Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Facioscapulohumeral Muscular Dystrophy. Core disease mechanisms, molecular...

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• Papers retrieved: 20
• Snippets retrieved: 20

Relevant Papers

[1] Determining the role of sarcomeric proteins in facioscapulohumeral muscular dystrophy: a study protocol

• Authors: S. Lassche, C. Ottenheijm, N. Voermans, H. Westeneng, B. Janssen et al.
• Year: 2013
• Venue: BMC Neurology
• URL: https://www.semanticscholar.org/paper/868ee81fe48b5199729eda6ddea2866f5512e503
• DOI: 10.1186/1471-2377-13-144
• PMID: 24119284
• PMCID: 3852245
• Citations: 15
• Influential citations: 1
• Summary: The results obtained in this study will increase the understanding of the pathophysiology of muscle weakness in FSHD, and possibly identify novel targets for therapeutic intervention.
• Evidence snippets:
• Snippet 1 (score: 0.605) > BackgroundAlthough muscle weakness is a hallmark of facioscapulohumeral muscular dystrophy (FSHD), the molecular mechanisms that lead to weakness in FSHD remain largely unknown. Recent studies suggest aberrant expression of genes involved in skeletal muscle development and sarcomere contractility, and activation of pathways involved in sarcomeric protein degradation. This study will investigate the contribution of sarcomeric protein dysfunction to the pathogenesis of muscle weakness in FSHD.Methods/DesignEvaluation of sarcomeric function using skinned single muscle fiber contractile studies and protein analysis in muscle biopsies (quadriceps femoris and tibialis anterior) from patients with FSHD and age- and gender-matched healthy controls. Patients with other forms of muscular dystrophy and inflammatory myopathy will be included as disease controls to assess whether results are due to changes specific for FSHD, or a consequence of muscle disease in general. A total of 56 participants will be included. Extensive clinical parameters will be measured using MRI, quantitative muscle studies and physical activity assessments.DiscussionThis study is the first to extensively investigate muscle fiber physiology in FSHD following an earlier pilot study suggesting sarcomeric dysfunction in FSHD. The results obtained in this study will increase the understanding of the pathophysiology of muscle weakness in FSHD, and possibly identify novel targets for therapeutic intervention.

[2] Diagnosis, Pathogenesis and Treatment of Muscular Dystrophy

• Authors: M. Bozzi
• Year: 2025
• Venue: Biomedicines
• URL: https://www.semanticscholar.org/paper/e9c585567287a136c52df952d8f374aa96ae1090
• DOI: 10.3390/biomedicines13081820
• PMID: 40868075
• PMCID: 12383284
• Summary: Muscular dystrophies are a group of inherited genetic disorders that involve an ever-growing number of genes [...].
• Evidence snippets:
• Snippet 1 (score: 0.587) > Muscular dystrophies are a group of inherited genetic disorders that involve an evergrowing number of genes. Nowadays, more than 50 genes have been linked to different muscular dystrophies [1]. This genetic variability accounts for the wide heterogeneity of phenotypes observed in patients. From a clinical and pathological standpoint, muscular dystrophies are characterized by varying ages of onset and a broad spectrum of symptoms, including severe forms that impact other organs and tissues, particularly the central nervous system. Nevertheless, muscular dystrophies exhibit common histopathological and molecular characteristics that reflect disease progression. The primary shared feature is the accumulation of fibrotic tissue, which results from muscle fiber degeneration and cell death, ongoing inflammation, and increased oxidative stress. These factors contribute to the infiltration of inflammatory cells and the oxidation of lipids and proteins [2]. In the most severe forms of muscular dystrophy, cardiomyopathy and respiratory dysfunction occur during disease progression, severely affecting the patients' quality of life and strongly reducing their lifespan. Duchenne muscular dystrophy, Myotonic dystrophy type 1, and Facioscapulohumeral muscular dystrophy are some of the most common forms of muscular dystrophies. In particular, due to mutations in the dystrophin gene, Duchenne muscular dystrophy has an incidence of about 1 in 5000 live males every year [3]. > Early diagnosis is essential for effectively managing disease progression, and it should include genetic testing. However, establishing an accurate diagnosis can be challenging, as individuals with mutations in the same gene may present with diverse clinical manifestations. Therefore, a comprehensive approach integrating clinical evaluation, molecular testing, and tissue analysis is critical for achieving a precise diagnosis and informing a reliable prognosis [4,5]. > At present, there is no definitive cure for muscular dystrophy. Glucocorticoid therapy remains the cornerstone of muscular dystrophy treatment, helping to delay disease progression and improve muscle strength. However, its use is associated with significant side effects, including adrenal suppression, growth delay, weakened bone health, and the onset of metabolic syndrome [6]. This highlights the need to develop innovative therapeutic strategies.

[3] Current Therapeutic Approaches in FSHD

• Authors: Leo H. Wang, R. Tawil
• Year: 2020
• Venue: Journal of Neuromuscular Diseases
• URL: https://www.semanticscholar.org/paper/65038a0ff08223c00ba4710a13bd42c87be28ac6
• DOI: 10.3233/JND-200554
• PMID: 33579868
• PMCID: 8203219
• Citations: 30
• Influential citations: 1
• Summary: The underlying disease mechanism, potential therapeutic approaches as well as the state of trial readiness in the planning and execution of future clinical trials in FSHD are reviewed.
• Evidence snippets:
• Snippet 1 (score: 0.580) > 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. With a clear therapeutic target, there is increasing interest in drug development for FSHD, an interest buoyed by the recent therapeutic successes in other neuromuscular diseases. Herein, we review the underlying disease mechanism, potential therapeutic approaches as well as the state of trial readiness in the planning and execution of future clinical trials in FSHD.

[4] The Notch signaling pathway in skeletal muscle health and disease

• Authors: D. Vargas-Franco, R. Kalra, Isabelle Draper, C. A. Pacak, A. Asakura et al.
• Year: 2022
• Venue: Muscle & Nerve
• URL: https://www.semanticscholar.org/paper/2bc32ef6a1acc95f1c31b7e3ef5a268aadda4024
• DOI: 10.1002/mus.27684
• PMID: 35968817
• PMCID: 9804383
• Citations: 37
• Summary: The clinical syndromes associated with pathogenic variants in each of these genes, known molecular and cellular functions of their protein products with a particular focus on the Notch signaling pathway, and potential novel therapeutic targets that may emerge from further investigations of these diseases are reviewed.
• Evidence snippets:
• Snippet 1 (score: 0.563) > Since the landmark discovery in 1986 of DMD (dystrophin), 1 the causative gene for Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD), dozens of additional genes have been associated with various phenotypic subtypes of muscular dystrophy. > Common disease mechanisms across multiple subtypes have, however, been more difficult to identify, with only a few major clusters such as the dystroglycanopathies identified to date. Given the common phenotypic features within muscular dystrophy categories, such as limb-girdle muscular dystrophy (LGMD), there is a high likelihood that convergent disease mechanisms exist across more muscular dystrophy subtypes than is currently recognized. > There are therapeutic implications of identifying deeper biological ties between muscular dystrophy subtypes. In recent years, the US Food and Drug Administration (FDA) has approved several molecular and genetic therapies for neuromuscular disorders that target specific genes and even specific mutation types within those genes. These approaches are being applied to ever rarer forms of muscular dystrophies. However, proceeding through the preclinical and clinical research studies needed to attain FDA approval for a new therapy is lengthy and costly, and on the current trajectory it will be decades before molecular and genetic therapies are available for all known subtypes of muscular dystrophy. > The identification and characterization of disease mechanisms that are shared by multiple muscular dystrophy subtypes could pave the way for new pathway-based treatments that have therapeutic effects for multiple disease subtypes. 2 This has the potential to accelerate the timeline for broader therapeutic coverage of patients with muscular dystrophy, with a greater impact on the entire muscular dystrophy population. > One disease mechanism that bears further analysis is the Notch signaling pathway, which is known to maintain muscle stem cell (MuSC, also known as satellite cell) quiescence. Recently, three different muscle disease genes that are known to interact with the Notch signaling pathway have been identified: MEGF10, POGLUT1, and most recently JAG2.

[5] Meeting report: the 2021 FSHD International Research Congress

• Authors: S. Jagannathan, Jessica C. de Greef, Lawrence J. Hayward, K. Yokomori, D. Gabellini et al.
• Year: 2022
• Venue: Skeletal Muscle
• URL: https://www.semanticscholar.org/paper/7444edfc105226463dbdb4a3252fa3cc611a2048
• DOI: 10.1186/s13395-022-00287-8
• Summary: The 2021 FSHD International Research Congress, held virtually on June 24–25, convened over 350 researchers and clinicians to share the most recent advances in the understanding of the disease mechanism, discuss the proliferation of interventional strategies and refinement of clinical outcome measures, including results from the ReDUX4 trial, a phase 2b clinical trial of losmapimod in FSHd.
• Evidence snippets:
• Snippet 1 (score: 0.561) > Facioscapulohumeral muscular dystrophy (FSHD) is the second most common genetic myopathy, characterized by slowly progressing and highly heterogeneous muscle wasting with a typical onset in the late teens/early adulthood [1]. Although the etiology of the disease for both FSHD type 1 and type 2 has been attributed to gain-of-toxic function stemming from aberrant DUX4 expression, the exact pathogenic mechanisms involved in muscle wasting have yet to be elucidated [2–4]. The 2021 FSHD International Research Congress, held virtually on June 24–25, convened over 350 researchers and clinicians to share the most recent advances in the understanding of the disease mechanism, discuss the proliferation of interventional strategies and refinement of clinical outcome measures, including results from the ReDUX4 trial, a phase 2b clinical trial of losmapimod in FSHD [NCT04003974].

[6] Facioscapulohumeral Muscular Dystrophy.

• Authors: Renatta N Knox
• Year: 2018
• Venue: Continuum
• URL: https://www.semanticscholar.org/paper/aeb5eff3a6fc5398a8b8f1485693ed1a6cc4746a
• DOI: 10.1007/978-1-4614-6430-3_84-2
• PMID: 41037169
• Citations: 225
• Influential citations: 19
• Summary: An overview of the distinctive genetic mechanisms underlying FSHD, its clinical manifestations, including pediatric-specific features, treatment, and the evolving landscape of clinical trials targeting disease-modifying therapies is provided.
• Evidence snippets:
• Snippet 1 (score: 0.555) > OBJECTIVE > Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common forms of muscular dystrophy, affecting individuals across the lifespan with variable severity. This article provides an overview of the distinctive genetic mechanisms underlying FSHD, its clinical manifestations, including pediatric-specific features, treatment, and the evolving landscape of clinical trials targeting disease-modifying therapies. > LATEST DEVELOPMENTS > FSHD arises from derepression of the transcription factor DUX4, which is toxic to skeletal muscle. This misexpression leads to a characteristic and progressive pattern of muscle weakness involving the facial, shoulder girdle, upper extremity, trunk, and leg muscles. Extramuscular manifestations, such as pain and fatigue, are frequently reported. Children with a severe, early-onset phenotype experience higher rates of extramuscular features, including hearing loss, cognitive impairment, and spinal deformities. Advances in the understanding of DUX4 as the causative gene, combined with innovations in gene therapy, gene editing, small-molecule development, and drug delivery, have catalyzed the initiation of several clinical trials focusing on disease-targeted treatments in the near future. > ESSENTIAL POINTS > FSHD is caused by toxic expression of DUX4 and presents with progressive, often asymmetric muscle weakness and extramuscular manifestations in a subset of patients. Advances in genetic understanding and therapeutic development have led to clinical trials targeting DUX4. Although care remains supportive, the field is entering an era of promising disease-modifying strategies.

[7] The Unexplored Role of Connexin Hemichannels in Promoting Facioscapulohumeral Muscular Dystrophy Progression

• Authors: Macarena Díaz-Ubilla, Mauricio A Retamal
• Year: 2025
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/2fc946973feb1d3970f29459e88eb639d3cd5bf9
• DOI: 10.3390/ijms26010373
• PMID: 39796228
• PMCID: 11719937
• Summary: This review summarizes the current understanding of the mechanisms underlying FSHD progression, with a focus on hormones, inflammation, reactive oxygen species (ROS), and mitochondrial function and explores the potential of targeting hemichannels as a therapeutic strategy to slow disease progression by preventing the spread of pathogenic factors between muscle cells.
• Evidence snippets:
• Snippet 1 (score: 0.539) > Facioscapulohumeral Muscular Dystrophy (FSHD) is one of the most prevalent types of muscular dystrophy, affecting between 1 in 8000 to 1 in 22,000 people worldwide [1][2][3]. This condition is caused by a genetic mutation and is characterized by a slow, progressive, and asymmetric weakening of specific muscle groups, including the muscles of the face, shoulder girdle, arms, abdominal wall, hips, and thighs [2,4]. The clinical presentation of FSHD is highly variable, even among individuals with the same genetic background, such as monozygotic twins, where differences in disease severity and muscle involvement have been documented [5,6]. This variability extends to the pattern of disease progression, which is often unpredictable and varies widely from person to person [3,7,8]. The unpredictable nature of FSHD likely reflects underlying uncertainties at the molecular level, particularly the factors governing the expression of the disease-causing gene, DUX4. Although DUX4 is a critical factor in the pathogenesis of FSHD, its expression is rare, detected in only 1 out of 1000 FSHD myoblasts and in approximately 1 out of 200 myotube nuclei during in vitro studies [9]. Despite extensive research, the DUX4 protein has not been successfully detected in muscle biopsies from FSHD patients [9,10]. However, even with such low levels of DUX4 expression, muscle atrophy continues to progress, affecting both initially impacted and surrounding healthy muscle fibers and eventually spreading to additional muscle groups. This suggests that FSHD involves a broader mechanism of pathogenic factor transmission between muscle cells, which accelerates muscle damage. One possible mechanism behind this transmission involves connexin (Cx) hemichannels, which facilitate the exchange of signaling molecules between the cell cytoplasm and the extracellular environment [11][12][13].

[8] Cellular and molecular mechanisms underlying muscular dystrophy

• Authors: F. Rahimov, L. Kunkel
• Year: 2013
• Venue: The Journal of Cell Biology
• URL: https://www.semanticscholar.org/paper/f40d5c11c05bfed36ed352efec2330b6b6ade1ba
• DOI: 10.1083/jcb.201212142
• PMID: 23671309
• PMCID: 3653356
• Citations: 233
• Influential citations: 12
• Summary: The muscular dystrophies are a group of heterogeneous genetic diseases characterized by progressive degeneration and weakness of skeletal muscle and distinct molecular and cellular mechanisms that link genetic mutations to diverse muscle wasting phenotypes are revealed.
• Evidence snippets:
• Snippet 1 (score: 0.538) > The muscular dystrophies are a group of heterogeneous genetic diseases characterized by progressive degeneration and weakness of skeletal muscle. Since the discovery of the first muscular dystrophy gene encoding dystrophin, a large number of genes have been identified that are involved in various muscle-wasting and neuromuscular disorders. Human genetic studies complemented by animal model systems have substantially contributed to our understanding of the molecular pathomechanisms underlying muscle degeneration. Moreover, these studies have revealed distinct molecular and cellular mechanisms that link genetic mutations to diverse muscle wasting phenotypes.

[9] Therapeutic advances in muscular dystrophy

• Authors: D. Leung, K. Wagner
• Year: 2013
• Venue: Annals of Neurology
• URL: https://www.semanticscholar.org/paper/22bac6d00e252299778eb2908eb9c77674e1b562
• DOI: 10.1002/ana.23989
• PMID: 23939629
• PMCID: 3886293
• Citations: 79
• Influential citations: 1
• Summary: Treatment developments in 3 of the most common forms of muscular dystrophy are discussed, with the large number of novel pharmacologic agents in development with good biologic rationale and strong proof of concept suggesting there will be an improved quality of life for individuals with muscular dystroke.
• Evidence snippets:
• Snippet 1 (score: 0.533) > The muscular dystrophies comprise a heterogeneous group of genetic disorders that produce progressive skeletal muscle weakness and wasting. There has been rapid growth and change in our understanding of these disorders in recent years, and advances in basic science are being translated into increasing numbers of clinical trials. This review will discuss therapeutic developments in 3 of the most common forms of muscular dystrophy: Duchenne muscular dystrophy, facioscapulohumeral muscular dystrophy, and myotonic dystrophy. Each of these disorders represents a different class of genetic disease (monogenic, epigenetic, and repeat expansion disorders), and the approach to therapy addresses the diverse and complex molecular mechanisms involved in these diseases. The large number of novel pharmacologic agents in development with good biologic rationale and strong proof of concept suggests there will be an improved quality of life for individuals with muscular dystrophy. Ann Neurol 2013;74:404–411

[10] A Hypothesis for Mechanisms of Weakness Distribution in Muscular Dystrophies

• Authors: Alexander Khlebtovsky, F. Benninger, I. Steiner
• Year: 2018
• Venue: Journal of neurological disorders
• URL: https://www.semanticscholar.org/paper/bef89c402a7ddbbd127f4c1fd0472b4c04e87b7e
• DOI: 10.4172/2329-6895.1000389
• Citations: 2
• Influential citations: 1
• Summary: A classification of muscle weakness in muscular dystrophies could enable predicting the function of newly identified myopathy-related genes according to their clinical presentation, and show that muscle weakness often follows a common pattern.
• Evidence snippets:
• Snippet 1 (score: 0.530) > Abnormal proteins that present with more or less simultaneous involvement of proximal and distal muscles are briefly reviewed according to: protein location and function, name of disease caused with possible mechanisms of myopathy, and levels of proof for the pathophysiological mechanism/s. Proteins in this group have a wide range of functions, including: cell signalling, muscle differentiation and apoptosis. However, the pathophysiology causing myopathy is unknown. > additional factors are involved other than proper protein dysfunction and muscle cell signaling. Furthermore, the degenerative muscle diseases caused by more complicated mechanisms than isolated protein dysfunction, such as myotonic dystrophy and facioscapulohumeral muscular dystrophy, represent exceptions to our hypothesis.

[11] Pharmacotherapeutic Approaches to Treatment of Muscular Dystrophies

• Authors: A. Rawls, Bridget K. Diviak, Cameron I. Smith, Grant W. Severson, Sofia A. Acosta et al.
• Year: 2023
• Venue: Biomolecules
• URL: https://www.semanticscholar.org/paper/2d7f023c19774543c7e0bfca5c0dfb0b1aab2b39
• DOI: 10.3390/biom13101536
• PMID: 37892218
• PMCID: 10605463
• Citations: 9
• Summary: The pathophysiology, genetic background, and emerging therapeutic strategies for muscular dystrophies are examined to develop new pharmacotherapeutic approaches to limit inflammation and fibrosis to reduce muscle damage and promote repair.
• Evidence snippets:
• Snippet 1 (score: 0.525) > Muscular dystrophies (MDs) are genetic degenerative neuromuscular diseases characterized by progressive muscle weakness that results in significant morbidity.To date, mutations in 57 genes have been identified that cause nine specific classes of muscular dystrophy [1].Dystrophies are classified based on the specific gene involved and clinical features such as muscles affected, rate of disease progression, histopathology, and age of diagnosis.Inflammation is a common factor in the pathogenesis and progression of many types of MD.Chronic inflammation exacerbates muscle damage, induces fibrotic deposition and fatty replacement of myofibers, and impedes the regenerative process of skeletal muscle. > There are no curative treatments for any dystrophies currently, but new AAV and base editing approaches to provide the missing proteins or fix the genetic lesion provide hope.Though there is tremendous curative potential, these genetic approaches will not treat all dystrophies or even all versions of a single dystrophy.For example, there are more than 7000 known mutations in dystrophin that result in Duchenne muscular dystrophy (DMD) [2].Therefore, understanding the mechanisms underlying inflammation and other pathogenic processes will aid in identifying therapeutic approaches that can ameliorate the progression of these diseases.Preclinical and clinical treatments that specifically target inflammation and fibrosis are the subject of this review.

[12] Human iPSC Models to Study Orphan Diseases: Muscular Dystrophies

• Authors: Guangbin Xia, N. Terada, T. Ashizawa
• Year: 2018
• Venue: Current Stem Cell Reports
• URL: https://www.semanticscholar.org/paper/94a0f0ec0fcc7956f4f564ed7b9052cad3b908ce
• DOI: 10.1007/s40778-018-0145-5
• PMID: 30524939
• PMCID: 6244555
• Citations: 13
• Summary: Current applications of iPSC as disease models of MDs for studies of pathogenic mechanisms and therapeutic development and high-throughput screening using disease-specific human iPSCs has become a powerful technology in drug discovery.
• Evidence snippets:
• Snippet 1 (score: 0.515) > In genotype-phenotype correlations in MDs, we should note two types of heterogeneities: (1) the same pattern of muscular dystrophies can be caused by mutations in different genes and (2) the different mutations in the same gene may cause different patterns of muscular dystrophy. In terms of pathogenic mechanism, myotonic dystrophy type 1 (DM1) and type 2 (DM2) and oculopharyngeal muscular dystrophy (OPMD) belong to a distinct group of muscular dystrophy caused by RNA gain-of-function from trinucleotide repeat expansion [2][3][4][7][8][9][10], while facioscapulohumeral muscular dystrophy (FSHD) is caused by the contraction of microsatellite D4Z4 repeats [11], and the remaining MDs are caused by point mutations, deletions, duplications, and inversions [6]. Patents with MDs are often succumbed to a long arduous clinical course of progressive muscle weakness and wasting often resulting in significant disability and various complications. There is currently no cure for MDs, and available treatments are supportive care or of limited efficacy. Appropriate disease models are important for elucidation of disease mechanism and identification of treatment target.

[13] The FSHD jigsaw: are we placing the tiles in the right position?

• Authors: Valentina Salsi, G. Vattemi, R. Tupler
• Year: 2023
• Venue: Current Opinion in Neurology
• URL: https://www.semanticscholar.org/paper/7a8931a1a0f0ce046716d159fe70a749fc6ef3c8
• DOI: 10.1097/WCO.0000000000001176
• PMID: 37338810
• PMCID: 10487374
• Citations: 12
• Summary: The main objectives of the scientific community on Facioscapulohumeral muscular dystrophy were summarized and the moving trajectories of research from the past to the present were summarized.
• Evidence snippets:
• Snippet 1 (score: 0.515) > Purpose of review Facioscapulohumeral muscular dystrophy (FSHD) is one of the most common myopathies, involving over 870,000 people worldwide and over 20 FSHD national registries. Our purpose was to summarize the main objectives of the scientific community on this topic and the moving trajectories of research from the past to the present. Recent findings To date, research is mainly oriented toward deciphering the molecular and pathogenetic basis of the disease by investigating DUX4-mediated muscle alterations. Accordingly, FSHD drug development has been escalating in the last years in an attempt to silence DUX4 or to block its downstream effectors. Breakthroughs in the field include the awareness that new biomarkers and outcome measures are required for tracking disease progression and patient stratification. The need to develop personalized therapeutic strategies is also crucial according to the phenotypic variability observed in FSHD subjects. Summary We analysed 121 literature reports published between 2021 and 2023 to assess the most recent advances in FSHD clinical and molecular research.

[14] Current Genetic Survey and Potential Gene-Targeting Therapeutics for Neuromuscular Diseases

• Authors: W. Chiu, Ya-Hsin Hsun, Kao-Jung Chang, A. Yarmishyn, Yu-Jer Hsiao et al.
• Year: 2020
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/421f0212b8e3f567e050b3191da99fe550b243a8
• DOI: 10.3390/ijms21249589
• PMID: 33339321
• PMCID: 7767109
• Citations: 14
• Summary: The current development of gene therapy is reviewed and focus on NMDs that are available in published reports, including Duchenne Muscular Dystrophy, Becker muscular dystrophy (BMD), X-linked myotubular myopathy (XLMTM), Spinal Muscular Atrophy (SMA), and Limb-girdle muscular dystrophies Type 2C (LGMD2C).
• Evidence snippets:
• Snippet 1 (score: 0.515) > Facioscapulohumeral Muscular Dystrophy (FSHD) is one of the most common muscular dystrophies with a prevalence ranging between 2.03 and 6.8 per 100,000 persons [95]. The disease onset typically occurs in the twenties but is also detected at other ages. The muscle weakness deteriorates as the onset persists in a classic pattern: first, the facial and shoulder girdle muscles are affected, then the lower extremities, both distal and proximal. Variations in the age of onset, disease pattern, disease progression, and severity of muscle weakness among FSHD individuals results in disease severity ranging from mildly affected/asymptomatic to wheelchair-bound (20% of FSDH patients) [96,97]. Extramuscular manifestations include hearing loss [98,99] and loss of vision resulting from retinal vascular abnormalities [100,101], exudative retinopathy, and Coat's syndrome [102]. > Autosomal dominant FSHD is caused by the derepression of DUX4, a transcriptional regulator, whose target genes are toxic to skeletal muscle [103][104][105]. Unlike DMD, which is caused by mutations in the coding region of a single gene, FSHD requires mixed aberrations of genetic and epigenetic nature to result in DUX4 derepression and cause clinical symptoms. DUX4 is located on D4Z4 macrosatellite repeat array on chromosome 4q35 with each D4Z4 repeat (3.3 kb) including a DUX4 gene, and it is expressed in germline cells but silenced in somatic tissues [103,106]. The silencing can be reversed as a result of DNA hypomethylation and consequent opening of the chromatin structure by the following two mechanisms. In facioscapulohumeral muscular dystrophy type 1 (FSHD1) accounting for 95% of cases, an internal contraction of D4Z4 repeats occurs, leading to a reduced number of repeats, 1 to 10 repeat units, while the unaffected individuals contain 11 to 100 D4Z4 units [106,107].

[15] A pediatric case report and literature review of facioscapulohumeral muscular dystrophy type1

• Authors: Ting Xiao, Haiyang Yang, Siyi Gan, Liwen Wu
• Year: 2021
• Venue: Medicine
• URL: https://www.semanticscholar.org/paper/d39bf2d0a9f15060d81e0f8a73cc4ca3e15083c8
• DOI: 10.1097/MD.0000000000027907
• PMID: 34964760
• PMCID: 8615324
• Citations: 6
• Summary: The clinical characteristics of 2 patients with early-onset facial and shoulder brachial muscular dystrophy are reported to improve clinicians’ understanding of this particular condition and identify early identification and genetic diagnosis to improve patient prognosis.
• Evidence snippets:
• Snippet 1 (score: 0.514) > Facioscapulohumeral muscular dystrophy (FSHD) is a slowly progressive muscular dystrophy. Currently, there are 2 genetically distinct types of FSHD, FSHD1, and FSHD2. [5] Facioscapulohumeral muscular dystrophy type 1 (FSHD1, OMIM: 158900) is an autosomal dominant genetic disease in which integral copies of the 3.3 kb tandem repeat unit D4Z4 are deleted in the subtelomere region of chromosome 4q35.41. [8] Some studies have shown that there is a negative correlation between the number of D4Z4 repetitions and the severity of FSHD. Therefore, studies have shown that very short alleles (1-3 D4Z4 repeats) are related to the most severe form of the disease. [7,8] The D4Z4 repeat sequence contains the DUX4 gene, which is abnormally expressed in skeletal muscle cells of FSHD patients. The abnormal expression of DUX4 leads to dysregulation of molecular pathways that are involved in muscle differentiation, oxidative stress responses, immune responses, and protein turnover. However, the precise mechanism leading to FSHD is still unknown. [3,9,10] acioscapulohumeral muscular dystrophy type 2 (FSHD2, OMIM: 158901) is associated with mutations of the structural maintenance of the chromosome flexible hinge domain-containing protein 1 [11] (SMCHD1) gene on chromosome 18p1143 or the DNA methyltransferase 3B [12] (DNMT3B) gene on chromosome 20q11 in the presence of a disease-permissive 4qA haplotype. Both types of mutations are associated with insufficient epigenetic repression of D4Z4 repeats, leading to aberrant expression of double homeobox protein 4 (DUX4) in skeletal muscles and consequently, disease progression. FSHD2 can present with autosomal dominant or recessive inheritance. [3,5]

[16] Cellular Stress in the Pathogenesis of Muscular Disorders—From Cause to Consequence

• Authors: Alexander Mensch, S. Zierz
• Year: 2020
• Venue: International Journal of Molecular Sciences
• URL: https://www.semanticscholar.org/paper/22b8c2f84f84b8479f611e296ca9b32813c3bf6c
• DOI: 10.3390/ijms21165830
• PMID: 32823799
• PMCID: 7461575
• Citations: 15
• Summary: This review aimed to summarize the available evidence regarding a deregulation of the cellular stress response in individual muscle diseases and relevant therapeutic approaches that aim to abrogate defects of cellular Stress response in muscular disorders are outlined.
• Evidence snippets:
• Snippet 1 (score: 0.513) > Muscular dystrophies are a phenotypically and genotypically heterogeneous group of inherited muscular disorders that share common histopathologic features, including degeneration/necrosis, regeneration, and endo-and perimysial fibrosis, as well as increased adipose tissue [121]. Causative gene mutations leading to individual muscular dystrophies reflect a broad spectrum of cellular functions, including extracellular matrix proteins, members of the dystrophin-glycoprotein complex, nuclear envelope proteins, and mitochondrial membrane proteins, amongst others [122]. Beside the pathogenetic consequences arising from individual gene mutations, additional aggrieving mechanisms have been identified that are not causally related to the gene product primarily affected in the individual muscular dystrophy. In this regard, ER-stress has been identified as a relevant source of muscular damage in several muscular dystrophies. The individual muscular dystrophies that show a deregulated ER-stress response/UPR can be found in Table 1. As for the underlying cause of ER-stress in muscular dystrophies, there has been a variety of suggestions. Hypotheses discussed include accumulation of misfolded protein due to the respective mutation in structural proteins and altered protein folding capacity because of oxidative stress and ROS production, as well as changes in calcium homeostasis. However, specific experimental evidence is missing to a great extent [13,17]. > Dystrophinopathies are the most prevalent forms of muscular dystrophies. While Duchenne muscular dystrophy (DMD) is a devastating muscle disease leading to rapid progression of muscular weakness, early loss of ambulation and premature death, Becker muscular dystrophy (BMD) usually shows a milder phenotype. The causative DMD gene encodes for the dystrophin protein, a core component of the dystrophin-glycoprotein complex that connects the muscle cell to the extracellular matrix [123]. Due to its prone function in muscle cell structure, the primary pathogenetic mechanism appears to be a disintegration of muscle cell organization and reduced resistance to mechanical stress.

[17] Serum miRNAs as biomarkers for the rare types of muscular dystrophy.

• Authors: A. Koutsoulidou, Demetris Koutalianos, K. Georgiou, Andrea C. Kakouri, A. Oulas et al.
• Year: 2022
• Venue: Neuromuscular disorders : NMD
• URL: https://www.semanticscholar.org/paper/66fe911cc2daff3c136f30d6771b2ec4807cfed9
• DOI: 10.1016/j.nmd.2022.03.003
• PMID: 35393236
• Citations: 11
• Influential citations: 2
• Summary: New evidence is provided that certain circulating miRNAs may be used as biomarkers for three types of rare muscular dystrophies, as well as identifying manymiRNAs that associate with muscular dystrophy patients compared to controls.
• Evidence snippets:
• Snippet 1 (score: 0.511) > Muscular dystrophies are a group of disorders which share similar clinical and pathological characteristics including progressive weakness, wasting and degeneration [1] . More than 50 distinct types of muscular dystrophies were identified which are caused by different mutations in various genes ascribing for the phenotype of each muscular dystrophy [2] . Several clinical phenotypes characterize each type of muscular dystrophy, including the groups of primarily affected muscles, the degree of weakness, the time of onset and the rate of progression. Currently, there is an increasing interest for the development of biomarkers for this family of disorders either for monitoring the disease progress or the response to new therapeutic interventions. In particular, emphasis has been placed on the research for identifying biomarkers for Duchene Muscular Dystrophy (DMD) which is the most common childhood onset muscular dystrophy with very severe symptoms in the affected boys [3][4][5][6] . A large number of circulating miRNAs and protein biomarkers have been identified for DMD, some of which were correlated to the disease severity and clinical assessments of the patients, suggesting that they can be used as monitoring biomarkers for the disorder [7][8][9][10][11] . Furthermore, miRNAs have been suggested as potential biomarkers for Myotonic Dystrophy type 1 (DM1), the most common muscular dystrophy in adults [12][13][14][15] . Importantly, four musclespecific miRNAs, miR-1, miR-133a, miR-133b and miR-206, were found to be correlated with muscle wasting in DM1 patients and were therefore suggested as monitoring biomarkers for the disease progression [ 12 , 13 ]. Regarding the other types of muscular dystrophies, very limited information exists for the presence of circulating biomarkers, especially for the rare types of muscular dystrophies such as Facioscapulohumeral muscular dystrophy (FSHD), Limb-Girdle Muscular dystrophy (LGMD) and Myotonic Dystrophy type 2 (DM2). > FSHD is

[18] Identification of hub genes related to Duchenne muscular dystrophy by weighted gene co-expression network analysis

• Authors: Yan-li Wei, Qisheng Su, Xiao-Hua Li
• Year: 2022
• Venue: Medicine
• URL: https://www.semanticscholar.org/paper/270eedbe2a86196967455d575878a3326f57e676
• DOI: 10.1097/MD.0000000000032603
• PMID: 36596079
• PMCID: 9803489
• Citations: 4
• Summary: SerPING1, F13A1, C1S, C 1R, and HLA-DPA1 may participate in the development of DMD by regulating innate immunity and inflammation, and they are expected to be a potential biomarker and novel therapeutic targets for DMD.
• Evidence snippets:
• Snippet 1 (score: 0.510) > Muscular dystrophy (MD) is a genetic disorder in which genetic abnormalities lead to abnormalities in a group of proteins that maintain stability of skeletal muscle cell structure and function. Chronic and progressive muscle weakness or muscle atrophy is the main clinical manifestation of MD. Common muscular dystrophy are Duchenne muscular dystrophy (DMD), Bekerer muscular dystrophy (BMD), myotonic muscular dystrophy (MD), congenital muscular dystrophy (CMD), limb girdle type Muscular dystrophy (LGMD), facial scapulohumeral muscular dystrophy (FSMD), distal muscular dystrophy, ophthalmopharyngeal muscular dystrophy (OPMD), Emery-Dreifuss muscular dystrophy (EDMD), etc. Among them, DMD is an X-recessive genetic disease caused by mutations in the anti-atropin gene. It is the most common type of progressive muscular dystrophy and the most severe type in childhood. [1] Most of the patients with DMD were found to have disease at the age of 3 to 5 years, often accompanied by delayed motor development, progressive skeletal muscle atrophy, scoliosis, joint spasm, respiratory muscle weakness, and dilated heart disease. Most patients with DMD died of respiratory failure and heart failure around the age of 20. [2,3] At present, there are a lot of studies on DMD. Gene substitution with adenovirus and CRISPR gene editing are considered as potential therapeutic methods for DMD. [4] Some targets have been found to delay the development of DMD. p. 5] Although great progress has been made in the treatment of DMD, there is still much room for exploration. [7] We believe that exploring the molecular and mechanism involved in the occurrence and development of DMD may help to find new therapeutic targets for DMD, and may provide help for the treatment of DMD. > Weighted gene co-expression network analysis (WGCNA) is 1 way to identify gene modules and key genes related to phenotypic traits. [8]

[19] Immunohistochemical Characterization of FacioscapulohumeralMuscular Dystrophy Muscle Biopsies

• Authors: J. Statland, K. Odrzywolski, Bharati Shah, D. Henderson, A. Fricke et al.
• Year: 2015
• Venue: Journal of Neuromuscular Diseases
• URL: https://www.semanticscholar.org/paper/1783c8861ca01161de60ef8ace8851890ba7c39c
• DOI: 10.3233/JND-150077
• PMID: 26345300
• PMCID: 4560242
• Citations: 28
• Influential citations: 1
• Summary: Preliminary evidence for increased apoptosis rates and reduced capillary density may reflect histopathological correlates of disease activity in FSHD.
• Evidence snippets:
• Snippet 1 (score: 0.509) > Facioscapulohumeral Muscular Dystrophy (FSHD) is one of the most common progressive muscular dystrophies (prevalence 1:15000) [1,2]. Recent studies have suggested that both Facioscapulohumeral muscular dystrophy (FSHD) types 1 and 2 operate through a common downstream genetic mechanism of de-repression of a retrogene DUX4, not normally expressed in somatic muscle tissue [3,4]. Gene expression profiling from FSHD muscle has shown altered regulation of large number of genes associated with myogenesis, increased susceptibility to oxidative stress, angiogenensis, vascular smooth muscle or endothelial cells, muscle isoenzymes, cholesterol metabolism, and the actin cytoskeleton [5][6][7][8]. Expression of DUX4 in vitro inhibits myogenesis, increases oxidative stress in myogenic precursors, and induces apoptosis [9][10][11]. DUX4 is a transcription factor normally expressed in the luminal cells of the testis, which activates genes involved in the germline and early stem cell development [12]. One line of thinking posits induction of a mitotic program in a post-mitotic cell results in apoptosis. Another line of thinking proposes DUX4 may affect satellite cell renewal. The muscle immunohistochemical correlates to these posited pathological mechanisms are unknown. A better understanding of the muscle pathology in FSHD can be important in two ways: 1) providing insights into the patho-mechanism in FSHD, and 2) providing potential biomarkers for proof of concept or early phase clinical studies. > Here we perform a retrospective cross-sectional histopathological study in genetically confirmed FSHD muscle biopsies. We quantify the apoptotic rates, satellite cell counts, and nuclear and capillary density and compare to healthy volunteers (CON) and myotonic dystrophy type 1 (DM1) as a disease control.

[20] LGMD phenotype due to a new gene and dysferlinopathy investigated by next-generation sequencing

• Authors: C. Angelini
• Year: 2015
• Venue: Neurology: Genetics
• URL: https://www.semanticscholar.org/paper/2c55b9718099ba1a33fa6f6ea43815046be1c557
• DOI: 10.1212/NXG.0000000000000039
• PMID: 27066575
• PMCID: 4811386
• Citations: 5
• Summary: 3 cases of limb-girdle muscular dystrophy phenotype with mental retardation or hyperCKemia found by next-generation sequencing (NGS) to have a variant in the POMGNT2 gene, which has so far been recognized only as causing congenital muscular Dystrophy (CMD).
• Evidence snippets:
• Snippet 1 (score: 0.501) > The progression of muscle weakness is usually symmetrical and variable among individuals and genetic type. The term LGMD, used to molecularly classify the disease, is, however, inappropriate for many patients when it is used to describe the clinical severity. Indeed, these disorders present a wide spectrum of muscle involvement and wasting, spanning from very severe forms, such as those with childhood onset and rapid progression, to relatively benign forms with late onset. > The clinical phenotypes due to mutation in the LGMD genes include severe childhood-onset forms, distal and proximal myopathies, pseudometabolic myopathies, eosinophilic myositis, and hyperCKemia. Furthermore, patients with a clinically typical LGMD phenotype might carry mutations in the gene encoding emerin, which usually cause Emery-Dreifuss muscular dystrophy (EDMD) phenotype. Because there is a spectrum of phenotypes under the same genetic entity and a wide genetic heterogeneity under the same phenotype, it is crucial to identify suitable selection criteria to be used when screening patients for the proteins and genes responsible for LGMD. > As LGMD is relatively rare in most populations, other more likely diagnoses need to be excluded. Among these, dystrophinopathies (Duchenne dystrophy, Becker dystrophy, and female carriers of Duchenne dystrophy) are the most relevant, and these diagnoses can be ruled out based on dystrophin protein testing and/or DNA mutation analysis in the dystrophin gene. Another diagnosis that can usually be resolved by DNA analysis is facioscapulohumeral muscular dystrophy (FSHD): about 8% of patients with a diagnosis of LGMD may actually have FSHD, and the misdiagnosis can occur in families with autosomal dominant inheritance, especially when both pelvic and shoulder girdles are involved and facial weakness is minimal. Molecular investigation to exclude FSHD is worthwhile, especially in patients with a positive family history.

Notes

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