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European Heart Journal Dec 2023
Topics: Humans; Muscular Dystrophy, Emery-Dreifuss; Heart Diseases; Arrhythmias, Cardiac; Heart Failure
PubMed: 37941127
DOI: 10.1093/eurheartj/ehad735 -
Current Opinion in Pharmacology Jun 2024Sarcoglycanopathies are rare autosomal recessive diseases belonging to the family of limb-girdle muscular dystrophies. They are caused by mutations in the genes coding... (Review)
Review
Sarcoglycanopathies are rare autosomal recessive diseases belonging to the family of limb-girdle muscular dystrophies. They are caused by mutations in the genes coding for α-, β-, γ-, and δ-sarcoglycan. The mutations impair the assembly of a key structural complex, which normally protects the sarcolemma of striated muscle from contraction-derived stress. Although heterogeneous, sarcoglycanopathies are characterized by progressive muscle degeneration, increased serum creatine kinase levels, loss of ambulation often during adolescence, and variable cardio-respiratory impairment. Genetic defects can impair sarcoglycan synthesis or produce a protein that is defective in folding. There is currently no effective treatment available; however, both gene replacement strategy and small molecule-based approaches show great promise and have entered or are starting to enter clinical trials.
Topics: Humans; Sarcoglycanopathies; Animals; Sarcoglycans; Genetic Therapy; Mutation
PubMed: 38713975
DOI: 10.1016/j.coph.2024.102459 -
Muscle & Nerve Mar 2024Anecdotally, patients with facioscapulohumeral muscular dystrophy (FSHD) describe gastrointestinal (GI) and genitourinary (GU) symptoms. We explored the prevalence of GI...
INTRODUCTION/AIMS
Anecdotally, patients with facioscapulohumeral muscular dystrophy (FSHD) describe gastrointestinal (GI) and genitourinary (GU) symptoms. We explored the prevalence of GI and GU symptoms and their impact on quality of life (QOL) in people with FSHD compared to healthy household controls.
METHODS
In this descriptive, cross-sectional study, we emailed a survey exploring GI and GU symptoms to all FSHD Society patient contacts (n = 3507). We invited those with FSHD and unaffected household controls to respond. Non-parametric statistics were used to compare symptom frequency and impact of symptoms between respondents with FSHD and household controls. Within the FSHD group, symptom frequency was assessed relative to measures of disease progression (need for ambulatory or respiratory support).
RESULTS
Surveys from 701 respondents (652 with FSHD) ≥18 years old were included in analysis. Those with FSHD had symptoms affecting both GI and GU systems more frequently than controls using ordinal rating of symptom frequency. Within the FSHD group, more advanced disease was associated with increased symptom frequency. QOL was negatively impacted by the GI and GU symptoms. There was no difference between groups in use of medications to treat these symptoms.
DISCUSSION
Recognition and treatment of GI and GU symptoms in people with FSHD, particularly those with more advanced disease, could improve QOL. Additional investigation is required to confirm these findings and understand the physiology.
Topics: Humans; Adolescent; Muscular Dystrophy, Facioscapulohumeral; Quality of Life; Cross-Sectional Studies; Prevalence; Surveys and Questionnaires
PubMed: 38158588
DOI: 10.1002/mus.28028 -
Scientific Reports Jun 2024Muscular dystrophy is a group of genetic disorders that lead to muscle wasting and loss of muscle function. Identifying genetic modifiers that alleviate symptoms or...
Muscular dystrophy is a group of genetic disorders that lead to muscle wasting and loss of muscle function. Identifying genetic modifiers that alleviate symptoms or enhance the severity of a primary disease helps to understand mechanisms behind disease pathology and facilitates discovery of molecular targets for therapy. Several muscular dystrophies are caused by genetic defects in the components of the dystrophin-glycoprotein adhesion complex (DGC). Thrombospondin-4 overexpression has been shown to mitigate dystrophic disease in mouse models for Duchenne muscular dystrophy (dystrophin deficiency) and limb-girdle muscular dystrophy type 2F (LGMD2F, δ-sarcoglycan deficiency), while deletion of the thrombospondin-4 gene exacerbated the diseases. Hence, thrombospondin-4 has been considered a candidate molecule for therapy of muscular dystrophies involving the DGC. We have investigated whether thrombospondin-4 could act as a genetic modifier for other DGC-associated diseases: limb-girdle muscular dystrophy type 2E (LGMD2E, β-sarcoglycan deficiency) and laminin α2 chain-deficient muscular dystrophy (LAMA2-RD). Deletion of the thrombospondin-4 gene in mouse models for LGMD2E and LAMA2-RD, respectively, did not result in worsening of the dystrophic phenotype. Loss of thrombospondin-4 did not enhance sarcolemma damage and did not impair trafficking of transmembrane receptors integrin α7β1 and dystroglycan in double knockout muscles. Our results suggest that thrombospondin-4 might not be a relevant therapeutic target for all muscular dystrophies involving the DGC. This data also demonstrates that molecular pathology between very similar diseases like LGMD2E and 2F can differ significantly.
Topics: Animals; Laminin; Sarcoglycans; Mice; Thrombospondins; Mice, Knockout; Disease Models, Animal; Muscle, Skeletal; Gene Deletion; Muscular Dystrophies; Muscular Dystrophy, Animal
PubMed: 38926599
DOI: 10.1038/s41598-024-65473-8 -
International Journal of Molecular... May 2024Dysferlin is a large transmembrane protein involved in critical cellular processes including membrane repair and vesicle fusion. Mutations in the dysferlin gene () can... (Review)
Review
Dysferlin is a large transmembrane protein involved in critical cellular processes including membrane repair and vesicle fusion. Mutations in the dysferlin gene () can result in rare forms of muscular dystrophy; Miyoshi myopathy; limb girdle muscular dystrophy type 2B (LGMD2B); and distal myopathy. These conditions are collectively known as dysferlinopathies and are caused by more than 600 mutations that have been identified across the gene to date. In this review, we discuss the key molecular and clinical features of LGMD2B, the causative gene , and the associated dysferlin protein structure. We also provide an update on current approaches to LGMD2B diagnosis and advances in drug development, including splice switching antisense oligonucleotides. We give a brief update on clinical trials involving adeno-associated viral gene therapy and the current progress on CRISPR/Cas9 mediated therapy for LGMD2B, and then conclude by discussing the prospects of antisense oligomer-based intervention to treat selected mutations causing dysferlinopathies.
Topics: Humans; Muscular Dystrophies, Limb-Girdle; Dysferlin; Genetic Therapy; Mutation; Oligonucleotides, Antisense; Animals
PubMed: 38891760
DOI: 10.3390/ijms25115572 -
Stem Cell Reviews and Reports Jan 2024Duchenne Muscular Dystrophy (DMD) is an inherited genetic disorder characterized by progressive degeneration of muscle tissue, leading to functional disability and... (Review)
Review
Duchenne Muscular Dystrophy (DMD) is an inherited genetic disorder characterized by progressive degeneration of muscle tissue, leading to functional disability and premature death. Despite extensive research efforts, the discovery of a cure for DMD continues to be elusive, emphasizing the need to investigate novel treatment approaches. Cellular therapies have emerged as prospective approaches to address the underlying pathophysiology of DMD. This review provides an examination of the present situation regarding cell-based therapies, including CD133 + cells, muscle precursor cells, mesoangioblasts, bone marrow-derived mononuclear cells, mesenchymal stem cells, cardiosphere-derived cells, and dystrophin-expressing chimeric cells. A total of 12 studies were found eligible to be included as they were completed cell therapy clinical trials, clinical applications, or case reports with quantitative results. The evaluation encompassed an examination of limitations and potential advancements in this particular area of research, along with an assessment of the safety and effectiveness of cell-based therapies in the context of DMD. In general, the available data indicates that diverse cell therapy approaches may present a new, safe, and efficacious treatment modality for patients diagnosed with DMD. However, further studies are required to comprehensively understand the most advantageous treatment approach and therapeutic capacity.
Topics: Humans; Muscular Dystrophy, Duchenne; Muscle, Skeletal; Mesenchymal Stem Cells; Treatment Outcome; Cell- and Tissue-Based Therapy
PubMed: 37955832
DOI: 10.1007/s12015-023-10653-8 -
Current Opinion in Neurology Oct 2023Missense mutations in valosin-containing protein (VCP) can lead to a multisystem proteinopathy 1 (MSP1) with any combination of limb-girdle distribution inclusion body... (Review)
Review
PURPOSE OF REVIEW
Missense mutations in valosin-containing protein (VCP) can lead to a multisystem proteinopathy 1 (MSP1) with any combination of limb-girdle distribution inclusion body myopathy (IBM) (present in about 90% of cases), Paget's disease of bone, and frontotemporal dementia (IBMPFD). VCP mutations lead to gain of function activity with widespread disarray in cellular function, with enhanced ATPase activity, increased binding with its cofactors, and reduced mitofusin levels.
RECENT FINDINGS
This review highlights novel therapeutic approaches in VCP-MSP in in-vitro and in-vivo models. Furthermore, we also discuss therapies targeting mitochondrial dysfunction, autophagy, TDP-43 pathways, and gene therapies in other diseases with similar pathway involvement which can also be applicable in VCP-MSP.
SUMMARY
Being a rare disease, it is challenging to perform large-scale randomized control trials (RCTs) in VCP-MSP. However, it is important to recognize potential therapeutic targets, and assess their safety and efficacy in preclinical models, to initiate RCTs for potential therapies in this debilitating disease.
Topics: Humans; Valosin Containing Protein; Frontotemporal Dementia; Genetic Therapy; Muscular Dystrophies, Limb-Girdle
PubMed: 37678339
DOI: 10.1097/WCO.0000000000001184 -
Human Molecular Genetics Jul 2023Limb-girdle muscular dystrophy R7 (LGMDR7) is an autosomal recessive hereditary muscular dystrophy caused by mutations in titin-cap (TCAP). Here, we summarized the...
Limb-girdle muscular dystrophy R7 (LGMDR7) is an autosomal recessive hereditary muscular dystrophy caused by mutations in titin-cap (TCAP). Here, we summarized the clinical characteristics and TCAP mutations in a Chinese cohort of 30 patients with LGMDR7. The onset age of Chinese patients was 19.89 ± 6.70 years old, which is later than European and South Asian patients (P < 0.05). Clinically speaking, 20.0% of patients presented with predominant distal weakness, and 73.3% of patients presented with predominant pelvic girdle weakness. Radiological study revealed semitendinosus and magnus adductor were severely involved in Chinese LGMDR7 patients. Rectus femoris, vastus lateralis, vastus intermedius, soleus and tibialis anterior were moderately to severely involved. The most prevalent mutation in this cohort is c.26_33dupAGGTGTCG, while c.165dupG and c.110 + 5G > A are unique in Chinese population as two of the common mutations. Besides, variant c.26_33dupAGGGTGTCG might be a founder mutation in Asian patients. Internal nuclei, lobulated fibers, and scattered rimmed vacuoles were typical morphological changes in Chinese LGMDR7 patients. This is the largest LGMDR7 cohort in the Chinese population and in the world. This article also expands the clinical, pathological, mutational and radiological spectrum of patients with LGMDR7 in China and in the world.
Topics: Adolescent; Adult; Humans; Young Adult; East Asian People; Muscle, Skeletal; Muscular Dystrophies, Limb-Girdle; Mutation
PubMed: 37216648
DOI: 10.1093/hmg/ddad090 -
Current Topics in Developmental Biology 2024Muscle stem cells (MuSCs) are crucial to the repair and homeostasis of mature skeletal muscle. MuSC dysfunction and dysregulation of the myogenic program can contribute... (Review)
Review
Muscle stem cells (MuSCs) are crucial to the repair and homeostasis of mature skeletal muscle. MuSC dysfunction and dysregulation of the myogenic program can contribute to the development of pathology ranging from cancers like rhabdomyosarcoma (RMS) or muscle degenerative diseases such as Duchenne muscular dystrophy (DMD). Both diseases exhibit dysregulation at nearly all steps of myogenesis. For instance, MuSC self-renewal processes are altered. In RMS, this leads to the creation of tumor propagating cells. In DMD, impaired asymmetric stem cell division creates a bias towards producing self-renewing stem cells instead of committing to differentiation. Hyperproliferation of these cells contribute to tumorigenesis in RMS and symmetric expansion of the self-renewing MuSC population in DMD. Both diseases also exhibit a repression of factors involved in terminal differentiation, halting RMS cells in the proliferative stage and thus driving tumor growth. Conversely, the MuSCs in DMD exhibit impaired differentiation and fuse prematurely, affecting myonuclei maturation and the integrity of the dystrophic muscle fiber. Finally, both disease states cause alterations to the MuSC niche. Various elements of the niche such as inflammatory and migratory signaling that impact MuSC behavior are dysregulated. Here we show how these seemingly distantly related diseases indeed have similarities in MuSC dysfunction, underlying the importance of considering MuSCs when studying the pathophysiology of muscle diseases.
Topics: Rhabdomyosarcoma; Humans; Animals; Muscle, Skeletal; Cell Differentiation; Muscular Dystrophy, Duchenne; Muscle Development; Stem Cells; Muscular Dystrophies
PubMed: 38670717
DOI: 10.1016/bs.ctdb.2024.01.019 -
International Journal of Molecular... Sep 2023Myotonic dystrophy 2 (DM2) is a genetic multi-systemic disease primarily affecting skeletal muscle. It is caused by CCTGn expansion in intron 1 of the gene, which... (Review)
Review
Myotonic dystrophy 2 (DM2) is a genetic multi-systemic disease primarily affecting skeletal muscle. It is caused by CCTGn expansion in intron 1 of the gene, which encodes a zinc finger protein. DM2 disease has been successfully modeled in allowing the identification and validation of new pathogenic mechanisms and potential therapeutic strategies. Here, we describe the principal tools used in to study and dissect molecular pathways related to muscular dystrophies and summarize the main findings in DM2 pathogenesis based on DM2 models. We also illustrate how may be successfully used to generate a tractable animal model to identify novel genes able to affect and/or modify the pathogenic pathway and to discover new potential drugs.
Topics: Animals; Drosophila melanogaster; Myotonic Dystrophy; Drosophila; Introns; Muscle, Skeletal; RNA-Binding Proteins; Drosophila Proteins
PubMed: 37762484
DOI: 10.3390/ijms241814182