormal myogenesis, and muscle inflammation. We hypothesized that DUX4-induced aberrant expression of genes triggers a sustained autoimmune response against skeletal muscle cells. Read More

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Systemic antisense therapeutics inhibiting DUX4 expression ameliorates FSHD-like pathology in an FSHD mouse model.

Hum Mol Genet 2021 May 13. Epub 2021 May 13.

Department of Biological Sciences, School of Life Sciences and the Environment, Royal Holloway University of London, Egham, Surrey, TW20 0EX, UK.

Aberrant expression of the double homeobox 4 (DUX4) gene in skeletal muscle causes muscle deterioration and weakness in Facioscapulohumeral Muscular Dystrophy (FSHD). Since the presence of a permissive pLAM1 polyadenylation signal is essential for stabilization of DUX4 mRNA and translation of DUX4 protein, disrupting the function of this structure can prevent expression of DUX4. We and others have shown promising results using antisense approaches to reduce DUX4 expression in vitro and in vivo following local intramuscular administration. Read More

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ETV4/5 drive synovial sarcoma through control of the cell cycle and the DUX4 embryonic pathway.

J Clin Invest 2021 May 13. Epub 2021 May 13.

Department of Medicine, Division of Medical Oncology, University of Miami Miller School of Medicine, Miami, United States of America.

Synovial sarcoma is an aggressive malignancy with no effective treatments for patients with metastasis. The synovial sarcoma fusion, SS18-SSX, which recruits the SWI/SNF-BAF chromatin remodeling and polycomb repressive complexes, results in epigenetic activation of FGFR signaling. In genetic FGFR knockout models, culture, and xenograft synovial sarcoma models treated with the FGFR inhibitor BGJ398, we show that FGFR1, FGFR2, and FGFR3 were crucial for tumor growth. Read More

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Phase 1 clinical trial of losmapimod in facioscapulohumeral dystrophy: Safety, tolerability, pharmacokinetics, and target engagement.

Br J Clin Pharmacol 2021 Apr 30. Epub 2021 Apr 30.

Centre for Human Drug Research (CHDR), Leiden, The Netherlands.

Aims: Evaluate safety, tolerability, pharmacokinetics (PK) and target engagement (TE) of losmapimod in blood and muscle in facioscapulohumeral dystrophy (FSHD).

Methods: This study included Part A: 10 healthy volunteers randomized to single oral doses of losmapimod (7.5 mg then 15 mg; n = 8) or placebo (both periods; n = 2); Part B: 15 FSHD subjects randomized to placebo (n = 3), or losmapimod 7. Read More

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Screening for oropharyngeal dysphagia in adult patients with neuromuscular diseases using the Sydney Swallow Questionnaire.

Muscle Nerve 2021 Apr 23. Epub 2021 Apr 23.

Institut de Recherche Expérimentale et Clinique, Pôle de Pneumologie, ORL & Dermatologie, Groupe Recherche en Kinésithérapie Respiratoire, Université Catholique de Louvain, Brussels, Belgium.

Introduction/aims: Oropharyngeal dysphagia is common in patients with neuromuscular diseases (NMDs). Its early recognition is vital for proper management. We tested a large cohort of adult NMD patients for oropharyngeal dysphagia using the Sydney Swallow Questionnaire (SSQ). Read More

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Control of DUX4 Expression in Facioscapulohumeral Muscular Dystrophy and Cancer.

Trends Mol Med 2021 Jun 13;27(6):588-601. Epub 2021 Apr 13.

UMR 9018, CNRS, Université Paris Saclay, Institut Gustave Roussy, Villejuif F-94805, France; Koltzov Institute of Developmental Biology, Moscow 117334, Russia. Electronic address:

DUX4, a gene encoding a transcription factor involved in early embryogenesis, is located within the D4Z4 subtelomeric repeat on chromosome 4q35. In most healthy somatic tissues, DUX4 is heavily repressed by multiple genetic and epigenetic mechanisms, and its aberrant expression is linked to facioscapulohumeral muscular dystrophy (FSHD) where it has been extensively studied. Recently, DUX4 expression has been implicated in oncogenesis, although this is much less explored. Read More

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Ultrasound pattern of anterolateral leg muscles in facioscapulohumeral muscular dystrophy.

Acta Neurol Scand 2021 Apr 12. Epub 2021 Apr 12.

Department of Neurology, Neuromuscular Center, University of Patras, Patras, Greece.

Background/aims Of Study: To evaluate the degree of tibialis anterior (TA) and peroneus longus (PL) muscle involvement in facioscapulohumeral muscular dystrophy (FSHD) patients using ultrasound.

Methods: We performed qualitative and quantitative assessments of muscle echogenicity, using Heckmatt's rating scale and gray scale analysis, respectively, in eight patients (five males, mean age 36.9 ± 8. Read More

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The facioscapulohumeral muscular dystrophy Rasch-built overall disability scale (FSHD-RODS).

Eur J Neurol 2021 Jul 2;28(7):2339-2348. Epub 2021 May 2.

Department of Neurology, Curaçao Medical Center, Willemstad, Curaçao.

Background And Objectives: Facioscapulohumeral muscular dystrophy (FHSD) is a debilitating inherited muscle disease for which various therapeutic strategies are being investigated. Thus far, little attention has been given in FSHD to the development of scientifically sound outcome measures fulfilling regulatory authority requirements. The aim of this study was to design a patient-reported Rasch-built interval scale on activity and participation for FSHD. Read More

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Genetic Approaches for the Treatment of Facioscapulohumeral Muscular Dystrophy.

Front Pharmacol 2021 12;12:642858. Epub 2021 Mar 12.

Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal dominant disorder characterized by progressive, asymmetric muscle weakness at the face, shoulders, and upper limbs, which spreads to the lower body with age. It is the third most common inherited muscular disorder worldwide. Around 20% of patients are wheelchair-bound, and some present with extramuscular manifestations. Read More

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Resting Metabolic Rate in Adults with Facioscapulohumeral Muscular Dystrophy (FSHD).

Appl Physiol Nutr Metab 2021 Mar 18. Epub 2021 Mar 18.

University of Minnesota, 5635, Rehabilitation Medicine, Minneapolis, Minnesota, United States.

Determine whether resting metabolic rate (RMR) is altered in adults with facioscapulohumeral muscular dystrophy (FSHD). Eleven people with FSHD (51±12yrs, 2 females) and eleven controls (48±14yrs, 2 females) completed one visit, including 30-minutes of indirect calorimetry and dual-energy x-ray absorptiometry (DXA) scanning. RMR was calculated from resting oxygen consumption/carbon dioxide production; regional/whole-body fat mass and lean mass were collected from the DXA scan. Read More

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Fast Open-Source Toolkit for Water T2 Mapping in the Presence of Fat From Multi-Echo Spin-Echo Acquisitions for Muscle MRI.

Front Neurol 2021 26;12:630387. Epub 2021 Feb 26.

Department of Neurology, Buffalo Neuroimaging Analysis Center, Jacobs School of Medicine and Biomedical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, United States.

Imaging has become a valuable tool in the assessment of neuromuscular diseases, and, specifically, quantitative MR imaging provides robust biomarkers for the monitoring of disease progression. Quantitative evaluation of fat infiltration and quantification of the T2 values of the muscular tissue's water component (wT2) are two of the most essential indicators currently used. As each voxel of the image can contain both water and fat, a two-component model for the estimation of wT2 must be used. Read More

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February 2021

Facioscapulohumeral muscular dystrophy: genetics, gene activation and downstream signalling with regard to recent therapeutic approaches: an update.

Orphanet J Rare Dis 2021 03 12;16(1):129. Epub 2021 Mar 12.

Institute of Precision Medicine, Medical and Life Sciences Faculty, Furtwangen University, Jakob-Kienzle-Straße 17, 78054, Villingen-Schwenningen, Germany.

Whilst a disease-modifying treatment for Facioscapulohumeral muscular dystrophy (FSHD) does not exist currently, recent advances in complex molecular pathophysiology studies of FSHD have led to possible therapeutic approaches for its targeted treatment. Although the underlying genetics of FSHD have been researched extensively, there remains an incomplete understanding of the pathophysiology of FSHD in relation to the molecules leading to DUX4 gene activation and the downstream gene targets of DUX4 that cause its toxic effects. In the context of the local proximity of chromosome 4q to the nuclear envelope, a contraction of the D4Z4 macrosatellite induces lower methylation levels, enabling the ectopic expression of DUX4. Read More

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Nanopore direct RNA sequencing detects DUX4-activated repeats and isoforms in human muscle cells.

Hum Mol Genet 2021 May;30(7):552-563

Micro/Nano Technology Center, Tokai University, Hiratsuka, Kanagawa 259-1292, Japan.

Facioscapulohumeral muscular dystrophy (FSHD) is an inherited muscle disease caused by misexpression of the DUX4 gene in skeletal muscle. DUX4 is a transcription factor, which is normally expressed in the cleavage-stage embryo and regulates gene expression involved in early embryonic development. Recent studies revealed that DUX4 also activates the transcription of repetitive elements such as endogenous retroviruses (ERVs), mammalian apparent long terminal repeat (LTR)-retrotransposons and pericentromeric satellite repeats (Human Satellite II). Read More

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Longitudinal study of MRI and functional outcome measures in facioscapulohumeral muscular dystrophy.

BMC Musculoskelet Disord 2021 Mar 10;22(1):262. Epub 2021 Mar 10.

Department of Radiology, University of Washington, Seattle, Washington, USA.

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. Read More

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Scapular winging secondary to serratus anterior dysfunction: analysis of clinical presentations and etiology in a consecutive series of 96 patients.

J Shoulder Elbow Surg 2021 Mar 4. Epub 2021 Mar 4.

Department of Orthopaedics, University Hospitals Birmingham, Birmingham, UK.

Background: This study aimed to establish the relative incidence of etiologies causing serratus anterior (SA) dysfunction in patients with proven abnormality on needle electromyography.

Methods: This was a retrospective review of patients with scapular winging secondary to SA dysfunction. Each patient underwent a detailed clinical, radiological, and neurophysiological assessment to arrive at the precise etiological diagnosis. Read More

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Increased resistance towards fatigability in patients with facioscapulohumeral muscular dystrophy.

Eur J Appl Physiol 2021 Jun 1;121(6):1617-1629. Epub 2021 Mar 1.

Criams-Sport Medicine Centre Voghera, University of Pavia, Voghera, Italy.

Purpose: In facioscapulohumeral muscular dystrophy (FSHD) fatigue is a major complaint. We aimed to investigate whether during isometric sustained elbow flexions, performance fatigability indexes differ in patients with FSHD with respect to healthy controls.

Methods: Seventeen patients with FSHD and seventeen healthy controls performed two isometric flexions of the dominant biceps brachii at 20% of their maximal voluntary contraction (MVC) for 2 min and then at 60% MVC until exhaustion. Read More

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Psychological parameters impact health-related quality of life in mental and physical domains in adults with muscular dystrophy.

Neuromuscul Disord 2021 04 19;31(4):328-335. Epub 2021 Jan 19.

Research Centre for Musculoskeletal Science & Sports Medicine, Department of Sport and Exercise Sciences, Manchester Metropolitan University, Manchester M15 6BH, United Kingdom.

The impacts of potentially treatable psychological parameters on quality of life are relatively unreported in adults with Facioscapulohumeral, Becker and Limb-girdle muscular dystrophy. The purpose of this study was to compare quality of life, psychological parameters, and physical function between adults with muscular dystrophy and controls, and to examine relationships among these parameters in muscular dystrophy. Twenty-one adults with muscular dystrophy (n = 7 Becker, n = 8 Facioscapulohumeral, n = 6 Limb-girdle) and ten age-matched controls participated. Read More

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Current Therapeutic Approaches in FSHD.

J Neuromuscul Dis 2021 ;8(3):441-451

Department of Neurology, University of Rochester, Rochester, NY, USA.

Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common muscular dystrophies. Over the last decade, a consensus was reached regarding the underlying cause of FSHD allowing-for the first time-a targeted approach to treatment. FSHD is the result of a toxic gain-of-function from de-repression of the DUX4 gene, a gene not normally expressed in skeletal muscle. Read More

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January 2021