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Muscle & Nerve May 2013Duchenne muscular dystrophy (DMD) is a devastating muscle disorder that affects 1 in 3,500 boys. Despite years of research and considerable progress in understanding the... (Review)
Review
Duchenne muscular dystrophy (DMD) is a devastating muscle disorder that affects 1 in 3,500 boys. Despite years of research and considerable progress in understanding the molecular mechanism of the disease and advancement of therapeutic approaches, there is no cure for DMD. The current treatment options are limited to physiotherapy and corticosteroids, and although they provide a substantial improvement in affected children, they only slow the course of the disorder. On a more optimistic note, more recent approaches either significantly alleviate or eliminate muscular dystrophy in murine and canine models of DMD and importantly, many of them are being tested in early phase human clinical trials. This review summarizes advancements that have been made in viral and nonviral gene therapy as well as stem cell therapy for DMD with a focus on the replacement and repair of the affected dystrophin gene.
Topics: Genetic Therapy; Humans; Muscular Dystrophies; Stem Cell Transplantation
PubMed: 23553671
DOI: 10.1002/mus.23738 -
Current Opinion in Neurology Oct 2018Muscle and bone are intrinsically linked, and therefore, it is not surprising that many muscular dystrophies are associated with impaired bone health and increased risk... (Review)
Review
PURPOSE OF REVIEW
Muscle and bone are intrinsically linked, and therefore, it is not surprising that many muscular dystrophies are associated with impaired bone health and increased risk of osteoporosis. Osteoporotic fracture is an important and preventable cause of morbidity and mortality. This article will firstly review the general causes of impaired bone health in muscular dystrophies and then focus on the evidence available for the diagnosis and treatment of osteoporosis in specific conditions.
RECENT FINDINGS
With the exception of DMD, there is a paucity of data regarding bone health in muscular dystrophies. However, it appears that in common with all types of muscular dystrophies that cause a significant level of muscle weakness and disability there is an increased risk of falls, fractures and decreased vitamin D levels. A better understanding of the extent of the impaired bone health and underlying causes could help to identify potential new therapeutic agents and aid clinical care.
SUMMARY
It would be prudent for clinicians to assess fracture risk in their muscular dystrophy patients and if appropriate, arrange surveillance and recommend vitamin D supplementation. Additionally, fracture should be considered in any patient presenting with new-onset bone pain.
Topics: Bone Diseases; Bone and Bones; Humans; Muscular Dystrophies; Osteoporotic Fractures; Risk Assessment
PubMed: 30080716
DOI: 10.1097/WCO.0000000000000603 -
Journal of Medical Genetics Oct 1989Emery-Dreifuss muscular dystrophy is characterised by the triad of (1) early contractures of the elbows, Achilles tendons, and postcervical muscles; (2) slowly... (Review)
Review
Emery-Dreifuss muscular dystrophy is characterised by the triad of (1) early contractures of the elbows, Achilles tendons, and postcervical muscles; (2) slowly progressive muscle wasting and weakness with a humeroperoneal distribution in the early stages; and (3) a cardiomyopathy usually presenting as heart block. The early recognition of the condition is essential because the insertion of a cardiac pacemaker can be life saving. The disorder is usually inherited as an X linked recessive trait (linked to DNA markers around Xq28). However, occasionally it can be inherited as an autosomal dominant trait and there is an indication that this and the X linked form may in some cases have a neurogenic basis. For these reasons it has recently been proposed that the appellation 'Emery-Dreifuss syndrome' be used for this triad of symptoms and signs.
Topics: Cardiomyopathies; Diagnosis, Differential; Genes, Dominant; Genetic Linkage; Humans; Male; Muscular Dystrophies; Prognosis; Syndrome; X Chromosome
PubMed: 2685312
DOI: 10.1136/jmg.26.10.637 -
Matrix Biology : Journal of the... Aug 2018The production of force and power are inherent properties of skeletal muscle, and regulated by contractile proteins within muscle fibers. However, skeletal muscle... (Review)
Review
The production of force and power are inherent properties of skeletal muscle, and regulated by contractile proteins within muscle fibers. However, skeletal muscle integrity and function also require strong connections between muscle fibers and their extracellular matrix (ECM). A well-organized and pliant ECM is integral to muscle function and the ability for many different cell populations to efficiently migrate through ECM is critical during growth and regeneration. For many neuromuscular diseases, genetic mutations cause disruption of these cytoskeletal-ECM connections, resulting in muscle fragility and chronic injury. Ultimately, these changes shift the balance from myogenic pathways toward fibrogenic pathways, culminating in the loss of muscle fibers and their replacement with fatty-fibrotic matrix. Hence a common pathological hallmark of muscular dystrophy is prominent fibrosis. This review will cover the salient features of muscular dystrophy pathogenesis, highlight the signals and cells that are important for myogenic and fibrogenic actions, and discuss how fibrosis alters the ECM of skeletal muscle, and the consequences of fibrosis in developing therapies.
Topics: Animals; Clinical Trials as Topic; Extracellular Matrix; Fibrosis; Humans; Muscle, Skeletal; Muscular Dystrophies; Signal Transduction
PubMed: 29408413
DOI: 10.1016/j.matbio.2018.01.014 -
Brain Pathology (Zurich, Switzerland) Apr 2001The muscular dystrophies are characterised by progressive muscle weakness and wasting. Pathologically the hallmarks are muscle fibre degeneration and fibrosis. Several... (Review)
Review
The muscular dystrophies are characterised by progressive muscle weakness and wasting. Pathologically the hallmarks are muscle fibre degeneration and fibrosis. Several recessive forms of muscular dystrophy are caused by defects in proteins localised to the sarcolemma. However, it is now apparent that others are due to defects in a wide range of proteins including those which are either nuclear-related (Emery-Dreifuss type muscular dystrophies, oculopharyngeal muscular dystrophy), enzymatic (limb-girdle muscular dystrophy 2A, myotonic dystrophy) or sarcomeric (limb-girdle muscular dystrophies 1A and 2G). Although the clinical and molecular basis of these disorders is heterogeneous all display myopathic morphological features. These include variation in fibre size, an increase in internal nuclei, and some myofibrillar distortion. Degeneration and fibrosis occur, but usually not to the same extent as in muscular dystrophies associated with sarcolemmal protein defects. This review outlines the genetic basis of these "non-sarcolemmal" forms of dystrophy and discusses current ideas on their pathogenesis.
Topics: Enzymes; Humans; Muscle Proteins; Muscle, Skeletal; Muscular Dystrophies; Sarcolemma
PubMed: 11303795
DOI: 10.1111/j.1750-3639.2001.tb00392.x -
The FEBS Journal Sep 2013Cells encounter many physical, chemical and biological stresses that perturb plasma membrane integrity, warranting an immediate membrane repair response to regain cell... (Review)
Review
Cells encounter many physical, chemical and biological stresses that perturb plasma membrane integrity, warranting an immediate membrane repair response to regain cell homeostasis. Failure to respond properly to such perturbation leads to individual cell death, which may also produce systemic influence by triggering sterile immunological responses. In this review, we discuss recent progress on understanding the mechanisms underlying muscle cell membrane repair and the potential mediators of innate immune activation when the membrane repair system is defective, specifically focusing on pathology associated with dysferlin deficiency.
Topics: Animals; Cell Membrane; Dysferlin; Immunity, Innate; Membrane Proteins; Mice; Mice, Knockout; Muscle, Skeletal; Muscular Dystrophies
PubMed: 23527661
DOI: 10.1111/febs.12261 -
Methods in Molecular Biology (Clifton,... 2023In vivo testing of glucocorticoid steroids in dystrophic mice offers important insights in benefits and risks of those drugs in the pathological context of muscular...
In vivo testing of glucocorticoid steroids in dystrophic mice offers important insights in benefits and risks of those drugs in the pathological context of muscular dystrophy. Frequency of dosing changes the spectrum of glucocorticoid effects on muscle and metabolic homeostasis. Here, we describe a combination of non-invasive and invasive methods to quantitatively discriminate the specific effects of intermittent (once-weekly) versus mainstay (once-daily) regimens on muscle fibrosis, muscle function, and metabolic homeostasis in murine models of Duchenne and limb-girdle muscular dystrophies.
Topics: Mice; Animals; Glucocorticoids; Disease Models, Animal; Muscle, Skeletal; Muscular Dystrophy, Duchenne; Muscular Dystrophies, Limb-Girdle
PubMed: 36401044
DOI: 10.1007/978-1-0716-2772-3_24 -
Neuroscience Letters Oct 2012Our Translational Gene Therapy Center has used small molecules for exon skipping and mutation suppression and gene transfer to replace or provide surrogate genes as... (Review)
Review
Our Translational Gene Therapy Center has used small molecules for exon skipping and mutation suppression and gene transfer to replace or provide surrogate genes as tools for molecular-based approaches for the treatment of muscular dystrophies. Exon skipping is targeted at the pre-mRNA level allowing one or more exons to be omitted to restore the reading frame. In Duchenne Muscular Dystrophy (DMD), clinical trials have been performed with two different oligomers, a 2'O-methyl-ribo-oligonucleoside-phosphorothioate (2'OMe) and a phosphorodiamidate morpholino (PMO). Both have demonstrated early evidence of efficacy. A second molecular approach involves suppression of stop codons to promote readthrough of the DMD gene. We have been able to establish proof of principle for mutation suppression using the aminoglycoside, gentamicin. A safer, orally administered, alternative agent referred to as Ataluren (PTC124) has been used in clinical trials and is currently under consideration for approval by the FDA. Using a gene therapy approach, we have completed two trials and have initiated a third. For DMD, we used a mini-dystrophin transferred in adeno-associated virus (AAV). In this trial an immune response was seen directed against transgene product, a quite unexpected outcome that will help guide further studies. For limb girdle muscular dystrophy 2D (alpha-sarcoglycan deficiency), the transgene was again transferred using AAV but in this study, a muscle specific creatine kinase promoter controlled gene expression that persisted for six months. A third gene therapy trial has been initiated with transfer of the follistatin gene in AAV directly to the quadriceps muscle. Two diseases with selective quadriceps muscle weakness are undergoing gene transfer including sporadic inclusion body myositis (sIBM) and Becker muscular dystrophy (BMD). Increasing the size and strength of the muscle is the goal of this study. Most importantly, no adverse events have been encountered in any of these clinical trials.
Topics: Clinical Trials as Topic; Codon, Terminator; Creatine Kinase; Dependovirus; Dystrophin; Exons; Follistatin; Genetic Therapy; Genetic Vectors; Humans; Muscular Dystrophies; Muscular Dystrophy, Duchenne; Mutation; Myositis, Inclusion Body; Oxadiazoles; Promoter Regions, Genetic; RNA Precursors; Sarcoglycans
PubMed: 22609847
DOI: 10.1016/j.neulet.2012.04.078 -
International Journal of Experimental... Dec 2014There are over 30 mouse models with mutations or inactivations in the dystrophin-associated protein complex. This complex is thought to play a crucial role in the... (Review)
Review
There are over 30 mouse models with mutations or inactivations in the dystrophin-associated protein complex. This complex is thought to play a crucial role in the functioning of muscle, as both a shock absorber and signalling centre, although its role in the pathogenesis of muscular dystrophy is not fully understood. The first mouse model of muscular dystrophy to be identified with a mutation in a component of the dystrophin-associated complex (dystrophin) was the mdx mouse in 1984. Here, we evaluate the key characteristics of the mdx in comparison with other mouse mutants with inactivations in DAPC components, along with key modifiers of the disease phenotype. By discussing the differences between the individual phenotypes, we show that the functioning of the DAPC and consequently its role in the pathogenesis is more complicated than perhaps currently appreciated.
Topics: Animals; Disease Models, Animal; Dystroglycans; Dystrophin; Humans; Mice, Inbred mdx; Mice, Knockout; Multiprotein Complexes; Muscular Dystrophies
PubMed: 25270874
DOI: 10.1111/iep.12095 -
Journal of Neuromuscular Diseases 2023Neuromuscular disease (NMD) research is experiencing tremendous growth as a result of progress in diagnostics and therapeutics yet there continues to be a significant...
BACKGROUND
Neuromuscular disease (NMD) research is experiencing tremendous growth as a result of progress in diagnostics and therapeutics yet there continues to be a significant clinical data shortage for these rare diseases. To maximize the development and impact of new therapies, the Muscular Dystrophy Association (MDA) created the neuroMuscular ObserVational Research Data Hub (MOVR) as an observational research study that collects disease-specific measures from individuals living with NMDs in the United States.
OBJECTIVE
This manuscript provides a description of MOVR, participants enrolled in MOVR, and longitudinal data availability.
METHODS
MOVR collects longitudinal data from individuals diagnosed with ALS, BMD, DMD, FSHD, LGMD, Pompe disease, or SMA, and who are seen for care at a participating MDA Care Center. Data are entered from medical records into standardized electronic case report forms (eCRFs). These eCRFs capture participants' demographics, diagnostic journeys, clinical visits, and discontinuation from the study.
RESULTS
From January 2019 to May 2022, MOVR collected data from 50 participating care centers and 1,957 participants. Data from 1,923 participants who participated in MDA's pilot registry were migrated into MOVR, creating a total of 3,880 participants in MOVR. Initial analysis of aggregated data demonstrated that 91% of eCRFs were complete. Forty-three percent of participants had 3 or more encounters and 50% of all encounters were 5 months or less from the previous encounter.
DISCUSSION
As a centralized data hub for multiple NMDs, MOVR serves as a platform that can be used to inform disease understanding, guide clinical trial design, and accelerate drug development for NMDs.
Topics: Humans; Muscular Dystrophies; Neuromuscular Diseases; Rare Diseases; Glycogen Storage Disease Type II; Registries
PubMed: 36911943
DOI: 10.3233/JND-221551