Carrier detection and prenatal diagnosis in Duchenne and Becker muscular dystrophy.
Hodgson S V,Bobrow M
British medical bulletin
Estimating carrier risks for female relatives of Duchenne (DMD) and Becker (BMD) dystrophy sufferers depends upon calculation of segregational risks, supplemented by enzyme tests which show considerable overlap between carrier and control data. Linkage analysis has substantially increased the accuracy of segregational risk estimation, but a small error rate is still inherent when interpreting results, owing to recombination between the mutation causing the disease, and the marker used. It also requires family studies, which may be difficult to complete. The presence of intragenic DNA deletions in about half of D/BMD boys, allows direct detection of the D/BMD mutation, and is a powerful diagnostic tool. These techniques can be used for both prenatal diagnosis and carrier detection.
Duchenne Muscular Dystrophy: From Diagnosis to Therapy.
Falzarano Maria Sofia,Scotton Chiara,Passarelli Chiara,Ferlini Alessandra
Molecules (Basel, Switzerland)
Duchenne muscular dystrophy (DMD) is an X-linked inherited neuromuscular disorder due to mutations in the dystrophin gene. It is characterized by progressive muscle weakness and wasting due to the absence of dystrophin protein that causes degeneration of skeletal and cardiac muscle. The molecular diagnostic of DMD involves a deletions/duplications analysis performed by quantitative technique such as microarray-based comparative genomic hybridization (array-CGH), Multiple Ligation Probe Assay MLPA. Since traditional methods for detection of point mutations and other sequence variants require high cost and are time consuming, especially for a large gene like dystrophin, the use of next-generation sequencing (NGS) has become a useful tool available for clinical diagnosis. The dystrophin gene is large and finely regulated in terms of tissue expression, and RNA processing and editing includes a variety of fine tuned processes. At present, there are no effective treatments and the steroids are the only fully approved drugs used in DMD therapy able to slow disease progression. In the last years, an increasing variety of strategies have been studied as a possible therapeutic approach aimed to restore dystrophin production and to preserve muscle mass, ameliorating the DMD phenotype. RNA is the most studied target for the development of clinical strategies and Antisense Oligonucleotides (AONs) are the most used molecules for RNA modulation. The identification of delivery system to enhance the efficacy and to reduce the toxicity of AON is the main purpose in this area and nanomaterials are a very promising model as DNA/RNA molecules vectors. Dystrophinopathies therefore represent a pivotal field of investigation, which has opened novel avenues in molecular biology, medical genetics and novel therapeutic options.
Mutation-Based Therapeutic Strategies for Duchenne Muscular Dystrophy: From Genetic Diagnosis to Therapy.
Journal of personalized medicine
Duchenne and Becker muscular dystrophy (DMD/BMD) are X-linked muscle disorders caused by mutations of the gene, which encodes the subsarcolemmal protein dystrophin. In DMD, dystrophin is not expressed due to a disruption in the reading frame of the gene, resulting in a severe phenotype. Becker muscular dystrophy exhibits a milder phenotype, having mutations that maintain the reading frame and allow for the production of truncated dystrophin. To date, various therapeutic approaches for DMD have been extensively developed. However, the pathomechanism is quite complex despite it being a single gene disorder, and dystrophin is expressed not only in a large amount of skeletal muscle but also in cardiac, vascular, intestinal smooth muscle, and nervous system tissue. Thus, the most appropriate therapy would be complementation or restoration of dystrophin expression, such as gene therapy using viral vectors, readthrough therapy, or exon skipping therapy. Among them, exon skipping therapy with antisense oligonucleotides can restore the reading frame and yield the conversion of a severe phenotype to one that is mild. In this paper, I present the significance of molecular diagnosis and the development of mutation-based therapeutic strategies to complement or restore dystrophin expression.
Biomarkers for Duchenne muscular dystrophy: myonecrosis, inflammation and oxidative stress.
Grounds Miranda D,Terrill Jessica R,Al-Mshhdani Basma A,Duong Marisa N,Radley-Crabb Hannah G,Arthur Peter G
Disease models & mechanisms
Duchenne muscular dystrophy (DMD) is a lethal, X-linked disease that causes severe loss of muscle mass and function in young children. Promising therapies for DMD are being developed, but the long lead times required when using clinical outcome measures are hindering progress. This progress would be facilitated by robust molecular biomarkers in biofluids, such as blood and urine, which could be used to monitor disease progression and severity, as well as to determine optimal drug dosing before a full clinical trial. Many candidate DMD biomarkers have been identified, but there have been few follow-up studies to validate them. This Review describes the promising biomarkers for dystrophic muscle that have been identified in muscle, mainly using animal models. We strongly focus on myonecrosis and the associated inflammation and oxidative stress in DMD muscle, as the lack of dystrophin causes repeated bouts of myonecrosis, which are the key events that initiate the resultant severe dystropathology. We discuss the early events of intrinsic myonecrosis, along with early regeneration in the context of histological and other measures that are used to quantify its incidence. Molecular biomarkers linked to the closely associated events of inflammation and oxidative damage are discussed, with a focus on research related to protein thiol oxidation and to neutrophils. We summarise data linked to myonecrosis in muscle, blood and urine of dystrophic animal species, and discuss the challenge of translating such biomarkers to the clinic for DMD patients, especially to enhance the success of clinical trials.
Natural products, PGC-1 , and Duchenne muscular dystrophy.
Suntar Ipek,Sureda Antoni,Belwal Tarun,Sanches Silva Ana,Vacca Rosa Anna,Tewari Devesh,Sobarzo-Sánchez Eduardo,Nabavi Seyed Fazel,Shirooie Samira,Dehpour Ahmad Reza,Xu Suowen,Yousefi Bahman,Majidinia Maryam,Daglia Maria,D'Antona Giuseppe,Nabavi Seyed Mohammad
Acta pharmaceutica Sinica. B
Peroxisome proliferator-activated receptor (PPAR) is a transcriptional coactivator that binds to a diverse range of transcription factors. PPAR coactivator 1 (PGC-1) coactivators possess an extensive range of biological effects in different tissues, and play a key part in the regulation of the oxidative metabolism, consequently modulating the production of reactive oxygen species, autophagy, and mitochondrial biogenesis. Owing to these findings, a large body of studies, aiming to establish the role of PGC-1 in the neuromuscular system, has shown that PGC-1 could be a promising target for therapies targeting neuromuscular diseases. Among these, some evidence has shown that various signaling pathways linked to PGC-1 are deregulated in muscular dystrophy, leading to a reduced capacity for mitochondrial oxidative phosphorylation and increased reactive oxygen species (ROS) production. In the light of these results, any intervention aimed at activating PGC-1 could contribute towards ameliorating the progression of muscular dystrophies. PGC-1 is influenced by different patho-physiological/pharmacological stimuli. Natural products have been reported to display modulatory effects on PPAR activation with fewer side effects in comparison to synthetic drugs. Taken together, this review summarizes the current knowledge on Duchenne muscular dystrophy, focusing on the potential effects of natural compounds, acting as regulators of PGC-1.
Anti-Inflammatory and General Glucocorticoid Physiology in Skeletal Muscles Affected by Duchenne Muscular Dystrophy: Exploration of Steroid-Sparing Agents.
Herbelet Sandrine,Rodenbach Arthur,Paepe Boel De,De Bleecker Jan L
International journal of molecular sciences
In Duchenne muscular dystrophy (DMD), the activation of proinflammatory and metabolic cellular pathways in skeletal muscle cells is an inherent characteristic. Synthetic glucocorticoid intake counteracts the majority of these mechanisms. However, glucocorticoids induce burdensome secondary effects, including hypertension, arrhythmias, hyperglycemia, osteoporosis, weight gain, growth delay, skin thinning, cushingoid appearance, and tissue-specific glucocorticoid resistance. Hence, lowering the glucocorticoid dosage could be beneficial for DMD patients. A more profound insight into the major cellular pathways that are stabilized after synthetic glucocorticoid administration in DMD is needed when searching for the molecules able to achieve similar pathway stabilization. This review provides a concise overview of the major anti-inflammatory pathways, as well as the metabolic effects of glucocorticoids in the skeletal muscle affected in DMD. The known drugs able to stabilize these pathways, and which could potentially be combined with glucocorticoid therapy as steroid-sparing agents, are described. This could create new opportunities for testing in DMD animal models and/or clinical trials, possibly leading to smaller glucocorticoids dosage regimens for DMD patients.
Therapeutic Strategies for Duchenne Muscular Dystrophy: An Update.
Sun Chengmei,Shen Luoan,Zhang Zheng,Xie Xin
Neuromuscular disorders encompass a heterogeneous group of conditions that impair the function of muscles, motor neurons, peripheral nerves, and neuromuscular junctions. Being the most common and most severe type of muscular dystrophy, Duchenne muscular dystrophy (DMD), is caused by mutations in the X-linked gene. Loss of dystrophin protein leads to recurrent myofiber damage, chronic inflammation, progressive fibrosis, and dysfunction of muscle stem cells. Over the last few years, there has been considerable development of diagnosis and therapeutics for DMD, but current treatments do not cure the disease. Here, we review the current status of DMD pathogenesis and therapy, focusing on mutational spectrum, diagnosis tools, clinical trials, and therapeutic approaches including dystrophin restoration, gene therapy, and myogenic cell transplantation. Furthermore, we present the clinical potential of advanced strategies combining gene editing, cell-based therapy with tissue engineering for the treatment of muscular dystrophy.
Current and emerging therapies for Duchenne muscular dystrophy and spinal muscular atrophy.
Iftikhar Mohsan,Frey Justin,Shohan Md Jasimuddin,Malek Sohail,Mousa Shaker A
Pharmacology & therapeutics
Many neuromuscular diseases are genetically inherited or caused by mutations in motor function proteins. Two of the most prevalent neuromuscular diseases are Duchenne Muscular Dystrophy (DMD) and Spinal Muscular Atrophy (SMA), which are often diagnosed during the early years of life, contributing to life-long debilitation and shorter longevity. DMD is caused by mutations in the dystrophin gene resulting in critical muscle wasting, with cardiac or respiratory failure by age 30. Lack of dystrophin protein is the leading cause of degeneration of skeletal and cardiac muscle. Corticosteroids and artificial respirators remain as the gold-standard management of complications and have significantly extended the life span of these patients. Additionally, drug therapies including eteplirsen (EXONDYS 51®), golodirsen (VYONDYS 53™), and viltolarsen (VILTEPSO®) have been approved by the FDA to treat specific types of DMD. SMA is defined by the degeneration of the anterior horn cells in the spinal cord and destruction of motor neuron nuclei in the lower brain-stem caused by SMN1 gene deletion. Loss of SMN1 protein is partly compensated by SMN2 protein synthesis with disease severity being affected by the success of SMN2 gene synthesis. Evidence-based recommendations for SMA are directed towards supportive therapy and providing adequate nutrition and respiratory assistance as needed. Treatment and prevention of complications of muscle weakness are crucial for reducing the phenotype expression of SMA. Furthermore, drug therapies including injectables such as onasemnogene abeparvovec-xioi (ZOLGENSMA®), nusinersen (SPINRAZA®), and an oral-solution, risdiplam (EVRYSDI™), are medications that have been FDA-approved for the treatment of SMA. This review discusses the current and emerging therapeutic options for patients with DMD and SMA.