Articoli di riviste: "Duchenne Muscular Dystrophy (DMD)"

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lordlin, Dr R. T. J. R. Lordlin, e Dr Franklin Shaju. "PHYSIO IN DUCHENNE MUSCULAR DYSTROPHY (DMD)". IDC International Journal 8, n. 4 (10 ottobre 2021): 1–4. http://dx.doi.org/10.47211/idcij.2021.v08i04.001.

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Abstract (sommario):

Duchenne muscular dystrophy is the most common and severe form of muscular dystrophy and is caused by mutations in the dystrophin gene. Dystrophin, together with several other protein components, is part of a complex known as the dystrophin glycoprotein complex (DGC). The DGC plays an essential role in maintaining the structural integrity of the muscle cell membrane by providing a link between the extracellular matrix and the cytoskeleton

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Spiro, Alfred J. "Muscular Dystrophy". Pediatrics In Review 16, n. 11 (1 novembre 1995): 437. http://dx.doi.org/10.1542/pir.16.11.437.

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Several varieties of muscular dystrophy can be distinguished on clinical, genetic, morphologic, and physiologic grounds. The classification includes Duchenne and Becker muscular dystrophies, both X-linked disorders; facioscapulohumeral muscular dystrophy, which is autosomal dominant; and limb-girdle muscular dystrophy, generally autosomal recessive. Duchenne muscular dystrophy (DMD), which occurs in approximately 1 in 3500 live male births, has no recognizable signs or symptoms at birth. However, markedly elevated serum creatine kinase always is demonstrable, even at birth. A molecular diagnosis can be made at any time in the patient's lifetime by demonstrating the defect in the dystrophin gene, the absence of dystrophin in a muscle biopsy, and the characteristic morphologic abnormalities.

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Sitzia, Clementina, Andrea Farini, Federica Colleoni, Francesco Fortunato, Paola Razini, Silvia Erratico, Alessandro Tavelli et al. "Improvement of Endurance of DMD Animal Model Using Natural Polyphenols". BioMed Research International 2015 (2015): 1–17. http://dx.doi.org/10.1155/2015/680615.

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Duchenne muscular dystrophy (DMD), the most common form of muscular dystrophy, is characterized by muscular wasting caused by dystrophin deficiency that ultimately ends in force reduction and premature death. In addition to primary genetic defect, several mechanisms contribute to DMD pathogenesis. Recently, antioxidant supplementation was shown to be effective in the treatment of multiple diseases including muscular dystrophy. Different mechanisms were hypothesized such as reduced hydroxyl radicals, nuclear factor-κB deactivation, and NO protection from inactivation. Following these promising evidences, we investigated the effect of the administration of a mix of dietary natural polyphenols (ProAbe) on dystrophic mdx mice in terms of muscular architecture and functionality. We observed a reduction of muscle fibrosis deposition and myofiber necrosis together with an amelioration of vascularization. More importantly, the recovery of the morphological features of dystrophic muscle leads to an improvement of the endurance of treated dystrophic mice. Our data confirmed that ProAbe-based diet may represent a strategy to coadjuvate the treatment of DMD.

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Danisovic, Lubos, Martina Culenova e Maria Csobonyeiova. "Induced Pluripotent Stem Cells for Duchenne Muscular Dystrophy Modeling and Therapy". Cells 7, n. 12 (7 dicembre 2018): 253. http://dx.doi.org/10.3390/cells7120253.

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Abstract (sommario):

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder, caused by mutation of the DMD gene which encodes the protein dystrophin. This dystrophin defect leads to the progressive degeneration of skeletal and cardiac muscles. Currently, there is no effective therapy for this disorder. However, the technology of cell reprogramming, with subsequent controlled differentiation to skeletal muscle cells or cardiomyocytes, may provide a unique tool for the study, modeling, and treatment of Duchenne muscular dystrophy. In the present review, we describe current methods of induced pluripotent stem cell generation and discuss their implications for the study, modeling, and development of cell-based therapies for Duchenne muscular dystrophy.

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Steen, Michelle S., Marvin E. Adams, Yan Tesch e Stanley C. Froehner. "Amelioration of Muscular Dystrophy by Transgenic Expression of Niemann-Pick C1". Molecular Biology of the Cell 20, n. 1 (gennaio 2009): 146–52. http://dx.doi.org/10.1091/mbc.e08-08-0811.

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Duchenne muscular dystrophy (DMD) and other types of muscular dystrophies are caused by the loss or alteration of different members of the dystrophin protein complex. Understanding the molecular mechanisms by which dystrophin-associated protein abnormalities contribute to the onset of muscular dystrophy may identify new therapeutic approaches to these human disorders. By examining gene expression alterations in mouse skeletal muscle lacking α-dystrobrevin (Dtna−/−), we identified a highly significant reduction of the cholesterol trafficking protein, Niemann-Pick C1 (NPC1). Mutations in NPC1 cause a progressive neurodegenerative, lysosomal storage disorder. Transgenic expression of NPC1 in skeletal muscle ameliorates muscular dystrophy in the Dtna−/− mouse (which has a relatively mild dystrophic phenotype) and in the mdx mouse, a model for DMD. These results identify a new compensatory gene for muscular dystrophy and reveal a potential new therapeutic target for DMD.

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Min, Yi-Li, Rhonda Bassel-Duby e Eric N. Olson. "CRISPR Correction of Duchenne Muscular Dystrophy". Annual Review of Medicine 70, n. 1 (27 gennaio 2019): 239–55. http://dx.doi.org/10.1146/annurev-med-081117-010451.

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The ability to efficiently modify the genome using CRISPR technology has rapidly revolutionized biology and genetics and will soon transform medicine. Duchenne muscular dystrophy (DMD) represents one of the first monogenic disorders that has been investigated with respect to CRISPR-mediated correction of causal genetic mutations. DMD results from mutations in the gene encoding dystrophin, a scaffolding protein that maintains the integrity of striated muscles. Thousands of different dystrophin mutations have been identified in DMD patients, who suffer from a loss of ambulation followed by respiratory insufficiency, heart failure, and death by the third decade of life. Using CRISPR to bypass DMD mutations, dystrophin expression has been efficiently restored in human cells and mouse models of DMD. Here, we review recent progress toward the development of possible CRISPR therapies for DMD and highlight opportunities and potential obstacles in attaining this goal.

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Li, Xing-Chuan, Song Wang, Jia-Rui Zhu, Yu-Shan Yin e Ni Zhang. "A Chinese boy with familial Duchenne muscular dystrophy owing to a novel hemizygous nonsense mutation (c.6283C>T) in an exon of the DMD gene". SAGE Open Medical Case Reports 10 (gennaio 2022): 2050313X2211008. http://dx.doi.org/10.1177/2050313x221100881.

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Duchenne muscular dystrophy is a severe, X-linked, progressive neuromuscular disorder clinically characterised by muscle weakening and extremely high serum creatine kinase levels. A 1-year-old Chinese patient was diagnosed with early-onset Duchenne muscular dystrophy. Next-generation gene sequencing was conducted and the Sanger method was used to validate sequencing. We identified a novel nonsense mutation (c.6283C>T) in DMD that caused the replacement of native arginine at codon 2095 with a premature termination codon (p.R2095X), which may have had a pathogenic effect against dystrophin in our patient’s muscle cell membranes. We discovered a novel nonsense mutation in DMD that will expand the pathogenic mutation spectrum for Duchenne muscular dystrophy.

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Teramoto, Naomi, Hidetoshi Sugihara, Keitaro Yamanouchi, Katsuyuki Nakamura, Koichi Kimura, Tomoko Okano, Takanori Shiga et al. "Pathological evaluation of rats carrying in-frame mutations in the dystrophin gene: a new model of Becker muscular dystrophy". Disease Models & Mechanisms 13, n. 9 (28 agosto 2020): dmm044701. http://dx.doi.org/10.1242/dmm.044701.

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ABSTRACTDystrophin, encoded by the DMD gene on the X chromosome, stabilizes the sarcolemma by linking the actin cytoskeleton with the dystrophin-glycoprotein complex (DGC). In-frame mutations in DMD cause a milder form of X-linked muscular dystrophy, called Becker muscular dystrophy (BMD), characterized by the reduced expression of truncated dystrophin. So far, no animal model with in-frame mutations in Dmd has been established. As a result, the effect of in-frame mutations on the dystrophin expression profile and disease progression of BMD remains unclear. In this study, we established a novel rat model carrying in-frame Dmd gene mutations (IF rats) and evaluated the pathology. We found that IF rats exhibited reduced expression of truncated dystrophin in a proteasome-independent manner. This abnormal dystrophin expression caused dystrophic changes in muscle tissues but did not lead to functional deficiency. We also found that the expression of additional dystrophin named dpX, which forms the DGC in the sarcolemma, was associated with the appearance of truncated dystrophin. In conclusion, the outcomes of this study contribute to the further understanding of BMD pathology and help elucidate the efficiency of dystrophin recovery treatments in Duchenne muscular dystrophy, a more severe form of X-linked muscular dystrophy.

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Khatri, Ravi Shankar, Mridul Ranajan e Shalini . "A COMPARATIVE AYURVEDIC REVIEW OF ETIOPATHOGENESIS OF DUCHENNE MUSCULAR DYSTROPHY (INHERITED DISORDER)". International Journal of Research in Ayurveda and Pharmacy 12, n. 1 (2 marzo 2021): 124–25. http://dx.doi.org/10.7897/2277-4343.120127.

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Duchenne muscular dystrophy (DMD) is an inherited disorder with severe progressive muscle weakness. In Ayurveda, Adibala Pravritta Vyadhi are also known as inherited diseases that caused by Matruja beeja dushti (Shonita) and Pitruja beeja dushti (Shukra). Duchenne muscular dystrophy (DMD) has been classified under Adibala Pravritta Vyadhi as per Ayurveda. The main objective of this article is to describe the various aspect of etiopathogenesis of Duchenne muscular dystrophy (DMD) as per Ayurvedic literature. This article will be helpful to making the Nidana (Diagnosis) as per Ayurveda and also help in the Chikitsa (Treatment) of Duchenne muscular dystrophy.

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Erkut, Esra, e Toshifumi Yokota. "CRISPR Therapeutics for Duchenne Muscular Dystrophy". International Journal of Molecular Sciences 23, n. 3 (6 febbraio 2022): 1832. http://dx.doi.org/10.3390/ijms23031832.

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Abstract (sommario):

Duchenne muscular dystrophy (DMD) is an X-linked recessive neuromuscular disorder with a prevalence of approximately 1 in 3500–5000 males. DMD manifests as childhood-onset muscle degeneration, followed by loss of ambulation, cardiomyopathy, and death in early adulthood due to a lack of functional dystrophin protein. Out-of-frame mutations in the dystrophin gene are the most common underlying cause of DMD. Gene editing via the clustered regularly interspaced short palindromic repeats (CRISPR) system is a promising therapeutic for DMD, as it can permanently correct DMD mutations and thus restore the reading frame, allowing for the production of functional dystrophin. The specific mechanism of gene editing can vary based on a variety of factors such as the number of cuts generated by CRISPR, the presence of an exogenous DNA template, or the current cell cycle stage. CRISPR-mediated gene editing for DMD has been tested both in vitro and in vivo, with many of these studies discussed herein. Additionally, novel modifications to the CRISPR system such as base or prime editors allow for more precise gene editing. Despite recent advances, limitations remain including delivery efficiency, off-target mutagenesis, and long-term maintenance of dystrophin. Further studies focusing on safety and accuracy of the CRISPR system are necessary prior to clinical translation.

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Sun, Chengmei, Luoan Shen, Zheng Zhang e Xin Xie. "Therapeutic Strategies for Duchenne Muscular Dystrophy: An Update". Genes 11, n. 8 (23 luglio 2020): 837. http://dx.doi.org/10.3390/genes11080837.

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Abstract (sommario):

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 dystrophin 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.

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Freund, Aline Andrade, Rosana Herminia Scola, Raquel Cristina Arndt, Paulo José Lorenzoni, Claudia Kamoy Kay e Lineu Cesar Werneck. "Duchenne and Becker muscular dystrophy: a molecular and immunohistochemical approach". Arquivos de Neuro-Psiquiatria 65, n. 1 (marzo 2007): 73–76. http://dx.doi.org/10.1590/s0004-282x2007000100016.

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Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are caused by mutations in the dystrophin gene. We studied 106 patients with a diagnosis of probable DMD/BMD by analyzing 20 exons of the dystrophin gene in their blood and, in some of the cases, by immunohistochemical assays for dystrophin in muscle biopsies. In 71.7% of the patients, deletions were found in at least one of the exons; 68% of these deletions were in the hot-spot 3' region. Deletions were found in 81.5% of the DMD cases and in all the BMD cases. The cases without deletions, which included the only woman in the study with DMD, had dystrophin deficiency. The symptomatic female carriers had no deletions but had abnormal dystrophin distribution in the sarcolemma (discontinuous immunostains). The following diagnoses were made for the remaining cases without deletions with the aid of a muscle biopsy: spinal muscular atrophy, congenital myopathy; sarcoglycan deficiency and unclassified limb-girdle muscular dystrophy. Dystrophin analysis by immunohistochemistry continues to be the most specific method for diagnosis of DMD/BMD and should be used when no exon deletions are found in the dystrophin gene in the blood.

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Coote, David J., Mark R. Davis, Macarena Cabrera, Merrilee Needham, Nigel G. Laing e Kristen J. Nowak. "CUGC for Duchenne muscular dystrophy (DMD)". European Journal of Human Genetics 26, n. 5 (12 gennaio 2018): 749–57. http://dx.doi.org/10.1038/s41431-017-0013-2.

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Hsu, John D., e Ros Quinlivan. "Scoliosis in Duchenne muscular dystrophy (DMD)". Neuromuscular Disorders 23, n. 8 (agosto 2013): 611–17. http://dx.doi.org/10.1016/j.nmd.2013.05.003.

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Niranjan, Nandita, Satvik Mareedu, Yimin Tian, Kasun Kodippili, Nadezhda Fefelova, Antanina Voit, Lai-Hua Xie, Dongsheng Duan e Gopal J. Babu. "Sarcolipin overexpression impairs myogenic differentiation in Duchenne muscular dystrophy". American Journal of Physiology-Cell Physiology 317, n. 4 (1 ottobre 2019): C813—C824. http://dx.doi.org/10.1152/ajpcell.00146.2019.

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Reduction in the expression of sarcolipin (SLN), an inhibitor of sarco(endo)plasmic reticulum (SR) Ca2+-ATPase (SERCA), ameliorates severe muscular dystrophy in mice. However, the mechanism by which SLN inhibition improves muscle structure remains unclear. Here, we describe the previously unknown function of SLN in muscle differentiation in Duchenne muscular dystrophy (DMD). Overexpression of SLN in C2C12 resulted in decreased SERCA pump activity, reduced SR Ca2+ load, and increased intracellular Ca2+ ([Formula: see text]) concentration. In addition, SLN overexpression resulted in altered expression of myogenic markers and poor myogenic differentiation. In dystrophin-deficient dog myoblasts and myotubes, SLN expression was significantly high and associated with defective [Formula: see text] cycling. The dystrophic dog myotubes were less branched and associated with decreased autophagy and increased expression of mitochondrial fusion and fission proteins. Reduction in SLN expression restored these changes and enhanced dystrophic dog myoblast fusion during differentiation. In summary, our data suggest that SLN upregulation is an intrinsic secondary change in dystrophin-deficient myoblasts and could account for the [Formula: see text] mishandling, which subsequently contributes to poor myogenic differentiation. Accordingly, reducing SLN expression can improve the [Formula: see text] cycling and differentiation of dystrophic myoblasts. These findings provide cellular-level supports for targeting SLN expression as a therapeutic strategy for DMD.

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Lim, Kenji Rowel Q., Quynh Nguyen, Kasia Dzierlega, Yiqing Huang e Toshifumi Yokota. "CRISPR-Generated Animal Models of Duchenne Muscular Dystrophy". Genes 11, n. 3 (24 marzo 2020): 342. http://dx.doi.org/10.3390/genes11030342.

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Abstract (sommario):

Duchenne muscular dystrophy (DMD) is a fatal X-linked recessive neuromuscular disorder most commonly caused by mutations disrupting the reading frame of the dystrophin (DMD) gene. DMD codes for dystrophin, which is critical for maintaining the integrity of muscle cell membranes. Without dystrophin, muscle cells receive heightened mechanical stress, becoming more susceptible to damage. An active body of research continues to explore therapeutic treatments for DMD as well as to further our understanding of the disease. These efforts rely on having reliable animal models that accurately recapitulate disease presentation in humans. While current animal models of DMD have served this purpose well to some extent, each has its own limitations. To help overcome this, clustered regularly interspaced short palindromic repeat (CRISPR)-based technology has been extremely useful in creating novel animal models for DMD. This review focuses on animal models developed for DMD that have been created using CRISPR, their advantages and disadvantages as well as their applications in the DMD field.

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Charleston, Jay S., Frederick J. Schnell, Johannes Dworzak, Cas Donoghue, Sarah Lewis, Lei Chen, G. David Young et al. "Eteplirsen treatment for Duchenne muscular dystrophy". Neurology 90, n. 24 (11 maggio 2018): e2146-e2154. http://dx.doi.org/10.1212/wnl.0000000000005680.

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ObjectiveTo describe the quantification of novel dystrophin production in patients with Duchenne muscular dystrophy (DMD) after long-term treatment with eteplirsen.MethodsClinical study 202 was an observational, open-label extension of the randomized, controlled study 201 assessing the safety and efficacy of eteplirsen in patients with DMD with a confirmed mutation in the DMD gene amenable to correction by skipping of exon 51. Patients received once-weekly IV doses of eteplirsen 30 or 50 mg/kg. Upper extremity muscle biopsy samples were collected at combined study week 180, blinded, and assessed for dystrophin-related content by Western blot, Bioquant software measurement of dystrophin-associated immunofluorescence intensity, and percent dystrophin-positive fibers (PDPF). Results were contrasted with matched untreated biopsies from patients with DMD. Reverse transcription PCR followed by Sanger sequencing of newly formed slice junctions was used to confirm the mechanism of action of eteplirsen.ResultsReverse transcription PCR analysis and sequencing of the newly formed splice junction confirmed that 100% of treated patients displayed the expected skipped exon 51 sequence. In treated patients vs untreated controls, Western blot analysis of dystrophin content demonstrated an 11.6-fold increase (p = 0.007), and PDPF analysis demonstrated a 7.4-fold increase (p < 0.001). The PDPF findings were confirmed in a re-examination of the sample (15.5-fold increase, p < 0.001). Dystrophin immunofluorescence intensity was 2.4-fold greater in treated patients than in untreated controls (p < 0.001).ConclusionTaken together, the 4 assays, each based on unique evaluation mechanisms, provided evidence of eteplirsen muscle cell penetration, exon skipping, and induction of novel dystrophin expression.Classification of evidenceThis study provides Class II evidence of the muscle cell penetration, exon skipping, and induction of novel dystrophin expression by eteplirsen, as confirmed by 4 assays.

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Vieira, Natassia M., Janelle M. Spinazzola, Matthew S. Alexander, Yuri B. Moreira, Genri Kawahara, Devin E. Gibbs, Lillian C. Mead, Sergio Verjovski-Almeida, Mayana Zatz e Louis M. Kunkel. "Repression of phosphatidylinositol transfer protein α ameliorates the pathology of Duchenne muscular dystrophy". Proceedings of the National Academy of Sciences 114, n. 23 (22 maggio 2017): 6080–85. http://dx.doi.org/10.1073/pnas.1703556114.

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Abstract (sommario):

Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disease caused by X-linked inherited mutations in the DYSTROPHIN (DMD) gene. Absence of dystrophin protein from the sarcolemma causes severe muscle degeneration, fibrosis, and inflammation, ultimately leading to cardiorespiratory failure and premature death. Although there are several promising strategies under investigation to restore dystrophin protein expression, there is currently no cure for DMD, and identification of genetic modifiers as potential targets represents an alternative therapeutic strategy. In a Brazilian golden retriever muscular dystrophy (GRMD) dog colony, two related dogs demonstrated strikingly mild dystrophic phenotypes compared with those typically observed in severely affected GRMD dogs despite lacking dystrophin. Microarray analysis of these “escaper” dogs revealed reduced expression of phosphatidylinositol transfer protein-α (PITPNA) in escaper versus severely affected GRMD dogs. Based on these findings, we decided to pursue investigation of modulation of PITPNA expression on dystrophic pathology in GRMD dogs, dystrophin-deficient sapje zebrafish, and human DMD myogenic cells. In GRMD dogs, decreased expression of Pitpna was associated with increased phosphorylated Akt (pAkt) expression and decreased PTEN levels. PITPNA knockdown by injection of morpholino oligonucleotides in sapje zebrafish also increased pAkt, rescued the abnormal muscle phenotype, and improved long-term sapje mutant survival. In DMD myotubes, PITPNA knockdown by lentiviral shRNA increased pAkt and increased myoblast fusion index. Overall, our findings suggest PIPTNA as a disease modifier that accords benefits to the abnormal signaling, morphology, and function of dystrophic skeletal muscle, and may be a target for DMD and related neuromuscular diseases.

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Kurenkov, Alexey L., Lyudmila M. Kuzenkova, Lale A. Pak, Bella I. Bursagova, Tatyana V. Podkletnova, Olga B. Kondakova, Anastasiya A. Lyalina et al. "Differential diagnosis of Duchenne muscular dystrophy". L.O. Badalyan Neurological Journal 2, n. 3 (30 settembre 2021): 159–66. http://dx.doi.org/10.46563/2686-8997-2021-2-3-159-166.

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Abstract (sommario):

Duchenne muscular dystrophy (DMD) is a disease with an X-linked recessive type of inheritance, belonging to a group of disorders with primary muscle damage, caused by pathogenic variants in the DMD gene and associated with dysfunction of the dystrophin protein. Since DMD is manifested by the gradual development of progressive, mainly proximal muscle weakness, the differential diagnosis is primarily carried out in the group of diseases with muscle damage - myopathies. Among these diseases, the leading candidates for differential diagnosis are hereditary myopathies (limb-girdle muscular dystrophies, facioscapulohumeral dystrophy, congenital muscular dystrophies, glycogenoses - the most common juvenile form of glycogenosis type II (Pompe disease)) and, much less often, congenital myopathies and other conditions of neuromuscular diseases). When conducting a differential diagnosis in a child with suspected DMD, the age of the onset of the disease, early initial clinical manifestations and the development of symptoms as they grow, genealogical analysis, laboratory tests (the level of creatine kinase, aspartate aminotransferase, alanine aminotransferase in blood serum), instrumental (electromyography, magnetic resonance imaging of the brain and muscles) and molecular genetics (polymerase chain reaction, multiplex ligation-dependent probe amplification, next-generation sequencing, Sanger sequencing, etc.) of studies, and in some cases, muscle biopsy data. Knowledge of the nuances of the differential diagnosis allows establishing a genetic diagnosis of DMD as early as possible, which is extremely important for the formation of the prognosis of the disease and the implementation of all available treatment methods, including pathogenetic therapy, and is also necessary for medical and genetic counselling of families with DMD patients.

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Timonen, Anne, Michele Lloyd-Puryear, David M. Hougaard, Liisa Meriö, Pauliina Mäkinen, Ville Laitala, Tuukka Pölönen et al. "Duchenne Muscular Dystrophy Newborn Screening: Evaluation of a New GSP® Neonatal Creatine Kinase-MM Kit in a US and Danish Population". International Journal of Neonatal Screening 5, n. 3 (27 agosto 2019): 27. http://dx.doi.org/10.3390/ijns5030027.

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Duchenne muscular dystrophy (DMD/Duchenne) is a progressive X-linked disease and is the most common pediatric-onset form of muscular dystrophy, affecting approximately 1:5000 live male births. DNA testing for mutations in the dystrophin gene confirms the diagnosis of this disorder. This study involves assessment of screening newborns for DMD using an immunoassay for muscle-type (MM) creatine kinase (CK) isoform—the GSP Neonatal CK-MM kit. Comparisons were made with CK activity determination by fluorescence measurement. In addition, the study evaluated the effect of gestational age, age of infant at time of sampling and how stable the CK-MM was over time. This assay discriminates well between normal, unaffected and Duchenne affected populations and is suitable for Duchenne newborn screening.

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Pelosi, Laura, Laura Forcina, Carmine Nicoletti, Bianca Maria Scicchitano e Antonio Musarò. "Increased Circulating Levels of Interleukin-6 Induce Perturbation in Redox-Regulated Signaling Cascades in Muscle of Dystrophic Mice". Oxidative Medicine and Cellular Longevity 2017 (2017): 1–10. http://dx.doi.org/10.1155/2017/1987218.

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Abstract (sommario):

Duchenne muscular dystrophy (DMD) is an X-linked genetic disease in which dystrophin gene is mutated, resulting in dysfunctional or absent dystrophin protein. The pathology of dystrophic muscle includes degeneration, necrosis with inflammatory cell invasion, regeneration, and fibrous and fatty changes. Nevertheless, the mechanisms by which the absence of dystrophin leads to muscle degeneration remain to be fully elucidated. An imbalance between oxidant and antioxidant systems has been proposed as a secondary effect of DMD. However, the significance and precise extent of the perturbation in redox signaling cascades is poorly understood. We report that mdx dystrophic mice are able to activate a compensatory antioxidant response at the presymptomatic stage of the disease. In contrast, increased circulating levels of IL-6 perturb the redox signaling cascade, even prior to the necrotic stage, leading to severe features and progressive nature of muscular dystrophy.

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Fortunato, Fernanda, Rachele Rossi, Maria Sofia Falzarano e Alessandra Ferlini. "Innovative Therapeutic Approaches for Duchenne Muscular Dystrophy". Journal of Clinical Medicine 10, n. 4 (17 febbraio 2021): 820. http://dx.doi.org/10.3390/jcm10040820.

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Abstract (sommario):

Duchenne muscular dystrophy (DMD) is the most common childhood muscular dystrophy affecting ~1:5000 live male births. Following the identification of pathogenic variations in the dystrophin gene in 1986, the underlining genotype/phenotype correlations emerged and the role of the dystrophin protein was elucidated in skeletal, smooth, and cardiac muscles, as well as in the brain. When the dystrophin protein is absent or quantitatively or qualitatively modified, the muscle cannot sustain the stress of repeated contractions. Dystrophin acts as a bridging and anchoring protein between the sarcomere and the sarcolemma, and its absence or reduction leads to severe muscle damage that eventually cannot be repaired, with its ultimate substitution by connective tissue and fat. The advances of an understanding of the molecular pathways affected in DMD have led to the development of many therapeutic strategies that tackle different aspects of disease etiopathogenesis, which have recently led to the first successful approved orphan drugs for this condition. The therapeutic advances in this field have progressed exponentially, with second-generation drugs now entering in clinical trials as gene therapy, potentially providing a further effective approach to the condition.

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Reid, Andrea L., e Matthew S. Alexander. "The Interplay of Mitophagy and Inflammation in Duchenne Muscular Dystrophy". Life 11, n. 7 (4 luglio 2021): 648. http://dx.doi.org/10.3390/life11070648.

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Abstract (sommario):

Duchenne muscular dystrophy (DMD) is an X-linked neuromuscular disease caused by a pathogenic disruption of the DYSTROPHIN gene that results in non-functional dystrophin protein. DMD patients experience loss of ambulation, cardiac arrhythmia, metabolic syndrome, and respiratory failure. At the molecular level, the lack of dystrophin in the muscle results in myofiber death, fibrotic infiltration, and mitochondrial dysfunction. There is no cure for DMD, although dystrophin-replacement gene therapies and exon-skipping approaches are being pursued in clinical trials. Mitochondrial dysfunction is one of the first cellular changes seen in DMD myofibers, occurring prior to muscle disease onset and progresses with disease severity. This is seen by reduced mitochondrial function, abnormal mitochondrial morphology and impaired mitophagy (degradation of damaged mitochondria). Dysfunctional mitochondria release high levels of reactive oxygen species (ROS), which can activate pro-inflammatory pathways such as IL-1β and IL-6. Impaired mitophagy in DMD results in increased inflammation and further aggravates disease pathology, evidenced by increased muscle damage and increased fibrosis. This review will focus on the critical interplay between mitophagy and inflammation in Duchenne muscular dystrophy as a pathological mechanism, as well as describe both candidate and established therapeutic targets that regulate these pathways.

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Srivastava, Niraj Kumar, Somnath Mukherjee e Vijay Nath Mishra. "Metabolic Disturbance in Patients with Muscular Dystrophy and Reflection of Altered Enzyme Activity in Dystrophic Muscle: One Critical View". Journal of Biomedical Research & Environmental Sciences 1, n. 8 (dicembre 2020): 393–403. http://dx.doi.org/10.37871/jbres1171.

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Abstract (sommario):

Muscular dystrophies are inherited myogenic diseases and considered by progressive muscle wasting and weakness with variable distribution and severity. The essential characteristics of muscular dystrophies are selective involvement, significant wasting and weakness of muscles. The most common and frequent types of muscular dystrophies are Duchenne Muscular Dystrophy (DMD), Becker Muscular Dystrophy (BMD), Facioscapulohumeral Dystrophy (FSHD) and Limb Girdle Muscular Dystrophy (LGMD). Metabolic disturbance is observed in muscular dystrophy patients (DMD, BMD, FSHD and LGMD-2B). Alteration in the level of metabolites (BCAA, Glu/ Gln, Ace, alanine, glucose, histidine, propionate, tyrosine and fumarate) in dystrophic muscle reflects the alteration in the activity of enzymes. Collectively, these observations propose that there is alteration in the rate of glycolysis, TCA cycle, fatty acid oxidation, gluconeogenesis pathway and protein metabolism (catabolism & anabolism) in the muscular dystrophy patients. Metabolic disturbance, further provide the explanation about the pathophysiology of muscular dystrophy.

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25

Dewi, I. Gusti Ayu Sri Mahendra, e Desak Made Cittarasmi Saraswati Seputra. "Duchenne muscular dystrophy: case series of rare inherited muscular disorder". International Journal of Advances in Medicine 9, n. 12 (23 novembre 2022): 1194. http://dx.doi.org/10.18203/2349-3933.ijam20223021.

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Duchenne muscular dystrophy (DMD) is a rare muscular disorder caused by mutation of gene encoding dystrophin protein which required for maintaining muscle stability during contraction. DMD occurs in 1 in 5000 male live births and characterized by progressive muscular weakness associated with motor development delay, loss of independent ambulation, respiratory failure, and cardiomyopathy. We present a case series of 3 DMD patients who were diagnosed at Prof. dr. I.G.N.G. Ngoerah general hospital, Denpasar over a period of four years (2019-2022). Clinical manifestation of patients includes progressive weakness of lower extremities and difficulty to stand up from sitting position. Physical examination revealed pseudohypertrophy of calf, winged scapula, positive Gower’s sign, and waddling gait in all three cases. Supporting examination showed an increase of alanine transaminase and aspartate transaminase 5.6 times and 6.1 times the upper limit of normal, respectively. Definitive diagnosis of all patient was made based on immunohistochemistry staining which revealed an absent of dystrophin protein around muscle membrane.

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Heutinck, Lotte, Nadine van Kampen, Merel Jansen e Imelda J. M. de Groot. "Physical Activity in Boys With Duchenne Muscular Dystrophy Is Lower and Less Demanding Compared to Healthy Boys". Journal of Child Neurology 32, n. 5 (23 gennaio 2017): 450–57. http://dx.doi.org/10.1177/0883073816685506.

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This study describes the amount of physical activity and perception of physical activity in boys with Duchenne muscular dystrophy (DMD) compared to healthy boys. A questionnaire described 6 domains of physical activity. Four Duchenne muscular dystrophy subgroups were made: early and late ambulatory, nonambulatory with relative good, or limited arm function. Eighty-four boys with Duchenne muscular dystrophy (15.0 ± 6.4 years) and 198 healthy boys (14.0 ± 4.3 years) participated. Daily activities were more passive for boys with Duchenne muscular dystrophy. Physical activity was less and low demanding compared to healthy boys. It decreased with disease severity ( P < .05), whereas screen time increased ( P < .05). Benefits of physical activity in boys with Duchenne muscular dystrophy were having fun and making friends. Barriers were lack of sport facilities and insufficient health. This study helps to quantify poor engagement in physical activity by boys with Duchenne muscular dystrophy, and demonstrates factors that contribute to it. Suggestions to stimulate physical activity are made.

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Abdul-Razak, Hayder, Alberto Malerba e George Dickson. "Advances in gene therapy for muscular dystrophies". F1000Research 5 (18 agosto 2016): 2030. http://dx.doi.org/10.12688/f1000research.8735.1.

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Abstract (sommario):

Duchenne muscular dystrophy (DMD) is a recessive lethal inherited muscular dystrophy caused by mutations in the gene encoding dystrophin, a protein required for muscle fibre integrity. So far, many approaches have been tested from the traditional gene addition to newer advanced approaches based on manipulation of the cellular machinery either at the gene transcription, mRNA processing or translation levels. Unfortunately, despite all these efforts, no efficient treatments for DMD are currently available. In this review, we highlight the most advanced therapeutic strategies under investigation as potential DMD treatments.

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Nampoothiri, Sheela, Dhanya Yesodharan e Radhika P. Ramachandran. "Duchenne Muscular Dystrophy (DMD): Pre-conceptional Counseling". Journal of Fetal Medicine 3, n. 1 (23 febbraio 2016): 19–24. http://dx.doi.org/10.1007/s40556-016-0077-z.

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29

Dubrovsky, Alberto L., Lilia Mesa, José Corderi, Patricia Marco e Daniel Flores. "Steroid therapy in duchenne muscular dystrophy (DMD)". Pediatric Neurology 8, n. 5 (settembre 1992): 353. http://dx.doi.org/10.1016/0887-8994(92)90121-e.

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30

Topaloglu, Haluk, Pervin Dinçer, Safiye Gögüs, Sükrüye Ayter e Meral Topçu. "Unusual case of duchenne muscular dystrophy (DMD)". Pediatric Neurology 8, n. 5 (settembre 1992): 410. http://dx.doi.org/10.1016/0887-8994(92)90352-y.

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31

Leger, P., e S. Sortor Leger. "Respiratory concerns in duchenne muscular dystrophy (DMD)". Pediatric Pulmonology 23, S16 (aprile 1997): 137–39. http://dx.doi.org/10.1002/ppul.1950230874.

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32

Hilton, Stephanie, Matthias Christen, Thomas Bilzer, Vidhya Jagannathan, Tosso Leeb e Urs Giger. "Dystrophin (DMD) Missense Variant in Cats with Becker-Type Muscular Dystrophy". International Journal of Molecular Sciences 24, n. 4 (6 febbraio 2023): 3192. http://dx.doi.org/10.3390/ijms24043192.

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Abstract (sommario):

Muscular dystrophy due to dystrophin deficiency in humans is phenotypically divided into a severe Duchenne and milder Becker type. Dystrophin deficiency has also been described in a few animal species, and few DMD gene variants have been identified in animals. Here, we characterize the clinical, histopathological, and molecular genetic aspects of a family of Maine Coon crossbred cats with clinically mild and slowly progressive muscular dystrophy. Two young adult male littermate cats exhibited abnormal gait and muscular hypertrophy with macroglossia. Serum creatine kinase activities were highly increased. Histopathologically, dystrophic skeletal muscle exhibited marked structural changes including atrophic, hypertrophic, and necrotic muscle fibers. Immunohistochemistry showed irregularly reduced expression of dystrophin but the staining of other muscle proteins such as β- and γ-sarcoglycans as well as desmin was also diminished. Whole genome sequencing of one affected cat and genotyping of the littermate found both to be hemizygous mutant at a single DMD missense variant (c.4186C>T). No other protein-changing variants in candidate genes for muscular dystrophy were detected. In addition, one clinically healthy male littermate was hemizygous wildtype, while the queen and one female littermate were clinically healthy, but heterozygous. The predicted amino acid exchange (p.His1396Tyr) resides in a conserved central rod spectrin domain of dystrophin. Various protein modeling programs did not predict major disruption of the dystrophin protein by this substitution, but the altered charge of the region may still affect protein function. This study represents the first genotype-to-phenotype correlation of Becker-type dystrophin deficiency in companion animals.

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Gaynetdinova, D. D., e A. A. Novoselova. "Current diagnosis and treatment of Duchenne muscular dystrophy". Kazan medical journal 101, n. 4 (12 agosto 2020): 530–37. http://dx.doi.org/10.17816/kmj2020-530.

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Abstract (sommario):

Duchenne muscular dystrophy (DMD) is an X-linked progressive disease from the group of primary myopathies caused by mutations in the DMD gene and a lack of dystrophin protein in the muscle fiber in males. The review considered the prevalence of pathology, the most common causes of dystrophinopathy, and the role of dystrophin not only in the functioning of muscles but also in the architectural organization of the Central nervous system. The disease classification based on stages and forms, initial clinical manifestations of the early and late stages of the disease, as well as neuropsychological, orthopedic, respiratory and cardiovascular disorders, are described in detail. The relevant to date diagnostic algorithm for suspected DMD, biochemical blood analysis, genetic, morphological (immunocytochemical staining of muscles with dystrophin antibodies) and instrumental (ultrasound, MRI) methods of examination are presented in detail. Particular attention in the diagnosis of DMD and objectification of disorders is given to assessment tests [Baileys and Griffiths scales, Albert's Test of Infant Posture and Motor Assessment Scale, Expanded Hammersmith Functional Motor Scale (HFMSE), the Gross Motor Function Measure (GMFM), and the 6-minute walk test (6MWT)]. The review presents the advantages and disadvantages of modern invasive and non-invasive diagnostic techniques of the disease, indicating their reliability and the possibility of application at early stages, including prenatal. In conclusion, the treatment of DMD and its most frequent complications, both widely used in practice and at the stage of clinical research, is highlighted. It was emphasized the importance of rehabilitation measures that improve the duration and quality of life of patients with DMD. The main task of analyzing available sources on the most pressing issues of Duchenne muscular dystrophy was to stimulate research and social activity in resolving unsolved problems today.

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Silva, Talita Dias da, Thais Massetti, Carlos Bandeira de Mello Monteiro, Isabela Lopes Trevizan, Claudia Arab, Fatima Aparecida Caromano, Mariana Callil Voos, Acary Souza Bulle Oliveira e Francis Meire Favero. "Pain characterization in Duchenne muscular dystrophy". Arquivos de Neuro-Psiquiatria 74, n. 9 (settembre 2016): 767–74. http://dx.doi.org/10.1590/0004-282x20160107.

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Abstract (sommario):

ABSTRACT Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder, characterized by progressive muscle weakness. Historically, pain has not been considered to be a major symptom in DMD. Objective To investigate the relationship between DMD and pain. Methods We conducted a systematic review in Medline/PubMed and BVS (virtual library in health) databases. We searched for articles that showed the terms “Muscular Dystrophy, Duchenne” and “Pain” in all fields. All studies included boys diagnosed with DMD and the occurrence/amount of pain on this population. Results Initially, there were 175 studies. 167 articles were excluded for not meeting the inclusion criteria. The remaining eight eligible studies, involving pain assessment in DMD, were analyzed. Conclusion Pain is a frequent problem in this population and this symptom is potentially tractable. Studies conclude that pain can directly influence the quality of life of this population.

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Klymiuk, N., C. Thirion, K. Burkhardt, A. Wuensch, S. Krause, A. Richter, B. Kessler et al. "238 TAILORED PIG MODEL OF DUCHENNE MUSCULAR DYSTROPHY". Reproduction, Fertility and Development 24, n. 1 (2012): 231. http://dx.doi.org/10.1071/rdv24n1ab238.

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Abstract (sommario):

Duchenne muscular dystrophy (DMD) is one of the most common genetic diseases in humans, affecting 1 in 3500 boys. It is characterised by progressive muscle weakness and wasting due to mutations in the dystrophin (DMD) gene resulting in absence of dystrophin protein in skeletal muscle. Although curative treatments are currently not available, genetic and pharmacological approaches are under investigation including early-phase clinical trials. Existing animal models in different species (e.g. mdx mouse, GRMD dog) have been instrumental to understand the pathophysiology of DMD, but have several limitations. Importantly, the causative point mutations (mdx mouse: nonsense mutation; GRMD dog: splice mutation) are different from the most common human mutations (out-of-frame deletion of one or several exons of the DMD gene). We used gene targeting in somatic cells and nuclear transfer to generate a genetically tailored pig model of DMD. A bacterial artificial chromosome (BAC) from the porcine DMD gene was modified by recombineering to replace exon 52, resulting in a frame shift in the transcript. Modified BAC were transfected into male neonatal kidney cells, which were screened by quantitative polymerase chain reaction for replacement of exon 52 in the X-linked DMD gene. Eight of 436 cell clones were successfully targeted and 2 of them were used for nuclear transfer. For each of the cell clones, a pregnancy was established by transfer of cloned embryos into recipient gilts. Four piglets of the first litter were live born and killed within 48 h and tissue samples were processed for histological characterisation. Two piglets of the second litter died during birth due to obstetric complications, whereas the other 2 piglets were delivered by Caesarean section and raised in an artificial feeding system. Their serum creatine kinase (CK) levels were grossly elevated. Although both piglets showed reduced mobility compared with age-matched controls, they were able to move and feed on their own. Immunofluorescence staining of dystrophin was negative in muscle fibres of DMD mutant piglets and the complete absence of dystrophin protein was confirmed by immunoblot analysis. Histological examination of biceps femoris muscle from DMD mutant pigs showed a degenerative myopathy with fibre size variation, rounded fibres, central nuclei, fibrosis and fatty replacement of muscle tissue mimicking the hallmarks of the human disease. In conclusion, we generated the first pig model for a genetic muscle disease. The DMD mutant pig appears to be a bona fide model of the human dystrophy as ascertained by absence of the dystrophin protein, elevated serum CK levels and early degenerative changes on muscle histology. Because deletion of exon 52 is one of the most frequent mutations found in human DMD, the exon 52 mutated DMD pig represents an excellent model for testing targeted genetic treatments. This study was supported by the Bayerische Forschungsstiftung.

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Nogami, Ken'ichiro, Yusuke Maruyama, Fusako Sakai-Takemura, Norio Motohashi, Ahmed Elhussieny, Michihiro Imamura, Satoshi Miyashita et al. "Pharmacological activation of SERCA ameliorates dystrophic phenotypes in dystrophin-deficient mdx mice". Human Molecular Genetics 30, n. 11 (5 aprile 2021): 1006–19. http://dx.doi.org/10.1093/hmg/ddab100.

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Abstract (sommario):

Abstract Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder characterized by progressive muscular weakness because of the loss of dystrophin. Extracellular Ca2+ flows into the cytoplasm through membrane tears in dystrophin-deficient myofibers, which leads to muscle contracture and necrosis. Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) takes up cytosolic Ca2+ into the sarcoplasmic reticulum, but its activity is decreased in dystrophic muscle. Here, we show that an allosteric SERCA activator, CDN1163, ameliorates dystrophic phenotypes in dystrophin-deficient mdx mice. The administration of CDN1163 prevented exercise-induced muscular damage and restored mitochondrial function. In addition, treatment with CDN1163 for 7 weeks enhanced muscular strength and reduced muscular degeneration and fibrosis in mdx mice. Our findings provide preclinical proof-of-concept evidence that pharmacological activation of SERCA could be a promising therapeutic strategy for DMD. Moreover, CDN1163 improved muscular strength surprisingly in wild-type mice, which may pave the new way for the treatment of muscular dysfunction.

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Naidoo, Michael, e Karen Anthony. "Dystrophin Dp71 and the Neuropathophysiology of Duchenne Muscular Dystrophy". Molecular Neurobiology 57, n. 3 (13 dicembre 2019): 1748–67. http://dx.doi.org/10.1007/s12035-019-01845-w.

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Abstract (sommario):

AbstractDuchenne muscular dystrophy (DMD) is caused by frameshift mutations in the DMD gene that prevent the body-wide translation of its protein product, dystrophin. Besides a severe muscle phenotype, cognitive impairment and neuropsychiatric symptoms are prevalent. Dystrophin protein 71 (Dp71) is the major DMD gene product expressed in the brain and mutations affecting its expression are associated with the DMD neuropsychiatric syndrome. As with dystrophin in muscle, Dp71 localises to dystrophin-associated protein complexes in the brain. However, unlike in skeletal muscle; in the brain, Dp71 is alternatively spliced to produce many isoforms with differential subcellular localisations and diverse cellular functions. These include neuronal differentiation, adhesion, cell division and excitatory synapse organisation as well as nuclear functions such as nuclear scaffolding and DNA repair. In this review, we first describe brain involvement in DMD and the abnormalities observed in the DMD brain. We then review the gene expression, RNA processing and functions of Dp71. We review genotype-phenotype correlations and discuss emerging cellular/tissue evidence for the involvement of Dp71 in the neuropathophysiology of DMD. The literature suggests changes observed in the DMD brain are neurodevelopmental in origin and that their risk and severity is associated with a cumulative loss of distal DMD gene products such as Dp71. The high risk of neuropsychiatric syndromes in Duchenne patients warrants early intervention to achieve the best possible quality of life. Unravelling the function and pathophysiological significance of dystrophin in the brain has become a high research priority to inform the development of brain-targeting treatments for Duchenne.

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Meyers, Tatyana A., e DeWayne Townsend. "Cardiac Pathophysiology and the Future of Cardiac Therapies in Duchenne Muscular Dystrophy". International Journal of Molecular Sciences 20, n. 17 (22 agosto 2019): 4098. http://dx.doi.org/10.3390/ijms20174098.

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Abstract (sommario):

Duchenne muscular dystrophy (DMD) is a devastating disease featuring skeletal muscle wasting, respiratory insufficiency, and cardiomyopathy. Historically, respiratory failure has been the leading cause of mortality in DMD, but recent improvements in symptomatic respiratory management have extended the life expectancy of DMD patients. With increased longevity, the clinical relevance of heart disease in DMD is growing, as virtually all DMD patients over 18 year of age display signs of cardiomyopathy. This review will focus on the pathophysiological basis of DMD in the heart and discuss the therapeutic approaches currently in use and those in development to treat dystrophic cardiomyopathy. The first section will describe the aspects of the DMD that result in the loss of cardiac tissue and accumulation of fibrosis. The second section will discuss cardiac small molecule therapies currently used to treat heart disease in DMD, with a focus on the evidence supporting the use of each drug in dystrophic patients. The final section will outline the strengths and limitations of approaches directed at correcting the genetic defect through dystrophin gene replacement, modification, or repair. There are several new and promising therapeutic approaches that may protect the dystrophic heart, but their limitations suggest that future management of dystrophic cardiomyopathy may benefit from combining gene-targeted therapies with small molecule therapies. Understanding the mechanistic basis of dystrophic heart disease and the effects of current and emerging therapies will be critical for their success in the treatment of patients with DMD.

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Suelves, Mònica, Berta Vidal, Antonio L. Serrano, Marc Tjwa, Josep Roma, Roser López-Alemany, Aernout Luttun et al. "uPA deficiency exacerbates muscular dystrophy in MDX mice". Journal of Cell Biology 178, n. 6 (4 settembre 2007): 1039–51. http://dx.doi.org/10.1083/jcb.200705127.

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Abstract (sommario):

Duchenne muscular dystrophy (DMD) is a fatal and incurable muscle degenerative disorder. We identify a function of the protease urokinase plasminogen activator (uPA) in mdx mice, a mouse model of DMD. The expression of uPA is induced in mdx dystrophic muscle, and the genetic loss of uPA in mdx mice exacerbated muscle dystrophy and reduced muscular function. Bone marrow (BM) transplantation experiments revealed a critical function for BM-derived uPA in mdx muscle repair via three mechanisms: (1) by promoting the infiltration of BM-derived inflammatory cells; (2) by preventing the excessive deposition of fibrin; and (3) by promoting myoblast migration. Interestingly, genetic loss of the uPA receptor in mdx mice did not exacerbate muscular dystrophy in mdx mice, suggesting that uPA exerts its effects independently of its receptor. These findings underscore the importance of uPA in muscular dystrophy.

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Wells, Dominic J., Aurora Ferrer e Kim E. Wells. "Immunological hurdles in the path to gene therapy for Duchenne muscular dystrophy". Expert Reviews in Molecular Medicine 4, n. 23 (4 novembre 2002): 1–23. http://dx.doi.org/10.1017/s146239940200515x.

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Abstract (sommario):

Patients with Duchenne muscular dystrophy (DMD), an X-linked lethal muscle-wasting disease, have abnormal expression of the protein dystrophin within their muscle fibres. In the mdx mouse model of this condition, both germline and neonatal somatic gene transfers of dystrophin cDNAs have demonstrated the potential of gene therapy in treating DMD. However, in many DMD patients, there appears to be no dystrophin expression when muscle biopsies are immunostained or western blots are performed. This raises the possibility that the expression of dystrophin following gene transfer might trigger a destructive immune response against this ‘neoantigen’. Immune responses can also be generated against the gene transfer vector used to transfect the dystrophic muscle, and the combined immune response could further damage the already inflamed muscle. These problems are now beginning to be investigated in immunocompetent mdx mice. Although much work remains to be done, there are promising indications that these immune responses might not prove as much of a concern as originally envisaged.

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Dwianingsih, Ery Kus, Meydita Fuzia Putri Insani, Linda Pratiwi, Irianiwati Widodo e Rusdy Ghazali Malueka. "Clinicopathologic and molecular profiles of Duchenne and Becker muscular dystrophy". Paediatrica Indonesiana 59, n. 5 (24 settembre 2019): 257–64. http://dx.doi.org/10.14238/pi59.5.2019.257-64.

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Abstract (sommario):

Background Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are allelic X-linked recessive diseases caused by mutations in the dystrophin (DMD) gene. To our knowledge, molecular analysis to differentiate between DMD and BMD has never been performed in Indonesia. Objective To elaborate the clinicopathologic and molecular profiles of DMD/BMD patients in Yogyakarta, Indonesia. Methods Eighteen muscle biopsy specimens of patients clinically suspected to have DMD/BMD were collected. Possible associations of clinical manifestations, histopathological grading, and immunohistochemistry (IHC) results were analyzed. Polymerase chain reaction (PCR) was performed to identify mutations in exon 52. Results. Positive Gower’s sign and high serum creatine kinase (CK) were observed in most patients. The IHC of dystrophin in two female patients suggested that they were manifesting carriers. Of the 16 male patients, 12 showed negative IHC staining, indicating DMD, while 4 patients demonstrated weak expression of dystrophin, indicating BMD. There was a significant association between high CK level and IHC results (P=0.005), indicating higher CK level in DMD patients. Histopathological grading of muscle biopsy was significantly associated with diagnosis of DMD/BMD using IHC (P=0.01), showing more severe tissue damage in DMD patients. None of the subjects had the single exon 52 deletion. Conclusion This is the first report of a clinicopathologic and molecular profile of DMD/BMD in an Indonesian population. Serum CK level and histopathological grading of muscle biopsy are useful in distinguishing DMD from BMD in settings where an IHC assay is not available.

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Istianah, Zakiah Nur, Sunartini Sunartini e Sasmito Nugroho. "Motor clinical progression in a series of pediatric Duchenne and Becker muscular dystrophy cases". Paediatrica Indonesiana 59, n. 2 (13 marzo 2019): 51–4. http://dx.doi.org/10.14238/pi59.2.2019.51-4.

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Abstract (sommario):

Muscular dystrophy is a neuromuscular disorder that begins with muscle weakness and impaired motor function. Duchenne muscular dystrophy (DMD) is more severe and destructive than Becker muscular dystrophy (BMD), and both are progressive in nature. These 2 types of muscular dystrophy are caused by mutations in related to X-chromosome genes.1 The mutations that occur in DMD are nonsense mutations. Deletion is present in 60% of DMD cases, while duplication occurs in 10% of DMD cases, resulting in loss of dystrophin protein. Mutations in BMD are missense mutations, so dystrophin is still formed, but in decreased amounts and quality.2,3 The prevalence of DMD was reported to be three times greater than that of BMD, with a prevalence of 1.02 per 10,000 male births vs. 0.36 per 10,000 male infants, respectiveley.4 Anatomical pathology examination revealed loss of dystrophin in the examination of muscle biopsy without the presence of evidence leading to other neuromuscular diseases. Clinical DMD symptoms begin to appear at the age of 2-4 years. The child is observed to fall often and has difficulty climbing stairs. Muscle weakness worsens, especially in the upper limbs, continuing with heart and respiratory problems. The main causes of death in DMD are respiratory failure and heart failure.5 The BMD has varied clinical symptoms, beginning with the appearance of myalgia, muscle cramps, and arm weakness progressing towards myopathy. Some patients are asymptomatic until the age of 15, but 50% of patients show symptoms at age 10, and almost all by age 20.6

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Blat, Yuval, e Shachar Blat. "Drug Discovery of Therapies for Duchenne Muscular Dystrophy". Journal of Biomolecular Screening 20, n. 10 (14 maggio 2015): 1189–203. http://dx.doi.org/10.1177/1087057115586535.

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Abstract (sommario):

Duchenne muscular dystrophy (DMD) is a genetic, lethal, muscle disorder caused by the loss of the muscle protein, dystrophin, leading to progressive loss of muscle fibers and muscle weakness. Drug discovery efforts targeting DMD have used two main approaches: (1) the restoration of dystrophin expression or the expression of a compensatory protein, and (2) the mitigation of downstream pathological mechanisms, including dysregulated calcium homeostasis, oxidative stress, inflammation, fibrosis, and muscle ischemia. The aim of this review is to introduce the disease, its pathophysiology, and the available research tools to a drug discovery audience. This review will also detail the most promising therapies that are currently being tested in clinical trials or in advanced preclinical models.

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Bellayou, Hanane, Khalil Hamzi, Mohamed Abdou Rafai, Mehdi Karkouri, Ilham Slassi, Houssine Azeddoug e Sellama Nadifi. "Duchenne and Becker Muscular Dystrophy: Contribution of a Molecular and Immunohistochemical Analysis in Diagnosis in Morocco". Journal of Biomedicine and Biotechnology 2009 (2009): 1–5. http://dx.doi.org/10.1155/2009/325210.

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Abstract (sommario):

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are X-linked recessive disorders caused by mutations of the DMD gene located at Xp21. In DMD patients, dystrophin is virtually absent; whereas BMD patients have 10% to 40% of the normal amount. Deletions in the dystrophin gene represent 65% of mutations in DMD/BMD patients. To explain the contribution of immunohistochemical and genetic analysis in the diagnosis of these dystrophies, we present 10 cases of DMD/BMD with particular features. We have analyzed the patients with immunohistochemical staining and PCR multiplex to screen for exons deletions. Determination of the quantity and distribution of dystrophin by immunohistochemical staining can confirm the presence of dystrophinopathy and allows differentiation between DMD and BMD, but dystrophin staining is not always conclusive in BMD. Therefore, only identification involved mutation by genetic analysis can establish a correct diagnosis.

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Filareto, Antonio, Katie Maguire-Nguyen, Qiang Gan, Garazi Aldanondo, Léo Machado, Jeffrey S. Chamberlain e Thomas A. Rando. "Monitoring disease activity noninvasively in the mdx model of Duchenne muscular dystrophy". Proceedings of the National Academy of Sciences 115, n. 30 (9 luglio 2018): 7741–46. http://dx.doi.org/10.1073/pnas.1802425115.

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Abstract (sommario):

Duchenne muscular dystrophy (DMD) is a rare, muscle degenerative disease resulting from the absence of the dystrophin protein. DMD is characterized by progressive loss of muscle fibers, muscle weakness, and eventually loss of ambulation and premature death. Currently, there is no cure for DMD and improved methods of disease monitoring are crucial for the development of novel treatments. In this study, we describe a new method of assessing disease progression noninvasively in the mdx model of DMD. The reporter mice, which we term the dystrophic Degeneration Reporter strains, contain an inducible CRE-responsive luciferase reporter active in mature myofibers. In these mice, muscle degeneration is reflected in changes in the level of luciferase expression, which can be monitored using noninvasive, bioluminescence imaging. We monitored the natural history and disease progression in these dystrophic report mice and found that decreases in luciferase signals directly correlated with muscle degeneration. We further demonstrated that this reporter strain, as well as a previously reported Regeneration Reporter strain, successfully reveals the effectiveness of a gene therapy treatment following systemic administration of a recombinant adeno-associated virus-6 (rAAV-6) encoding a microdystrophin construct. Our data demonstrate the value of these noninvasive imaging modalities for monitoring disease progression and response to therapy in mouse models of muscular dystrophy.

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Bianco, Bianca, Denise Maria Christofolini, Gabriel Seixas Conceição e Caio Parente Barbosa. "Preimplantation genetic diagnosis associated to Duchenne muscular dystrophy". Einstein (São Paulo) 15, n. 4 (21 settembre 2017): 489–91. http://dx.doi.org/10.1590/s1679-45082017rc3994.

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Abstract (sommario):

ABSTRACT Duchenne muscular dystrophy is the most common muscle disease found in male children. Currently, there is no effective therapy available for Duchenne muscular dystrophy patients. Therefore, it is essential to make a prenatal diagnosis and provide genetic counseling to reduce the birth of such boys. We report a case of preimplantation genetic diagnosis associated with Duchenne muscular dystrophy. The couple E.P.R., 38-year-old, symptomatic patient heterozygous for a 2 to 47 exon deletion mutation in DMD gene and G.T.S., 39-year-old, sought genetic counseling about preimplantation genetic diagnosis process. They have had a 6-year-old son who died due to Duchenne muscular dystrophy complications. The couple underwent four cycles of intracytoplasmic sperm injection (ICSI) and eight embryos biopsies were analyzed by polymerase chain reaction (PCR) for specific mutation analysis, followed by microarray-based comparative genomic hybridisation (array CGH) for aneuploidy analysis. Preimplantation genetic diagnosis revealed that two embryos had inherited the maternal DMD gene mutation, one embryo had a chromosomal alteration and five embryos were normal. One blastocyst was transferred and resulted in successful pregnancy. The other embryos remain vitrified. We concluded that embryo analysis using associated techniques of PCR and array CGH seems to be safe for embryo selection in cases of X-linked disorders, such as Duchenne muscular dystrophy.

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Joseph, Josiane, Dong Cho e Jason Doles. "Metabolomic Analyses Reveal Extensive Progenitor Cell Deficiencies in a Mouse Model of Duchenne Muscular Dystrophy". Metabolites 8, n. 4 (3 ottobre 2018): 61. http://dx.doi.org/10.3390/metabo8040061.

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Duchenne muscular dystrophy (DMD) is a musculoskeletal disorder that causes severe morbidity and reduced lifespan. Individuals with DMD have an X-linked mutation that impairs their ability to produce functional dystrophin protein in muscle. No cure exists for this disease and the few therapies that are available do not dramatically delay disease progression. Thus, there is a need to better understand the mechanisms underlying DMD which may ultimately lead to improved treatment options. The muscular dystrophy (MDX) mouse model is frequently used to explore DMD disease traits. Though some studies of metabolism in dystrophic mice exist, few have characterized metabolic profiles of supporting cells in the diseased environment. Using nontargeted metabolomics we characterized metabolic alterations in muscle satellite cells (SCs) and serum of MDX mice. Additionally, live-cell imaging revealed MDX-derived adipose progenitor cell (APC) defects. Finally, metabolomic studies revealed a striking elevation of acylcarnitines in MDX APCs, which we show can inhibit APC proliferation. Together, these studies highlight widespread metabolic alterations in multiple progenitor cell types and serum from MDX mice and implicate dystrophy-associated metabolite imbalances in APCs as a potential contributor to adipose tissue disequilibrium in DMD.

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Carmen, Laurino, Vadala’ Maria, Julio Cesar Morales-Medina, Annamaria Vallelunga, Beniamino Palmieri e Tommaso Iannitti. "Role of proteoglycans and glycosaminoglycans in Duchenne muscular dystrophy". Glycobiology 29, n. 2 (19 giugno 2018): 110–23. http://dx.doi.org/10.1093/glycob/cwy058.

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Abstract Duchenne muscular dystrophy (DMD) is an inherited fatal X-linked myogenic disorder with a prevalence of 1 in 3500 male live births. It affects voluntary muscles, and heart and breathing muscles. DMD is characterized by continuous degeneration and regeneration cycles resulting in extensive fibrosis and a progressive reduction in muscle mass. Since the identification of a reduction in dystrophin protein as the cause of this disorder, numerous innovative and experimental therapies, focusing on increasing the levels of dystrophin, have been proposed, but the clinical improvement has been unsatisfactory. Dystrophin forms the dystrophin-associated glycoprotein complex and its proteins have been studied as a promising novel therapeutic target to treat DMD. Among these proteins, cell surface glycosaminoglycans (GAGs) are found almost ubiquitously on the surface and in the extracellular matrix (ECM) of mammalian cells. These macromolecules interact with numerous ligands, including ECM constituents, adhesion molecules and growth factors that play a crucial role in muscle development and maintenance. In this article, we have reviewed in vitro, in vivo and clinical studies focused on the functional role of GAGs in the pathophysiology of DMD with the final aim of summarizing the state of the art of GAG dysregulation within the ECM in DMD and discussing future therapeutic perspectives.

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Vu Hong, Ai, Nathalie Bourg, Peggy Sanatine, Jerome Poupiot, Karine Charton, Evelyne Gicquel, Emmanuelle Massourides, Marco Spinazzi, Isabelle Richard e David Israeli. "Dlk1-Dio3 cluster miRNAs regulate mitochondrial functions in the dystrophic muscle in Duchenne muscular dystrophy". Life Science Alliance 6, n. 1 (20 ottobre 2022): e202201506. http://dx.doi.org/10.26508/lsa.202201506.

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Duchenne muscular dystrophy (DMD) is a severe muscle disease caused by impaired expression of dystrophin. Whereas mitochondrial dysfunction is thought to play an important role in DMD, the mechanism of this dysfunction remains to be clarified. Here we demonstrate that in DMD and other muscular dystrophies, a large number of Dlk1-Dio3 clustered miRNAs (DD-miRNAs) are coordinately up-regulated in regenerating myofibers and in the serum. To characterize the biological effect of this dysregulation, 14 DD-miRNAs were simultaneously overexpressed in vivo in mouse muscle. Transcriptomic analysis revealed highly similar changes between the muscle ectopically overexpressing 14 DD-miRNAs and the mdx diaphragm, with naturally up-regulated DD-miRNAs. Among the commonly dysregulated pathway we found repressed mitochondrial metabolism, and oxidative phosphorylation (OxPhos) in particular. Knocking down the DD-miRNAs in iPS-derived skeletal myotubes resulted in increased OxPhos activities. The data suggest that (1) DD-miRNAs are important mediators of dystrophic changes in DMD muscle, (2) mitochondrial metabolism and OxPhos in particular are targeted in DMD by coordinately up-regulated DD-miRNAs. These findings provide insight into the mechanism of mitochondrial dysfunction in muscular dystrophy.

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Farini, Andrea. "Special Issue: Pathophysiology and Therapeutic Perspectives in DMD: The Well-Defined Role of the Immune System". Biomedicines 9, n. 12 (14 dicembre 2021): 1911. http://dx.doi.org/10.3390/biomedicines9121911.

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