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Busch, H. F. M. "Het begon bij Duchenne." [S.l.] : Rotterdam : [de auteur] ; Erasmus University [Host], 1994. http://hdl.handle.net/1765/7462.
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Rabinowitz, Adam Howard. "Antisense therapies for Duchenne muscular dystrophy." Thesis, Imperial College London, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.444590.
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Smith, T. J. "Molecular analysis of Duchenne muscular dystrophy." Thesis, University of Oxford, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.233559.
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Hodgson, Shirley V. "Genetic studies in Duchenne muscular dystrophy." Thesis, University of Oxford, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.235878.
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Wakefield, Philip M. "Gene therapy for duchenne muscular dystrophy." Thesis, University of Oxford, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.365743.
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Koppaka, Sisir. "Imaging biomarkers for Duchenne muscular dystrophy." Thesis, Massachusetts Institute of Technology, 2015. http://hdl.handle.net/1721.1/106959.
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Thesis: S.M., Massachusetts Institute of Technology, School of Engineering, Center for Computational Engineering, Computation for Design and Optimization Program, 2015.<br>Cataloged from PDF version of thesis.<br>Includes bibliographical references (pages 75-78).<br>Duchenne muscular dystrophy (DMD) is the most common muscular dystrophy of childhood and affects 1 in 3600 male births. The disease is caused by mutations in the dystrophin gene leading to progressive muscle weakness which ultimately results in death due to respiratory and cardiac failure. Accurate, practical, and painless tests to diagnose DMD and measure disease progression are needed in order to test the effectiveness of new therapies. Current clinical outcome measures such as the sixminute walk test and North Star Ambulatory Assessment (NSAA) can be subjective and limited by the patient's degree of effort and cannot be accurately performed in the very young or severely affected older patients. We propose the use of image-based biomarkers with suitable machine learning algorithms instead. We find that force-controlled (precise acquisition at a certain force) and force-correlated (acquisition over a force sweep) ultrasound helps to reduce variability in the imaging process. We show that there is a high degree of inter-operator and intra-operator reliability with this integrated hardware-software setup. We also discuss how other imaging biomarkers, segmentation algorithms to target specific subregions, and better machine learning techniques may provide a boost to the performance reported. Optimizing the ultrasound image acquisition process by maximizing the peak discriminatory power of the images vis-à-vis force applied at the contact force is also discussed. The techniques presented here have the potential for providing a reliable and non-invasive method to discriminate, and eventually track the progression of DMD in patients.<br>by Sisir Koppaka.<br>S.M.
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Tay, Shaun Li Jian. "Duchenne Muscular Dystrophy—Insight and Treatment." Thesis, The University of Arizona, 2015. http://hdl.handle.net/10150/595055.
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Duchenne Muscular Dystrophy (DMD) is a genetic disorder characterized by progressive degeneration of muscle fibers and dystrophic changes on muscle biopsy¹. DMD accounts for approximately 50% of all dystrophinopathies, with around 21,000 male babies born with the disease each year², ³, ⁴, ⁵. It is also the most lethal X-linked recessive disorder as phenotypic traits are not immediately present at birth¹¹, ³. Patients usually do not live past their 20's without medical intervention to treat associated respiratory and cardiac dysfunctions¹¹, ³. For these reasons DMD remains one of the greatest threats, amongst a range of pediatric pathologies, to the normalcy of child development and parental care. Although treatment options have shown to mitigate the progression of DMD, most are controversial and costly - the estimated annual treatment cost of DMD per patient is $50,953⁵⁸. In light of this, disease awareness and public health education are critical components for acquiring funds needed for research towards a cure¹². My hope is that through this integrated overview of DMD, the medical layman will better understand the depths of this lethal disease, and how it can be detrimental to both the affected child and his caretaker.
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Matecki, Stefan. "Fonction respiratoire et myopathie de Duchenne." Montpellier 1, 1997. http://www.theses.fr/1997MON11135.
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vianello, sara. "Molecular modifiers in Duchenne muscular dystrophy." Doctoral thesis, Università degli studi di Padova, 2018. http://hdl.handle.net/11577/3426720.
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Duchenne muscular dystrophy (DMD) is an X-linked progressive neuromuscular disease affecting 1:3500 –1/5000 boys at birth. It is caused by the absence of dystrophin, a subsarcolemmal protein that confers membrane stability linking cytoskeletal actin to the extracellular matrix. Dystrophin is part of a multi-protein complex called dystrophin associated protein complex (DAPC), which contains, among the other components, β-dystroglycan and nitric oxide synthase (NOS). The consequences of the absence of dystrophin are: deregulation of calcium homeostasis, tissue necrosis, and progressive accumulation of fat and fibrosis and loss of contractile muscle fibers. The ensuing muscle weakness leads to progressive and severe disability, with loss of independent ambulation around the early teens, and cardiac and respiratory failure leading to patient’s death, usually around the age of 20-30 years.Despite all patients having a complete lack of dystrophin in muscle fibers, a relevant inter-patient variability in disease severity is observed (e.g. loss of ambulation may range from 8 to beyond 15 years of age). Emerging evidence points to genetic modifiers, i.e. polymorphisms in genes different form the disease gene, as one of the causes of this variability, but little is yet known about the underlying molecular mechanisms.My PhD work can be divided into 4 aims: Aim 1: To characterize the molecular mechanism underlying the modifier effect of the rs28357094 T>G SNP in the SPP1gene, encoding osteopontin (OPN) the first identified genetic modifier of DMD. I treated dystrophic and healthy cell line with two different concentrations of deflazacort (DFZ), one of the glucocorticoids mainly used to treat DMD patients, in order to analyze osteopontin expression in relation to genetic background at rs24357094. The results obtained revealed: (I) a developmental regulated expression pattern of OPN; (II) no difference of osteopontin expression are observed related to rs28357094 genotype; (III) an increase in OPN expression only in TG DFZ-treated myotubes, suggesting a possible interaction between glucocorticoid responsive elements (GRs) in the promoter of the SPP1gene and the glucocorticoid.Aim 2: To investigate the possible roles of SPP1splicing isoforms in DMDmuscle biopsies and cells. Three SPP1isoforms, named a, b and c, were analyzed. SPP1mRNA studies revealed that all three isoforms are overexpressed in DMD muscle compared to controls, but not in myogenic cell cultures. Moreover, SPP1isoforms expression was directly correlated withage in DMD patients’ muscle biopsies. Finally, muscle biopsies carrying the rs24357094 TT genotype showed an increased expression of all three SPP1isoforms compared to TG genotype.
Aim 3: To validate the known DMD geneticmodifiers in novel cohorts of DMD patients utilizing different outcome measures. First, we asked if SPP1genotype and LTBP4haplotype (the second identified modifier of DMD) can modulate the cardiac involvement in DMD. LTBP4haplotye and the SPP1rs28357094 were genotyped in 168 DMD patients. LTBP4haplotype is composed of 4 polymorphisms in perfect linkage disequilibrium (LD). The genotype at rs10880 resulted, as expected, to be associated to a delay at age of loss of ambulation (LoA) and, as novel finding, also to a delay in cardiomyopathy onset. The SPP1minor G allele at rs28357094 resulted also associated to a later cardiomyopathy onset.Finally, I participate to the identification of the third genetic modifier in DMD: CD40. CD40was identified through a GWAS approach in a large cohort of DMD patients.The CD40rs1883832 C>T polymorphism is located within the Kozak sequence of the gene and it causes a decrease of transcriptional activity of the promoter resulting in an increase of the CD40 secreted isoform. In order to validate CD40 as a genetic modifier in DMD in an independent cohort from the discovery cohort, rs1883832 was genotyped in 96 DMD patients.DMD patients carrying the minor T allele lost ambulation earlier compared to patients carrying the C allele. Moreover, in order to study the functional role of CD40 in DMD, RT-PCR and immunoblot were performed in a subset of patients’ muscle biopsies stratified according to rs1883832 genotype. Our results reveal that the minor T allele is associated to an increase of the transcript and a decrease of the protein compared to C genotype.Taken together these data contribute to clarify some aspects of the molecular mechanisms underlying the downstream consequences of genetic modifiers in DMD. Further studies are needed to fully translate the knowledge acquired in thefield of genetic modifiers in DMD to the clinic, e.g. to implement patient genotyping for genetic counseling, prognosis, planning of treatments, and stratification in clinical trials
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MARCHI, Michele. "DESIGN FOR DUCHENNE. Linee guida per il progetto di costruzione o ristrutturazione di abitazioni per famiglie Duchenne." Doctoral thesis, Università degli studi di Ferrara, 2015. http://hdl.handle.net/11392/2389086.
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Fisher, Rosie. "Utrophin in therapy of Duchenne muscular distrophy." Thesis, University of Oxford, 2001. http://ora.ox.ac.uk/objects/uuid:192fbccd-d037-4ce8-b1cd-0315afe1860d.
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Smith, Philip E. M. "Breathing during sleep in Duchenne muscular dystrophy." Thesis, University of Liverpool, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.235539.
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Babaria, Arati. "Molecular Mechanisms that Underlie Duchenne Muscular Dystrophy." Thesis, The University of Arizona, 2016. http://hdl.handle.net/10150/612573.
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Duchenne muscular dystrophy is an inherited, X-linked recessive skeletal muscle disorder that is characterized by mutations in the dystrophin gene [1]. Therefore, the disease affects primarily males and women are typically carriers. 1 in 3500 males in the United States are affected [1]. Dystrophin is a critical, large scaffolding protein in the dystrophin-glycoprotein complex found at the sarcolemma of skeletal muscle [1]. The complex helps maintain sarcolemma integrity and stability during muscle contractions by coupling the extracellular matrix proteins to the intracellular cytoskeleton in skeletal muscle [1]. Loss-of-function mutations in the dystrophin protein affect all skeletal muscle found throughout the human body. The 427 kD protein is also present in cardiac muscle, the brain, and peripheral nerves, thus affecting these tissues over time, as well [1]. One theory suggests the weakened stability of the dystrophin-glycoprotein complex when dystrophin is not expressed results in transient membrane tears during contraction, which permit pathological calcium influx [1]. Damaged skeletal muscle results in repair and regeneration of the tissue however, continual damage over time (referred to as muscle wasting) results in extensive fibrosis and loss of muscle fibers. The purpose of this thesis is to provide a comprehensive review on several molecular mechanisms that underlie Duchenne muscular dystrophy and to investigate current treatments and propose potential therapeutic targets for future research.
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Moura, Maria Clara Drummond Soares de. "Alterações atencionais na distrofia muscular de duchenne." Universidade de São Paulo, 2009. http://www.teses.usp.br/teses/disponiveis/47/47135/tde-31072009-151351/.
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A Distrofia Muscular de Duchenne (DMD) é uma doença de herança genética recessiva que gera um quadro de fraqueza muscular progressiva muitas vezes associada à deficiência mental. A atenção, considerada como o mecanismo cerebral que permite o processamento de uma informação em detrimento de outras, poderia estar alterada na doença contribuindo pelo menos em parte para o comprometimento cognitivo global observado. OBJETIVO: Investigou-se o desempenho atencional de meninos portadores de DMD utilizando-se testes psicofísicos específicos. MÉTODOS: Testou-se 30 meninos com DMD (GD) e 30 meninos saudáveis (GC), com idade entre 10 e 16 anos, em uma tarefa de tempo de reação de escolha, que consistia em responder o mais rapidamente possível a um estímulo alvo visual lateralizado com mão do mesmo lado. Antes do aparecimento deste estímulo, orientava-se a atenção automática do participante por meio de um estímulo visual periférico não-informativo espacialmente ou então sua atenção voluntária, por meio de um estímulo visual central que informava o local de maior probabilidade de aparecimento do estímulo alvo. RESULTADOS: Os tempos de reação (TR) foram maiores para o GD do que para o GC tanto no teste de atenção automática (p<0,001) quanto no teste de atenção voluntária (p<0,001). Os TR no teste de atenção voluntária foram menores do que no teste de atenção automática no caso do GD (p<0,001) mas não no caso do GC (p=0,20). O efeito atencional (diferença entre o TR na condição oposta/inválida e o TR na condição mesma/válida) não diferiu entre os dois grupos no caso da atenção automática (p=0,846), mas foi maior no GD do que no GC no caso da atenção voluntária (p<0,001). Não foram observadas quaisquer assimetrias interlaterais. DISCUSSÃO: Os resultados sugerem que os meninos com DMD apresentam prejuízo na capacidade de orientar a atenção no tempo e também gerenciam de modo anômalo para a idade a atenção espacial voluntária. O grande efeito atencional apresentado por eles é compatível com um atraso na maturação do seu sistema atencional.<br>OBJECTIVE: Considering the divergence in the literature regarding the base of the cognitive deficits in Duchenne Muscular Dystrophy (DMD) patients, the objective of this work was to investigate their attention performance using psychophysical tests. METHODS: 25 boys with DMD (GD) and 25 healthy boys (GC), which were 10 to 16 years old, were tested in a choice reaction time task. They were instructed to respond as fast as possible to a lateralized visual target stimulus with the same side hand. Attention was automatically oriented by a peripheral spatially non-informative prime stimulus or, alternatively, voluntarily oriented by a central spatially informative cue. RESULTS: Reaction times (RT) were higher for GD than for GC in both automatic attention (p<0,001) and voluntary attention tests (p<0,001), as expected. RTs in voluntary attention tests were smaller than on automatic attention tests for GD (p<0,001) but not for GC (p=0,200). The attentional effect (difference between RT in the opposite/invalid condition and RT in the same/valid condition) was found not to differ between the two groups in the case of automatic attention (p=0,846); however it was greater for GD than for GC in the case of voluntary attention (p<0,001). Interlateral asymmetries have not been observed. CONCLUSION: These results suggest that patients with DMD are less efficient to allocate both automatic and voluntary attention. The lack of the expected motor preparation by the patients when the peripheral prime stimulus was used suggests a disturbance of temporal attention. The larger cost and benefit observed when the endogenous visual cue was used suggests a delay in maturation of the executive functions necessary to adequately allocate voluntary attention.
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Skyrme, Sarah Louise. "Research decisions : living with Duchenne muscular dystrophy." Thesis, University of Newcastle upon Tyne, 2014. http://hdl.handle.net/10443/2678.
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Duchenne muscular dystrophy (DMD) is a severe form of muscular dystrophy that affects males. Muscle deterioration leads to increasing levels of disability during childhood and adolescence, with death commonly occurring in the late teens or early twenties, although changes in care and treatment are leading to increasing numbers of boys with DMD living into adulthood. Parents and parent-led charities are raising funds to find effective treatments and a cure, and much of the medical research they promote requires the participation of those with DMD. This raises questions about children and young people’s involvement in research, including their role and approach to consent and how willing they are to be involved in the medical research their parents and DMD charities advocate. Through qualitative interviews with nine boys and young men with DMD and one young woman with muscular dystrophy, I explored their thoughts on medical research and the broader issue of how they live and cope with their condition. As part of this discussion I examined how they might make a decision to participate in medical research, focusing on the processes, interactions and individuals they consider important in helping them to decide. My approach privileges the participants’ thoughts and opinions, positioning them as able social actors (James & Prout 1997) who can provide insight into their experiences. Currently little is known about the lives of children and young people with a significant, degenerative disability, particularly around their thoughts on medical research participation and decision-making (Dixon-Woods 2006). The views of my participants provide the basis for this research, with work from the sociology of childhood and from disability studies informing and contextualising it. The way in which parents are involved in daily life is discussed to gain an understanding of how the participants work with those they trust. This relationship may provide understandings of how decisions are influenced by family input and how support assists those who are young and have a degenerative condition. It is possible that this model of working with the significant people in their lives promotes agency and independence, aiding the participants towards, rather than away from autonomy.
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Dunant, Patrick. "Strategies for Molecular Therapy of Duchenne Muscular Dystrophy." Diss., lmu, 2003. http://nbn-resolving.de/urn:nbn:de:bvb:19-12429.
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Pertl, Cordula. "Neue Strategien molekularer Therapien bei der Duchenne Muskeldystrophie." Diss., Ludwig-Maximilians-Universität München, 2013. http://nbn-resolving.de/urn:nbn:de:bvb:19-160818.
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Bia, Britta Lydia. "Cardiomyopathy in mouse models of Duchenne muscular dystrophy." Thesis, University of Oxford, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.301799.
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Gardner, Rebecca Jane. "Mutation analysis of Duchenne and Becker muscular dystrophies." Thesis, King's College London (University of London), 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.321813.
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Markham, Larry W. "Reducing Cardiomyopathy in Duchenne Dystrophy with Steroid Treatment." University of Cincinnati / OhioLINK, 2006. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1155569714.
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Winnard, Alissa Vira. "Exception patients in Duchenne and Becker muscular dystrophy /." The Ohio State University, 1993. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487847309050842.
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Fusto, Aurora. "Genetic and clinical modifiers in Duchenne muscular dystrophy." Doctoral thesis, Università degli studi di Padova, 2019. http://hdl.handle.net/11577/3423193.
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La distrofia muscolare di Duchenne (DMD) è una malattia neuromuscolare causata da mutazioni del gene codificante per la distrofina (DMD) che ne impediscono la produzione. Sebbene tutti i pazienti affetti da DMD condividano lo stesso difetto biochimico di distofina, a livello fenotipico è osservabile una grande varietà in termini di progressione della malattia, ad esempio nell'età di perdita della deambulazione o nell'età di insorgenza di complicanze cardiache e respiratorie. Questa variabilità è dovuta a diversi fattori, alcuni di origine ambientale (ad esempio la qualità delle cure a cui hanno accesso i malati) e altri di natura genetica, suddivisibili in cis-acting, ossia l'effetto dei diversi tipi di mutazioni nel gene DMD sul fenotipo, e trans-acting, ovvero l'effetto di SNPs modificatori sul fenotipo. Questi ultimi sono polimorfismi in geni diversi da quello causativo della malattia, che hanno però un effetto sul suo fenotipo. Usando come outcome la perdita della deambulazione sono stati individuati numerosi SNPs modificatori, quali: rs28359074 in SPP1, rs2303729, rs1131620, rs1051303 e rs10880 in LTBP4, rs1883832 e rs6074022 in CD40, rs1815739 in ACTN3, rs2725797 and rs2624259 in THBS1.
L'obiettivo del mio percorso di dottorato è stato lo studio della variabilità genetica e clinica nella distrofia muscolare di Duchenne, conducendo indagini in vitro e studi osservazionali retrospettivi.
Il primo approccio è stato utilizzato per verificare l'interazione dello SNP modificatore rs28357094 nel gene SPP1, codificante la proteina osteopontina (OPN), e il trattamento farmacologico con glucocorticoidi (nello specifico deflazacort) in mioblasti e miotubi primari derivati da controlli sani e da pazienti DMD. Lo studio ha messo in evidenza che l'osteopontina è sovraespressa in miotubi con genotipo TG per lo SNP rs28357094, rispetto a TT. Inoltre, è stato rilevato che il trattamento con Deflazacort induce l'aumento della produzione di OPN solo nei miotubi con genotipo TG. Questi risultati hanno confermato l'interazione tra il modificatore genetico e il trattamento con glucocorticoidi, sottolineando l'importanza del genotipo di rs28357094 nella risposta al trattamento farmacologico nei pazienti DMD.
Successivamente, il nostro interesse si è rivolto allo studio dell'effetto non solo degli SNPs modificatori, ma anche dell'effetto delle diverse mutazioni nel gene della distrofina (DMD) e del trattamento farmacologico sul decorso della malattia nei pazienti DMD, focalizzando la nostra attenzione su diversi aspetti fenotipici, quali: la performance degli arti superiori, la funzione respiratoria e cardiaca. L'obiettivo di questi studi, resi possibili dalla collaborazione di numerosi centri italiani nella raccolta dei dati clinici, è stato quello di evidenziare potenziali nuovi target terapeutici e di fornire importanti informazioni per la stratificazione dei pazienti nel corso dei trial clinici.
Il nostro lavoro ha permesso di confermare l'influenza di alcuni degli SNPs, noti per il loro effetto sulla perdita della deambulazione, anche su altri parametri clinici consentendoci di identificare misure di efficacia clinica nella DMD. E' stato poi possibile documentare l'effetto protettivo del trattamento con glucocorticoidi anche su aspetti della malattia non strettamente correlati alla deambulazione, come la funzionalità respiratoria e cardiaca e dimostrare come alcune mutazioni nel gene DMD abbiano effetti diversi sull'espressione del fenotipo dei pazienti.
Infine, il mio interesse si è rivolto al modelling di malattie neuromuscolari in sistemi di coltura tridimensionali, con lo scopo di far luce sui meccanismi molecolari causativi e fornire piattaforme utili per la ricerca e il test di molecole con azione farmacologica.<br>Duchenne muscular dystrophy (DMD) is a neuromuscular disease caused by out-of-frame mutations in the DMD gene resulting in the lack of dystrophin in skeletal muscle fibres. Even though all DMD patients share the same molecular defect, it is possible to observe high variability in the disease's progression, i.e. differences in loss of ambulation age, onset of respiratory and cardiac failure.
This variability is due both to environmental and genetic factors. Genetic factors may be divided in cis-acting, nominally the type of DMD mutation, and trans-acting, or modifier SNPs. These are polymorphisms in genes, different from the causative DMD, that have and effect on the phenotype. There are several modifier SNPs known to alter age at loss of ambulation. These are: rs28359074 in SPP1, rs2303729, rs1131620, rs1051303 e rs10880 in LTBP4, rs1883832 e rs6074022 in CD40, rs1815739 in ACTN3, rs2725797 e rs2624259 in THBS1.
The main goal of my PhD was the study of clinical and genetic variability in DMD, through in vitro and observational retrospective studies.
We carried an in vitro research to verify the interaction of rs28357094 in SPP1, that codifies for osteopontin (OPN), and glucocorticoids treatment (Deflazacort) in primary myoblasts and myotubes derived from healthy individuals and DMD patients. We found that OPN is overexpressed in rs28357094 TG genotype myotubes, compare to TT genotype. Moreover, deflazacort treatment induces an increase in OPN production in TG myotubes. These results confirmed the interaction between rs28357094 and glucocorticoids treatment.
Afterwards, we studied the effect of the known modifiers, on multiple phenotypic aspects: upper limbs performance, respiratory and cardiac function. These analyses had been made possible thanks to the collaboration in the data collection phase of several Italian centres. Our goals were to find new potential therapeutic targets and to provide information useful for patients stratification in clinical trials.
We were able to confirm the effect of some SNPs, known to be modifier of age at loss of ambulation, on diverse outcomes measures as performance of upper limbs, respiratory and cardiac function. Furthermore, we assess the protective effect of glucocorticoids treatments on diseases aspects other than ambulation, and provide new information about the correlation between DMD mutations and phenotype severity.
Finally, I switched my interest to three-dimensional modelling of neuromuscular diseases, aiming to clarify pathological mechanisms and provide a versatile platform for drug screening and test.
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Duchêne, Benjamin. "Utilisation des technologies CRISPR/Cas9 pour le développement d'approches thérapeutiques pour le traitement de la dystrophie musculaire de Duchenne." Doctoral thesis, Université Laval, 2019. http://hdl.handle.net/20.500.11794/35436.
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La dystrophie musculaire de Duchenne, est une maladie qui résulte d’une mutation dans le gène codant pour la dystrophine. Cette mutation entraine l'absence de la protéine dystrophine dans les fibres musculaires et mène à une dégénérescence des différents muscles ce qui engendre une défaillance cardiorespiratoire suivie d’un décès prématuré. La récente découverte du système CRISPR/Cas9 ouvre de nouvelles perspectives pour le développement d’un traitement curatif pour la DMD. A l’aide d’un ARNg, reconnaissant une séquence cible protospacer localisée à proximité d’un PAM (protospacer adjacent motif), l’endonucléase Cas9 génère une coupure double brin dans l’ADN. Il a été démontré que l’utilisation d’une paire d’ARNgs ciblant des introns permettait de générer de larges délétions et de restaurer un cadre de lecture propice à l’expression d’une dystrophine tronquée dans des cellules de patients DMD. Cependant, cette approche ne prend pas en considération la structure de la dystrophine qui résulte de cette délétion. Il a été suggéré que chez les patients atteints de la dystrophie musculaire de Becker, produisant une dystrophine tronquée mais fonctionnelle, la sévérité de la maladie serait reliée au type de délétion et à la structure de la dystrophine qui en résulte. Il semble donc pertinent de travailler au développement d’une approche qui prend aussi en considération la structure des répétitions de type spectrine. D’autre part, le système CRISPR/Cas9 envahit progressivement toutes les sphères des sciences de la vie et soulève par la même occasion des questions de sécurité pour les patients. En effet, la possibilité de mutations hors-cible ou d’une réponse immunitaire dirigée contre ces endonucléases pourrait freiner l’application clinique de ces outils. Ainsi nous avons envisagé différentes approches qui contribueraient à limiter des tels effets pouvant s’avérer néfastes pour les patients. Nos résultats montrent qu’il est possible d’utiliser la Cas9 de S.aureus ainsi qu’une paire d’ARNgs ciblant des exons pour induire une délétion dans l’ADN génomique. Cette délétion permet la formation d’un exon hybride qui restaure non seulement le cadre de lecture du gène de la dystrophine[1], mais contribue aussi à la formation d’une répétition de type spectrine hybride correctement phasée. Lors de nos expérimentations, nous avons été capables d’induire la production de dystrophine in vitrosur des lignées de cellules de quatre patients DMD et in vivodans un modèle de souris dystrophique. Ensuite, avec la technologie du Feldan Shuttle nous avons montré qu’il était possible d’induire l’édition du gène de la dystrophine (gène humain ou murin) en livrant directement des complexes ribonucléoprotéiques dans le muscle d’une souris dystrophique. Cette édition a permis d’induire l’expression de protéine dystrophine dans les fibres musculaires, mais cette approche reste pour le moment réduite à des applications localisées. Enfin, nous avons démontré que l’inactivation de l’activité autocatalytique du ribozyme N79 serait une stratégie envisageable pour contrôler l’expression d’une endonucléase. Présentement, ce système n’a fait ses preuves que lors d’expérimentations in vitro, mais il ouvre la porte au développement de nouveaux moyens de contrôler pharmacologiquement l’édition du génome par le système CRISPR/Cas9. Finalement, l’ensemble de ces travaux contribuent à une meilleure compréhension des défis à relever pour mettre au point un traitement curatif pour la dystrophie musculaire de Duchenne, de façon plus efficace et sécuritaire.<br>Duchenne Muscular Dystrophy is one of the most severe genetic disease. It is caused by a mutation in the dystrophin gene. Such mutation is responsible for the absence of the dystrophin protein in the muscles thus leading to muscle wasting and to a premature death following cardiorespiratory failure. The discovery of the CRISPR/Cas9 systems opened the path for the establishment of curative treatments for genetic diseases, such as DMD. A Cas9 endonuclease can generate a double strand break in the DNA at a targeted locus through a guide RNA that specifically recognize a DNA protospacer sequence located closed to a protospacer adjacent motif (PAM). Recent work published by others demonstrated that the use of a pair of sgRNAs targeting introns permitted to create a genomic deletion that restores the DMD gene reading frame thus leading to de novosyn thesis of a truncated dystrophin protein. However, such deletion does not consider the resulting structure of the central part of the dystrophin. In Becker muscular dystrophic patients, a truncated dystrophin protein is synthesized but the severity of the disease could be related to the structure of this protein. Consequently, it seems relevant to develop a therapeutic approach that considers the structure of the spectrin-like repeat that forms the central rod-domain of the dystrophin protein. Further more, while CRISPR/Cas9 is on the rise it also raises safety issues for patients. Indeed, off-target mutations and immune response directed against such endonuclease can occur thus preventing the possibility of starting clinical trials. Consequently, there is an increasing need to develop safer approaches that may counter such undesirable effects. Our results demonstrated the feasibility of inducing a large genomic deletion with the Cas9 from S. aureus with a pair of sgRNAs targeting exons. Such deletion allows the formation of a hybrid exon that could, in addition to restoring the expression of the dystrophin protein, restore the correct structure of the spectrin-like repeat in its central rod-domain. We have been able to demonstrate such dystrophin expression in vitroand in vivoin four different DMD patient cell lines and in a dystrophic mouse model, respectively. Next, we envisioned the delivery of Cas9/sgRNA ribonucleoprotein complexes using the Feldan Shuttle technology. We provided proof-of-principle that such delivery permits the editing of the dystrophin gene in the TA of mouse models. Following the editing, dystrophin protein expression was restored in the treated muscles of a dystrophic mouse model. Since this approach remains restricted to in situ treatments, further development should be addressed to allow systemic delivery of Cas9/sgRNA. Finally, we provided evidence that the self-catalytic activity of the ribozyme N79 can be controlled using toyocamycin. Even if it only demonstrated its efficacy in vitro, this system opens the path to the development of a different tool for the pharmacological induction of endonuclease protein expression. Finally, this work contributes to the improvement of our understanding for the establishment of a potent and safe therapy to find a cure for DMD.
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Johansson, Camilla. "Exploring genotype to phenotype correlations in Duchenne muscular dystrophy." Thesis, KTH, Skolan för bioteknologi (BIO), 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-215302.
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Roberts, Thomas C. "Duchenne muscular dystrophy : RNA-based therapeutics and microRNA biology." Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:f53ea1f3-92db-4f90-ba95-01f2a56eae8f.
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Duchenne muscular dystrophy (DMD) is a progressive muscle wasting disorder caused by absence of functional dystrophin protein. This thesis describes investigations into the role of small non-coding RNAs in both DMD pathology, and as potential therapeutic molecules. MicroRNAs (miRNAs) are a class of small RNAs that regulate gene expression and are implicated in wide-ranging cellular processes and pathological conditions. This study has compared differential miRNA expression in proximal and distal limb muscles, diaphragm, heart and serum in the mdx dystrophic mouse model relative to wild-type controls. Global transcriptome analysis revealed muscle-specific patterns of differential miRNA expression as well as commonalities between tissues, including previously identified dystromirs. miR-1, miR-133a and miR-206 were found to be highly abundant in mdx serum, suggesting that these miRNAs are promising disease biomarkers. Indeed, the relative serum levels of these miRNAs were normalised in response to peptide-PMO mediated dystrophin restoration therapy. This study has revealed further complexity in the miRNA transcriptome of the mdx mouse, an understanding of which will be valuable for the development of novel DMD therapeutics and for monitoring their efficacy. Myostatin is a secreted growth factor that negatively regulates muscle mass and is therefore a potential pharmacological target for the treatment of muscle wasting disorders such as DMD. This study describes a novel myostatin inhibition approach in which small interfering RNAs (siRNAs) complementary to a promoter-associated transcript induce transcriptional gene silencing (TGS) in cultured myotubes. Silencing was sensitive to treatment with the histone deacetylase inhibitor Trichostatin A, and the silent state chromatin mark H3K9me2 was enriched at the myostatin promoter following siRNA transfection, suggesting epigenetic remodelling underlies the silencing effect. These observations suggest that long-term epigenetic silencing may be feasible for myostatin and that TGS is a promising novel therapeutic strategy for the treatment of muscle wasting disorders. The work in this thesis therefore demonstrates the potential of small RNAs as therapeutic agents and as disease biomarkers in the context of DMD.
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Zachi, Elaine Cristina. "Avaliação neuropsicológica de pacientes com distrofia muscular de Duchenne." Universidade de São Paulo, 2009. http://www.teses.usp.br/teses/disponiveis/47/47135/tde-22022010-100117/.
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A Distrofia Muscular de Duchenne (DMD) é provocada por mutações no gene distrofina. Este gene codifica a proteína distrofina, que exerce papel importante na manutenção da estabilidade da membrana da fibra muscular. Os objetivos do estudo consistiram em examinar o desempenho neuropsicológico de pacientes com DMD e verificar a influência de deleções downstream ao exon 45 sobre o mesmo. Foram avaliados os perfis de inteligência de 63 pacientes com DMD por meio das Escalas Wechsler de Inteligência ou o Teste de Raven. A faixa etária do grupo variou de 6 a 26 anos de idade e a escolaridade, 1 a 16 anos de estudo formal. Os pacientes com escores de inteligência normais (n=34) foram comparados com controles quanto às funções neuropsicológicas. O grupo controle foi composto por 34 jovens do sexo masculino pareados por idade. Os testes incluíram medidas de memória verbal (Teste de Aprendizado Verbal de Rey), habilidade viso-espacial (Teste de Organização Visual de Hooer), funções executivas (fluência verbal e Teste de Wisconsin de Classificação de Cartas). A avaliação também incluiu testes da bateria Cambridge Neuropsychological Test Automated Battery (CANTAB) para o exame de: tempo de reação simples (Simple Reaction Time); tempo de reação com dupla escolha (Choice Reaction Time), atenção visual sustentada (Rapid Visual Processing), amplitude atencional/memória operacional (Spatial Span, ordem direta e inversa), memória visual de curto e longo prazo (Pattern Recognition Memory), reconhecimento de estímulos complexos apresentados simultaneamente ou após intervalo (Delayed Matching to Sample), memória espacial (Spatial Recognition Memory) e tomada de decisão (Information Sampling Task). O Inventário de Depressão de Beck (BDI) foi administrado para exame de sintomas de depressão e o Inventário de Comportamentos da Infância e Adolescência (CBCL) foi utilizado como medida de alterações de comportamento. Utilizou-se a análise de variância (one-way ANOVA) na comparação entre grupos. As covariáveis foram controladas por meios estatísticos. Os pacientes com DMD obtiveram medias de QIs com 1 desvio padrão abaixo da media da população. Após controle para covariáveis, os pacientes com DMD mostraram desempenhos significantemente inferiores nos testes de Aritmética, Vocabulário, Compreensão, Dígitos e no Teste de Wisconsin (número de erros totais, erros perseverativos, respostas de nível conceitual e categorias completas). Também mostraram tempos de reação mais longos (Simple Reaction Time), menor amplitude atencional tanto na ordem direta, quanto inversa (Spatial Span) e menor número de acertos no teste de tomada de decisão (Information Sampling Task) (p<0,05). A proporção de pacientes com deleções no gene distrofina foi de 54% (34/63). Não foi encontrada associação entre os resultados de inteligência e dados genéticos. Comparados com controles, os 14 pacientes com deleção downstream ao exon 45 e QI≥80 mostraram dificuldades mais específicas. O tempo de reação foi discutido conforme a complexidade da tarefa. Os participantes do grupo controle apresentaram escores mais altos no BDI e CBCL, indicando maior ocorrência de sintomas. Possíveis fatores relacionados foram discutidos. Há evidências de que as deleções downstream ao exon 45 (relacionadas à isoforma cerebral da distrofina Dp140) estão envolvidas com a menor eficiência de tomada de decisão dentre os pacientes com DMD. Os achados também sugerem a associação entre a DMD e disfunções frontais.<br>Duchenne Muscular Dystrophy (DMD) is caused by mutations in the dystrophin gene. This gene codes for dystrophin, a protein important for maintaining the stability of muscle-fiber membranes. The objectives of the study were to examine neuropsychological performance in patients with DMD and the influence of deletions in the dystrophin gene (the Dp140 regulatory region) on neuropsychological function. General intelligence was investigated in 63 DMD patients using the Wechsler Intelligence Scale or the Raven\'s Matrices Test. The age range for DMD participants was from 6 to 26 years, with a range of 1 to 16 years of formal education. The participants who had intellectual scores in the normal range (n=34) were compared to controls in terms of neuropsychological function. The control group was composed of 34 male age-matched subjects. Patients were divided into groups according to the region of mutation in the dystrophin gene and those with delection downstream of exon 45 were also compared to controls. The battery included the Wechsler scale subtests and measures of verbal memory (Rey Auditory Verbal Learning Test), viso-perceptual skills (Hooper Visual Organization Test), executive function (FAS, animals and Wisconsin Card Sorting Test). The assessment also included tests of the Cambridge Neuropsychological Test Automated Battery (CANTAB) to examine reaction time (Simple Reaction Time and Choice Reaction Time), sustained attention (Rapid Visual Processing), working memory (Spatial Span, forward and reverse), short and long term visual memory (Pattern Recognition Memory), recognition memory for complex stimuli presented simultaneously or after short interval (Delayed Matching to Sample), spatial memory (Spatial Recognition Memory), and decision making (Information Sampling Task). The Beck Depression Inventory (BDI) was administered for depression symptoms assessment and the Child Behavior Checklist (CBCL) was used as a measure of disruptive behavior. Analysis of variance (one-way ANOVA) was used. Covariates were controlled statistically. The DMD patients had mean IQs about one standard deviation lower than population means. Verbal IQ was significantly lower than Performance IQ. After controlling for covariates, significant difference (p<0.05) appeared between DMD patients and controls and DMD was associated to lower IQs (Full Scale, Verbal, and Performance) and worse performances on Arithmetic, Vocabulary, Comprehension, Digit Span, Wisconsin Test (total errors, perseverative errors, conceptual level responses, and categories completed), Spatial Span (forward and reverse recall), and on the number of correct trials on Information Sampling Task. They also showed slower simple reaction times (Simple Reaction Time). The proportion of patients with dystrophin gene deletions was 54% (34/63). No relationship was established between intelligence results and genetic data. Compared to controls, 14 patients with delection downstream of exon 45 and normal IQs showed more specific deficits. Reaction time was discussed in terms of complexity of the task. Controls showed significant higher BDI and CBCL scores than DMD patients. Possible related factors were discussed. There is evidence to indicate that delections downstream of exon 45 (related to cerebral dystrophin isoform Dp140) are involved in decision making impairment in patients with DMD. The findings suggest that DMD may be related to frontal dysfunction.
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Geisemeyer, Sarah. "Duchenne muscular dystrophy : a genetic, cognitive and psychosocial approach." Thesis, Kingston University, 2017. http://eprints.kingston.ac.uk/40678/.
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Duchenne muscular dystrophy (DMD) is a severe, progressive muscle wasting disorder that affects 1 in 3600 male births. It is caused by genetic mutations in the dystrophin gene. This study investigated several aspects of the neuromuscular disorder within a population of Brazilian DMD boys and their families. This study's framework was laid out within the prism of an interacting cycle of genetic factors, cognitive functioning, and psychosocial aspects that underlie the neuromuscular disorder. It focuses on DMD's aetiology, history and previous research on genetic, cognitive and psychosocial aspects. Mixed methods were adopted to allow for a more encompassing view of the neuromuscular disorder: cognitive tests, an emotion recognition battery, genetic analyses, well-being questionnaires, and interviews were applied. Correspondent, quantitative and qualitative data analysis was carried out. The findings of 32 DMD patients (mean age 10.4 years, SD= 2 years) and 31 control subjects (mean age 9.4 years, SD= 3 years) revealed severe cognitive dysfunctioning in all assessed cognitive domains in the DMD population, as well as in the ability of emotion recognition. In the DMD group, it could be shown that poor executive functioning stood in a positive correlation with a poor ability of emotion recognition. The DMD patients' cognitive phenotypes were correlated with the genetic mutations in their dystrophin gene, but no relationship between the patients' genotype and cognitive phenotype could be confirmed. These results were contrary to previous research, which suggested that specific mutations in the dystrophin gene cause cognitive impairment. The DMD group scored poorly on the emotion recognition task, which is also a characteristic of autism spectrum disorder. However, when diagnosing for autistic characteristics through means of an interview, only a few similarities between the two disorders could be found. In order to assess the psychosocial components that come along with the disorder, well-being questionnaires were supplied. Interestingly, DMD boys scored higher on well-being than the boys in the control group. Moreover, 30 of the DMD caregivers (mean age app. 31 years) also revealed high levels of well-being, which correlated positively with the well-being of their sons, suggesting high levels of resilience. Given the participants' socio-economic hardship and the lack of governmental help, it was concluded that participants showed an incredible level of resilience that most likely resided within their faith, which nearly all of them stated to be the reason for their strength to strive. The relevant and new information about cognitive, genetic and social aspects of DMD uncovered in this study will pave the way for further (and much needed) studies into psychosocial aspects of the disorder.
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Buser, Karen N. Kamiri. "Parental Attitudes Regarding Newborn Screening for Duchenne Muscular Dystrophy." Case Western Reserve University School of Graduate Studies / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=case1307627473.
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Koenig, Michel. "Biologie moléculaire des myopathies de Duchenne de de Becker." Université Louis Pasteur (Strasbourg) (1971-2008), 1990. http://www.theses.fr/1990STR1M022.
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Santos, Maria Auxiliadora Bonfim [UNIFESP]. "Distrofia Muscular de Duchenne: análise eletrocardiográfica de 131 casos." Universidade Federal de São Paulo (UNIFESP), 2011. http://repositorio.unifesp.br/handle/11600/9340.
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Publico-12588b.pdf: 1611234 bytes, checksum: 5bb4cedebc746bef2f551f891a283a74 (MD5)<br>Fundamento: É conhecido o envolvimento cardíaco em pacientes com distrofia muscular de Duchenne (DMD). O eletrocardiograma (ECG) apresenta algumas alterações típicas na DMD, fato que o torna um exame útil no diagnóstico da lesão cardíaca nessa patologia. Objetivo: Avaliar as alterações eletrocardiográficas em pacientes portadores de DMD, correlacionando-as com a idade da população estudada. Métodos: Foram analisados os ECG de 131 pacientes com diagnóstico do DMD. Avaliaram-se diversas variáveis eletrocardiográficas, sendo os pacientes separados em dois grupos: aqueles com e sem alterações, por variável estudada. Fezse a correlação desses dois grupos com a idade dos pacientes. Foram utilizados os critérios de Garson para estabelecer os parâmetros eletrocardiográficos de normalidade. Resultados: O ECG estava anormal em 78,6% dos pacientes. Todos apresentavam ritmo sinusal. Foram os seguintes os percentuais encontrados para as principais variáveis estudadas: PR curto= 18,3%, ondas R anormais em V1 = 29,7%, onda Q anormais em V6 = 21,3%, alterações da repolarização ventricular = 54,9%, ondas QS anormais em paredes inferior e/ou lateral alta = 37,4%, distúrbios de condução pelo ramo direito = 55,7%, intervalo QTc prolongado = 35,8% e alargamento do QRS = 23,6%. O teste t, não pareado, foi utilizado para se estabelecer a correlação da idade com as variáveis eletrocardiográficas estudadas nos dois grupos e, apenas a variável alteração da repolarização mostrou diferença estatisticamente significante. Conclusão: As alterações eletrocardiográficas na DMD são frequentes, revelando comprometimento cardíaco precoce. Apenas a variável alteração da repolarização ventricular foi mais frequente, porém em faixa etária menor (p<0,05).<br>TEDE<br>BV UNIFESP: Teses e dissertações
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LANG, CATHERINE. "Aspects moleculaires des myopathies de duchenne et de becker." Strasbourg 1, 1994. http://www.theses.fr/1994STR15058.
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Fayssoil, Abdallah. "Phénotypage cardiaque des dystrophies musculaires à l'aide des ultrasons." Thesis, Versailles-St Quentin en Yvelines, 2014. http://www.theses.fr/2014VERS0062/document.
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Les myopathies d’origine génétique sont des pathologies musculaires en rapport avec des anomalies génétiques. Les myopathies sont à l’origine d’un handicap physique majeur et affectent souvent la fonction respiratoire et parfois le cœur. Nous nous sommes intéressés à la caractérisation myocardique de 4 types de myopathies d’origine génétique à l’aide de l’échocardiographie Doppler : myopathie de Duchenne, sarcoglycanopathies, MELAS syndrome et maladie de Pompe.Nous avons analysé la fonction cardiaque dans 2 modèles murins de dystrophies musculaires: la souris mdx et la souris sgca null. En clinique, nous avons analysé la fonction cardiaque des sujets atteints de myopathie de Duchenne, de sarcoglycanopathies, de MELAS syndrome et de maladie de Pompe en échocardiographie Doppler.Dans les modèles animaux, nous avons retrouvé des anomalies myocardiques chez la souris mdx et chez la souris sgca null. Chez l’homme, l’atteinte myocardique est sévère chez les sujets atteints de myopathie de Duchenne et certains patients présentent un asynchronisme ventriculaire soulevant les indications éventuelles de resynchronisation myocardique. Les sujets atteints de gamma sarcoglycanopathies présentent de façon significative des anomalies de contraction du ventricule gauche comparativement aux sujets atteints d’alpha-sarcoglycanopathies. La fonction ventriculaire droite et gauche est préservée chez les sujets atteints de maladie de Pompe. Les sujets atteints de MELAS présentent des hypertrophies du ventricule gauche. L’analyse génétique retrouve une corrélation significative entre le taux d’hétéroplamie et la survenue d’événements cliniques<br>Muscular dystrophies are genetic neuromuscular disorders that affect skeletal muscle. We sought to assess heat involvement in four genetic muscular disorders : Duchenne muscular dystrophy, sarcoglycanopathies, MELAS and adulte Pompe disease. In animal models, we sought to assess, using Echocardiography Doppler, mdx mice and sgca null mice. Myocardiac abnormalities were found in mdx mice and sgca null mice. Clinical studies found severe cardiac impairment in Duchenne muscular dystrophies and ventricular asynchrony was found in patients with severe heart failure. Patients with gamma sarcoglycanopathy have significant alteration of left ventricular function in comparison with patients with alpha sarcoglycanopathy. Left and right ventricular function were preserved in patients with Pompe disease. Left ventricular hypertrophy was found in patients with MELAS. Genetic analysis disclosed significant correlation between heteroplasmy and significant clinical events
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Oliveira, Daniela Moraes de. "Análise de expressão da distrofina, miostatina, tgf-β e nf-kappa β, durante a fase embrionária e fetal no modelo canino GRMD (Golden Retrivier Muscular Dystrophy)." Universidade de São Paulo, 2017. http://www.teses.usp.br/teses/disponiveis/10/10132/tde-27022018-121625/.
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A Distrofia Muscular de Duchenne (DMD) é uma doença genética neuromuscular hereditária, ligada ao cromossomo X, sendo encontrada em humanos do sexo masculino. Esta doença muscular é descrita em outras espécies. O modelo de estudo pré-clínico GRMD (Golden Retrievier Muscular Dystrophy) apresenta sintomas clínicos fenotipicamente característicos da DMD em humanos e, por esta razão, tem sido amplamente utilizado como modelo de estudos pré-clínicos. O objetivo da presente pesquisa foi avaliar o tecido muscular, no modelo canino distrófico, ao longo da gestação. Quatro fêmeas, portadoras do gene distrófico, foram inseminadas com sêmen fresco de cães distróficos. No 25º dia, pós-inseminação, as fêmeas foram submetidas a exames de ultrassonografia para confirmar a gestação. As fêmeas gestantes passaram por uma ovariosalpingohisterectomia (OSH) para a retirada dos embriões e fetos nos seguintes períodos gestacionais: 28º , 33º , 38º e 42º dias. Em seguida fragmentos de tecido muscular foram analisados macroscopicamente e microscopicamente. Para verificar expressões proteicas, amostras de tecido foram submetidas a técnicas imunológicas, e PCR para distrofina, miostatina, e utrofina. Aos, 33º e 38º dias de gestação, no grupo distrófico, foram observadas características teciduais que corroboram com desenvolvimento tardio do tecido muscular. Os resultados para detecção proteica sugerem que, a distrofina, miostatina e utrofina foram expressas igualmente nos grupos controle e distrófico, durante todos os períodos do desenvolvimento gestacional analisado. Por fim, os dados sugerem que animais distróficos apresentam músculo sadio durante a fase gestacional, o que pode ser benéfico para testes farmacológicos em idade precoce.<br>Duchenne Muscular Dystrophy (DMD) is a hereditary neuromuscular genetic disease linked to the X chromosome, being found in male humans. This muscle disease is described in other species. The pre-clinical GRMD (Golden Retrievier Muscular Dystrophy) study model presents phenotypically characteristic clinical symptoms of DMD in humans and,for this reason, has been widely used as a model for preclinical studies. The aim of the present study was to evaluate the muscular tissue, in the dystrophic canine model, throughout the gestation. Four females, carriers of the dystrophic gene, were inseminated with fresh semen from dystrophic dogs. On the 25th day, post-insemination, the females were submitted to ultrasonography to confirm the pregnancy. The pregnant females underwent an ovariosalpingohisterectomy (OSH) for the removal of the embryos and fetuses in the following gestational periods: 28º, 33º, 38º and 42º days. Then fragments of muscle tissue were analyzed macroscopically and microscopically. To verify protein expression, tissue samples were submitted to immunological techniques, and PCR for dystrophin, myostatin, and utrophin. At the 33 and 38th days of gestation, tissue characteristics were observed in the dystrophic group, which corroborate the late development of muscle tissue. The results for protein detection suggest that dystrophin, myostatin and utrophin were also expressed in the control and affected groups, during all periods of the gestational development analyzed. Lastly, the data suggest that dystrophic animals present healthy muscle during the gestational phase, which may be beneficial for pharmacological tests at an early age.
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Burkhardt, Katinka. "Generation of a tailored pig model of Duchenne muscular dystrophy." Diss., lmu, 2012. http://nbn-resolving.de/urn:nbn:de:bvb:19-142430.
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Thomas, Karen. "The mdx mouse as a model for Duchenne muscular dystrophy." Thesis, University of Cambridge, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.386990.
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Terry, Rebecca Louise. "Modification of skeletal muscle phenotype to treat Duchenne muscular dystrophy." Thesis, Royal Veterinary College (University of London), 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.618307.
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HARNOIS, MELISSA. "ANALYSIS OF MYOGENIC MARKERS IN DUCHENNE MUSCULAR DYSTROPHY CELL MODELS." Thesis, The University of Arizona, 2016. http://hdl.handle.net/10150/612963.
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The goal of this study is to compare the in vitro differentiation potential of Duchenne Muscular
Dystrophy (DMD) and non-diseased patient-derived skeletal muscle myoblasts during
myogenesis. The differentiation and fusion of myoblasts into multinucleate myotubes and the
maturity of these myotubes was assessed based on morphology, immunohistochemistry (IHC)
analysis of myotubes, as well as transcript profiles of myogenic markers. Human skeletal muscle
myoblasts derived from three non-diseased and three DMD human patients were evaluated in
multiple time course studies. Morphological evaluation as well as IHC analysis indicated that the
DMD patient-derived myoblasts have diminished capacity to differentiate and form mature
myotubes. Gene expression profiling also revealed significantly reduced basal transcript levels of
myogenic markers in DMD patient-derived cells as well as the impaired induction of these
transcripts during differentiation.
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Wells, Kim Elizabeth. "Optimisation of constructs for gene therapy of Duchenne muscular dystrophy." Thesis, Imperial College London, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.392669.
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Al-khalidi, Rasha. "P2RX7 purinoceptor as a therapeutic target in Duchenne muscular dystrophy." Thesis, University of Portsmouth, 2017. https://researchportal.port.ac.uk/portal/en/theses/p2rx7-purinoceptor-as-a-therapeutic-target-in-duchenne-muscular-dystrophy(7560e450-c050-41a0-a3a5-553ed42d6710).html.
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Duchenne muscular dystrophy (DMD) is the most common inherited muscle disease in men and currently there is no effective treatment for this debilitating and lethal disorder. Although the absence of dystrophin is identified as the main cause of DMD, multiple secondary changes have been found to result from the dystrophin deficiency both in muscle and in non-muscle tissues. Among these abnormalities, our laboratory and others have demonstrated a dramatic increase in the expression of the P2RX7 receptor in cells and tissues from DMD patients and the mdx mouse model of DMD. The aim of this study was to determine the effects of P2RX7 ablation on biological functions in mdx muscle in situ and to identify suitable diagnostic and prognostic biomarkers for use in studies on the pharmacological inhibition of P2RX7. RNA transcription was profiled in muscle from wild-type and mdx mice, and also from double knock-out mdx/P2rx7<sup>-/-</sup> mice which lack both functional Dmd and P2rx7 genes, and the effects of P2RX7 antagonists were assessed on pathological markers at the acute disease stage of disease in mdx mice, which resembles the human pathology. RNA sequencing was performed using the Illumina HiSeq 2000 platform to characterise the differential gene expression in tibialis anterior (TA) muscles from four week old wild type, mdx and mdx/P2rx7<sup>-/-</sup> mice. The biological functions and molecules that are most affected in mdx and corrected in mdx/P2rx7<sup>-/-</sup> tissues are those of the immune response, including the innate immune response, cytokine regulatory genes and the NF-кB pathway followed by fibrosis, telomerase regulatory genes, atherosclerosis signalling and the LXR/RXR activation pathway. Moreover, activation of the cell cycle, mitochondrial dysfunction, apoptosis and the adherens junction genes were found to be altered in mdx compared to wild type but not normalised in mdx/P2rx7<sup>-/-</sup> muscles. This analysis also demonstrated that the mdx mutation disrupts the non-sense-mediated RNA decay and splicing mechanisms, which leads to an increase in out-of-frame transcripts that may have unexpected cellular impact. One of these altered transcripts, Bmp7, was significantly down-regulated in the mdx myoblasts, myofibres and in TA muscles and restored to the normal level in mdx/P2rx7<sup>-/-</sup> muscle. Different analyses were used to map this alteration to the 5'exons of Bmp7 but the identification of this abnormal transcript was not successful. Four P2RX7 antagonists (oxidised ATP, A438079, AFC-5128 and azidothymidine (AZT)) were administered to male mdx mice and their effects on the pathology were analysed using different methods and biomarkers. All of the antagonists inhibited P2RX7 receptor-mediated responses in mdx mice without any detectable side effects. A438079 and AZT were found as the most effective in attenuating the wide range of the pathological features. The reduction in dystrophic features as results of ablation and antagonism the P2RX7 confirms the involvement of this purinoreceptor in the DMD pathology and making it an attractive target for a pharmacological treatment of this lethal disease. Additionally, as AZT is already in clinical use for other diseases, also in children, this drug could be relatively easily re-purposed and trialled for the treatment of DMD.
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Bagdatlioglu, Emine. "Investigating the brain in mouse models of Duchenne muscular dystrophy." Thesis, University of Newcastle upon Tyne, 2017. http://hdl.handle.net/10443/3931.
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Duchenne muscular dystrophy (DMD) is an X-linked recessive muscle wasting disease caused by mutations in the DMD gene, which encodes the large cytoskeletal protein dystrophin. Alongside severe muscle pathology, one-third of DMD patients exhibit cognitive problems ranging from reduced verbal intelligence to severe autism. There is conclusive evidence that the muscle pathology exhibited by DMD patients is progressive, yet it remains unknown whether the cognitive impairments in DMD are also progressive. Previous studies have highlighted a cognitive impairment in the mdx mouse model of DMD, but no studies have investigated if this cognitive impairment worsens with age. We assessed the consequences of dystrophin deficiency on brain morphology and cognitive function in two dystrophin-deficient mouse models (mdx and Cmah-/-mdx mice). The overall project aim was to identify outcome measures to monitor central nervous system (CNS) pathology non-invasively in DMD mice. Magnetic resonance imaging (MRI) identified a total brain volume increase in DMD mice, alongside morphological changes in brain ventricles. Behavioural testing revealed a deficit in hippocampal spatial learning and memory, particularly long-term memory, in mdx mice, which appears to progressively worsen with age. Immunoblotting identified a progressive reduction of aquaporin-4 (AQP4) expression, the major water channel of the CNS, in DMD mice. Moreover, contrast enhancing MRI and Evans blue extravasation demonstrated a progressive impairment in blood-brain barrier (BBB) integrity in mdx mice. Proteomic profiling of the mdx cerebellum identified changes in expression of mitochondrial subunit complexes, suggestive of changes in mitochondrial function. Additionally, elevated levels of inflammatory markers were identified and confirmed in the mdx cerebellum. Our studies suggest that dystrophin deficiency causes a progressive cognitive impairment in mdx mice. We also present evidence showing that changes in osmotic equilibrium may be involved in the pathogenesis of DMD, with reductions in AQP4 expression and BBB disruptions. We speculate that some of the changes in the mdx cerebellar proteome, in comparison to wild type mice, iii serve as compensatory mechanisms whilst others may contribute directly to cognitive dysfunction in DMD. These results support a role for dystrophin in normal brain morphology and cognitive function.
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Bénony, Hervé. "Les aspects psychopathologiques dans la myopathie de Duchenne de Boulogne." Paris 5, 1989. http://www.theses.fr/1989PA05H057.
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Bénony, Hervé. "Les Aspects psychopathologiques dans la myopathie de Duchenne de Boulogne." Lille 3 : ANRT, 1990. http://catalogue.bnf.fr/ark:/12148/cb37611751n.
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Grunwald, Stefanie. "Identifizierung und Charakterisierung von Muskeldystrophie Duchenne modifizierenden Genen und Stoffwechselwegen." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2010. http://dx.doi.org/10.18452/16108.
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Hintergrund und Zielsetzung: DMD ist die häufigste Form der Muskeldystrophie im Kindesalter und bis heute unheilbar. Sie wird durch das Fehlen des Proteins Dystrophin verursacht, welches verschiedene Signaltransduktionswege beeinflusst. Das Anliegen der Arbeit ist die Untersuchung und Modulation von Signaltransduktionswegen, die als alternative Therapiestrategie den Verlust von Dystrophin kompensieren könnten. Experimentelle Strategie: Für die Charakterisierung von Dystrophin nachgeschalteten Prozessen wurden mRNA-Expressionsanalysen in Muskelgeweben von DMD-Patienten und einem DMD-Brüderpaar mit einem infrafamiliär unterschiedlichen Verlauf der DMD durchgeführt. Aus diesen Expressionsdaten wurde erstmalig ein Petri-Netz entwickelt, welches Dystrophin mit in diesem Zusammenhang bisher unbekannten Signaltransduktionswegen verknüpft. Das Petri-Netz wurde auf Netzwerkintegrität und –verhalten mittels Invarianten- (INA) und theoretischen Knockout- (Mauritius Maps) Analysen untersucht. Durch beide Methoden läßt sich der maßgebliche Teilsignalweg bestimmen. In diesem Signalweg wurden die Proteinaktivität und die Genexpression durch siRNA, Vektor-DNA und chemische Substanzen in humanen SkMCs moduliert. Anschließend wurden die Proliferation und die Vitalität der Zellen sowie auch die Expression auf mRNA- und Protein-Niveau untersucht. Ergebnisse: RAP2B und CSNK1A1 waren in dem DMD-Brüderpaar differentiell exprimiert und konnten erstmalig in einem neuen, komplexen Signalweg in Zusammenhang mit Dystrophin nachgeschalteten Prozessen dargestellt werden. Mittelpunkt dieses Signalweges ist die De- und Aktivierung des Transkriptionsfaktors NFATc. Seine Zielgene umfassen neben anderen den negativen Proliferationsfaktor p21, das Dystrophin homologe UTRN und den Differenzierungsfaktor MYF5. Folglich würde ein Anstieg von UTRN eine unerwünschte Reduktion der Proliferationsrate von Myoblasten implizieren. Letzteres konnte bereits nachgewiesen werden und stellte das Motiv für weitere Studien dar. Jedoch zeigten siRNA- und Vektor-DNA-Experimente, daß NFATc nicht der ausschlaggebende Faktor für diese Zielgene ist. Die Substanzen Deflazacort (DFZ) und Cyclosporin A (CsA) wurden dagegen beschrieben, die Aktivierung von NFATc zu beeinflussen. Die Ergebnisse zeigten, daß beide Substanzen die Proliferation von Myoblasten erhöhen können. Die gleichzeitige Applikation von DFZ und CsA führte zu einem Anstieg der UTRN-Expression. Schlußfolgerung: Die Modulation der Proliferation und UTRN-Expression ist unabhängig von einander möglich. Entsprechend der Grundidee der Arbeit zeichnet sich eine neue Therapiestrategie ab, welche Dystrophin nachgeschaltete Prozesse einbezieht.<br>Background and aim: DMD is the most common muscular dystrophy in childhood and incurable to date. It is caused by the absence of dystrophin, what influences several signal transduction pathways. The thesis is interested in the investigation and modulation of signal transduction pathways that may compensate the lack of dystrophin as an alternative therapy strategy. Experimental strategy: To study Dystrophin downstream pathways the mRNA expression of DMD patients and two DMD siblings with an intra-familially different course of DMD were analysed in muscle tissue. On the basis of these expression data a Petri net was first developed implicating signal transduction pathways and Dystrophin downstream cascades. Invariant (INA) and theoretical knockout (Mauritius Maps) analyses were applied for studying network integrity and behaviour. Both methods provide information about the most relevant part of the network. In this part modulation of protein activity and of gene expression using siRNA, vector-DNA, and chemical substances were performed on human SkMCs. Subsequently, the cells were studied by proliferation and vitality tests as well as expression analyses at mRNA and protein level. Results: RAP2B and CSNK1A1 were differently expressed in two DMD siblings, and first are part of a signal transduction pathway implicating Dystrophin downstream processes. The central point of this pathway is the de- and activation of the transcription factor NFATc. Its target genes are, among others, the negative proliferation factor p21, the Dystrophin homologue UTRN, and the differentiation factor MYF5. Consequently, an increase in UTRN implicates an undesirably reduced myoblast proliferation rate. Latter was found in DMD patients and was target for further studies. But, siRNA and vector DNA experiments showed that NFATc is not the decisive factor for the target genes. Deflazacort and cyclosporin A are known to influence the activation of NFATc. The results first showed that both substances do induce myoblast proliferation. The use of deflazacort in combination with cyclosporin A resulted in an increase of UTRN expression. Conclusion: The modulation of proliferation and UTRN-expression independently of each other is possible. According to the basic idea of this study, a new therapeutic strategy becomes apparent, which considers Dystrophin downstream processes.
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Jaber, Abbass. "Lysosomal defects in Duchenne muscular dystrophy : advancing combined therapeutic approaches." Electronic Thesis or Diss., université Paris-Saclay, 2024. http://www.theses.fr/2024UPASL055.
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La dystrophie musculaire de Duchenne (DMD) est une maladie musculaire dégénérative touchant principalement les jeunes garçons, caractérisée par la perte de l'expression fonctionnelle de la dystrophine. Bien que la thérapie génique visant à restaurer une forme tronquée fonctionnelle de la dystrophine, appelée µ-dystrophine, ait montré des résultats prometteurs dans les études précliniques, son efficacité thérapeutique chez les patients DMD traités reste limitée, nécessitant des améliorations urgentes. Le travail présenté dans cette thèse vise d'abord à améliorer notre compréhension des perturbations métaboliques et cellulaires dans la DMD, puis à proposer de nouvelles approches thérapeutiques combinées, associant la thérapie génique aux traitements des dérégulations identifiées. Nous avons récemment identifié des dérégulations du métabolisme du cholestérol dans le muscle DMD, un phénomène souvent lié au dysfonctionnement lysosomal dans les troubles neurodégénératifs. Sur cette base, nous avons émis l'hypothèse d'une interaction potentielle entre l'accumulation de cholestérol et les perturbations lysosomales dans la pathogenèse de la DMD. Notre étude a identifié une augmentation de la Galectine-3 (LGALS3), un biomarqueur de la perméabilisation de la membrane des lysosomes (PML), dans les muscles dystrophiques des patients DMD et des modèles animaux, indiquant l'occurrence de la PML dans les myofibres dystrophiques. Ce phénomène a été corrélé à un stress lysosomal important, mis en évidence par des changements dans le nombre, la morphologie et le positionnement des lysosomes, ainsi que par l'activation des voies de biogenèse, de réparation et d'élimination des lysosomes. La PML a été exacerbée chez les souris nourries avec un régime riche en cholestérol et n'a pas été entièrement corrigée par la thérapie génique par µ-dystrophine. Pour remédier à cette limitation, nous avons sélectionné la tréhalose, un composé approuvé par la FDA et connu pour restaurer la fonction lysosomale, pour l'utiliser en combinaison avec une dose sous-optimale de thérapie génique par µ-dystrophine. Le traitement combiné a permis de corriger la PML et d'améliorer la correction des paramètres dystrophiques, y compris la fonction motrice, l'histologie musculaire et la signature transcriptomique, par rapport à la thérapie génique suboptimale de la µ-dystrophine seule. Les travaux de cette thèse soulignent l'importance des lésions lysosomales dans la physiopathologie de la DMD et suggèrent qu'une approche synergique combinant une supplémentation en tréhalose et une dose sous-optimale d'AAV µ-dystrophine est prometteuse pour améliorer les résultats thérapeutiques dans la DMD<br>Duchenne Muscular Dystrophy (DMD) is a muscle degenerative disease primarily affecting young boys, characterized by the loss of dystrophin expression. While gene therapy targeting the restoration of a functional truncated form of dystrophin, known as µ-dystrophin, has shown promise in preclinical studies, its therapeutic efficacy in treated DMD patients remains limited, necessitating urgent improvements. The aim of the work presented in this thesis is to first improve our understanding of the metabolic and cellular perturbations in DMD, and secondly to propose new combined therapy approaches, associating gene therapy to treatments of identified dysregulations. We have recently identified dysregulations of cholesterol metabolism in DMD muscle, a phenomenon frequently associated with lysosomal dysfunction in neurodegenerative disorders. Building upon this association, we hypothesized a potential interplay between cholesterol accumulation and lysosomal perturbations in DMD pathogenesis. Our study identified an upregulation of Galectin-3 (LGALS3), a known biomarker of lysosome membrane permeabilization (LMP), in the dystrophic muscle of DMD patients and animal models, indicating the occurrence of LMP within dystrophic myofibers. This correlated with significant lysosomal stress evidenced by changes in lysosome number, morphology, positioning and activation of lysosomal biogenesis, repair and removal pathways. Remarkably, LMP was exacerbated in mice fed a cholesterol-rich diet and was not fully corrected by µ-dystrophin gene therapy. Subsequently, we selected trehalose, an FDA-approved compound known to restore lysosomal function, for use in combination with a suboptimal dose of AAV-µ-dystrophin gene therapy. The combined treatment resulted in correction of lysosomal defects and improved correction of dystrophic parameters, including motor function, muscle histology, and transcriptome signature, compared to µ-dystrophin gene therapy alone. This work underscores the significance of lysosomal damage in DMD pathophysiology and suggests that a synergistic approach combining trehalose supplementation with a suboptimal dose of AAV µ-dystrophin holds promise for enhancing therapeutic outcomes in DMD
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Souza, Mariana Angélica de. "Efeito do uso da ankle-foot orthosis na biomecânica da marcha de pacientes com Distrofia Muscular de Duchenne." Universidade de São Paulo, 2014. http://www.teses.usp.br/teses/disponiveis/17/17152/tde-21012015-092933/.
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O objetivo deste estudo foi avaliar o efeito do uso noturno ou diurno da ankle-foot orthosis (AFO) na biomecânica da marcha de pacientes com DMD. Foram avaliados 20 pacientes deambuladores, do Ambulatório de Miopatias Infantis do CER do HCFMRP-USP, com diagnóstico de distrofia muscular de Duchenne (DMD), com idades entre 4 e 12 anos. Foi realizada a avaliação inicial (Av1) em todos os pacientes e, 7 pacientes foram reavaliados após 6 meses (Av2). Na Av1, os pacientes foram agrupados conforme o uso da órtese: grupo sem órtese (SO; n=7), grupo órtese noturna (ON; n=7), grupo órtese diurna (OD; n=6). Na Av1 e na Av2 foram obtidos dados de massa corporal, altura, composição corporal pela bioimpedância elétrica, escore funcional pela escala medida da função motora, amplitude passiva de movimento articular, força muscular isométrica pelo dinamômetro Handheld e avaliação biomecânica da marcha, na velocidade habitual do paciente. Os pacientes que faziam uso da órtese diurna foram avaliados sem e com órtese, sendo denominados grupos ODs e ODc, respectivamente. Os dados foram analisados de três formas: duas transversais e uma longitudinal. Nas análises transversais, foram realizados dois procedimentos: (i) comparando dados dos grupos SO x ON x ODs; (ii) comparando dados dos grupos SO x ON x ODc. Nestas, foi utilizado o teste ANOVA, considerando um nível de significância de 5%. Na análise longitudinal, foi realizada a análise descritiva comparando os dados obtidos na Av1 e Av2, individualmente para os 7 pacientes reavaliados. Transversalmente, o grupo ODc apresentou maiores picos do ângulo de dorsiflexão e do momento dorsiflexor, menor ângulo de flexão plantar e menor geração de potência de tornozelo (p<0,05) que o grupo SO. Porém, ao caminhar sem a AFO (grupo ODs) estes resultados não foram observados (p>0,05). Em relação ao grupo ON, o grupo ODc obteve menores picos do ângulo de flexão do quadril, de absorção de potência de quadril, do ângulo de flexão plantar e maior pico do momento dorsiflexor (p<0,05), sendo que ao retirar a AFO (ODs) essas diferenças não foram observadas (p>0,05). E ainda, o grupo ON obteve maior pico do ângulo de flexão do joelho e menor momento flexor de quadril (p<0,05) em relação ao grupo ON. Na comparação dos dados entre os grupos SO e ON, o grupo ON obteve maior pico do ângulo de flexão do joelho e maior absorção de potência de quadril (p<0,05). Na análise longitudinal individual foi observado que os 2 pacientes que iniciaram precocemente e mantiveram o uso noturno da AFO apresentaram na Av2 maior velocidade da marcha, maiores momentos extensor de quadril e flexor plantar e maior geração de potência de tornozelo, contrariamente aos paciente que interromperam o uso (noturno ou diurno) da AFO. Conclui-se que o uso diurno da AFO acarretou alterações positivas na biomecânica da marcha, minimizando compensações típicas da DMD na articulação do tornozelo. O uso noturno da AFO, quando iniciado precocemente, também afetou positivamente a marcha dos pacientes. Assim, sugere-se o início precoce e contínuo do uso diurno e noturno da AFO aos pacientes com DMD.<br>The aim of this study was to evaluate the effect of the ankle-foot orthosis (AFO) during nocturnal or daytime usage of the gait biomechanics in patients with Duchenne Muscular Dystrophy (DMD). Twenty ambulant patients from the Myopathies Infant Ambulatory of CER - HCFMRP-USP, were diagnosed with DMD between the ages of 4 and13 years and were evaluated. The initial evaluation (Ev1) was performed in all patients, and 7 patients were reevaluated after 6 months (Ev2). In Av1, patients were grouped according to orthosis use: group without orthosis (NoO, n = 7), group with nocturnal orthosis (NiO, n = 7), group with daytime orthosis (DO, n = 6). In Ev1 and Ev2 data were obtained according to the weight, height, body composition (bioelectrical impedance), functional score (Measure scale of motor function), passive joint range of motion, isometric muscle strength (dynamometer Handheld) and biomechanical gait analyses (usual velocity for the patient). Patients who used the daytime orthosis were evaluated with and without bracing, respectively. The data were analyzed in three ways; the first two were cross-sectional and the other one was longitudinal. In the cross-sectional analyzes, an exploratory analysis of the data from each evaluation was performed, and subsequently, the variables were compared between groups, considering the means and standard deviations. ANOVA test was used, and it was considered a significant level of 5%. In the longitudinal analysis, the description of the data obtained in the evaluation 1 compared to the data obtained in the evaluation 2 was individually performed in the 7 patients who were reevaluated. A cross-sectional analysis compared the data between NoO x NiO x DO groups considering the gait analysis data from the DO group without the orthosis (barefoot), being named DOno. The other cross-sectional analysis compared the data between NoO x NiO x DO groups considering the gait analysis data from the OD group with orthosis, being named DOwith. In individual longitudinal analysis, it was observed that patients who had started early and kept the nocturnal usage of AFO which has been already showed, in six months, an increment of gait velocity, hip extensor and plantar flexor moments and also the increment of ankle power generation, which is the opposite of the patient who has discontinued the AFO usage (daytime or nocturnal). In the cross-sectional analyzes it was observed that, compared to the NoO group, the DOwith group had a higher dorsiflexion angle peak and higher dorsiflexor moment peak (p<0.05). However, when they walked without the device these results were not maintained. There was no difference (p>0.05) between DOno and NoO groups for the kinematic parameters. And, the DOno group had lower plantar flexor moment maximum peak than the SO group (p>0.05). It was concluded that AFO daytime use cause positive changes in gait biomechanics, minimizing typical compensation of DMD in the ankle joint. The night use of AFO, when started early, also positively affected the gait of patients. Thus, it is suggested early prescription of daytime and nocturnal usage of AFO for DMD patients.
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Avargues, Laureen. "O papel da fisioterapia em crianças com Distrofia Muscular de Duchenne: revisão bibliográfica." Bachelor's thesis, [s.n.], 2021. http://hdl.handle.net/10284/10177.
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Projeto de Graduação apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Licenciada em Fisioterapia<br>Introdução: A Distrofia Muscular de Duchenne é uma doença genética que causa fraqueza muscular progressiva e leva à paralisia total e à morte súbita nos últimos anos da adolescência ou em adultos jovens. Objetivo: Avaliar a importância da Fisioterapia em crianças com Distrofia Muscular de Duchenne. Metodologia: Foi realizada uma pesquisa bibliográfica recorrendo as bases de dados PEDro, Pubmed, Web of Science, CINAHL e Scielo, incluindo artigos randomizados controlados em humanos, artigos em inglês e amostra constituída por idade inferior a 18 anos. Resultados: Obtiveram-se 67 artigos dos quais foram 5 para o estudo com um total de 107 participantes de acordo com os critérios de inclusão e exclusão. A qualidade metodológica dos artigos utilizados foi recolhida através da Escala de PEDro, tendo-se obtido um score médio de 5,6. Conclusão: A fisioterapia na vida do paciente DMD parece ter uma influência fundamental e importante para atrasar a progressão da doença e permitir uma melhor qualidade de vida.<br>Introduction: Duchenne muscular dystrophy is a genetic disease that causes progressive muscle weakness and leads to total paralysis and sudden death in late adolescence or young adults. Objective: Evaluate the importance of physical therapy in children with Duchenne muscular dystrophy. Methodology: A literature search was conducted using PEDro, Pubmed, Web of Science, CINAHL, and Scielo databases, including human randomized controlled articles, articles in English, and in a sample constituted under the age of 18 years. Results: 67 articles were obtained of which 5 were for the study with a total of 107 participants according to the inclusion and exclusion criteria. The methodological quality of the articles used was collected using the PEDro Scale, and a mean score of 5,6 was obtained. Conclusion: Physiotherapy in the life of the DMD patient seems to have a fundamental and important influence in delaying the progression of the disease and allowing a better quality of life.<br>N/A
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Goyenvalle, Aurélie. "Développement d'une stratégie thérapeutique pour la dystrophie musculaire de Duchenne : Restauration du cadre de lecture par saut d'exon." Paris 7, 2006. http://www.theses.fr/2006PA077104.
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La plupart des cas de Dystrophie musculaire de Duchenne (DMD) sont causés par des mutations dans le gène de la dystrophine qui interrompent le cadre de lecture de l'ARNm. Dans certains cas, l'exclusion artificielle d'un exon permet de restaurer ce cadre de lecture, donnant naissance à une dystrophine plus courte, mais tout de même fonctionnelle. L'objectif de ce travail a été de produire in situ à partir de vecteurs viraux, des molécules d'ARN ciblant les sites spécifiques d'épissage du gène de la dystrophine, pour induire le saut des exons associés à la maladie pendant l'épissage du pré-ARNm. Pour cela, nous avons choisi d'utiliser le petit ARN nucléaire U7 (U7snRNA) comme « navette » et avons dans un premier temps construit un vecteur AAV spécifique du gène de la dystrophine murine, permettant un saut très efficace de l'exon ciblé. Ce saut d'exon induit ainsi une restauration massive et stable de dystrophine, associée à une amélioration significative du phénotype dystrophique chez la souris. En parallèle de ces travaux sur le modèle murin mdx, nous avons développé cette approche sur le modèle canin GRMD de la dystrophie musculaire de Duchenne, et mis en évidence l'efficacité du saut d'exons multiples permettant une restauration importante de dystrophine. Ces résultats très prometteurs obtenus chez la souris mdx et chez le chien GRMD, nous ont conduit à appliquer cette stratégie sur le gène humain de la dystrophine et en particulier sur l'exon 51 pour lequel nous avons pu mettre en évidence un saut d'exon très efficace. L'ensemble de ces résultats indique l'efficacité de l'approche du saut d'exon médiée par U7snRNA, qui pourrait concerner près de 80% des patients DMD<br>Most cases of Duchenne muscular dystrophy (DMD) are caused by dystrophin gene mutations that disrupt the mRNA reading frame. In some cases, forced exclusion of a single exon can restore the reading frame, given rise to a shorter, but still functional dystrophin protein. Our objective in this work was to produce antisense sequences targeting splice junctions of dystrophin gene to induce removal of disease-associated exons during pre-mRNA processing. To achieve this exon-skipping, we proposed to use the U7 small nuclear RNA as carrier and we first developed AAV vectors harboring chimeric U7snRNA carrying antisense sequences able to promote skipping of exon 23 of the murine dystrophine gene. After intramuscular or intra-arterial injection in mdx mice, we detected efficient skipping of the exon 23 and a long term rescue of dystrophin expression. We next evaluated this strategy in the canine GRMD model and showed the possibility to skip several exons, leading to a very large restoration of dystrophin in injected muscles. These promising results obtained on the mouse and canine models led us to develop the strategy on the human dystrophin gene and especially on the exon 51. We confirmed the skipping of the exon 51 both in vitro in patient myoblasts after transduction with the lentiviral vector and in vivo after intramuscular injection of an AAV-U7ex51 vector in the transgenic hDMD mouse. This study provides evidence on the efficiency of the U7snRNA mediated exon skipping strategy for Duchenne muscular dystrophy, that could concern more than 80% of patients and offers very promising tools for clinical treatment of DMD
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Dahmani, Amina. "Développement de tolérance immunologique envers la greffe de myoblastes allogéniques, une thérapie potentielle pour la dystrophie musculaire de Duchenne." Thesis, Université Laval, 2013. http://www.theses.ulaval.ca/2013/29819/29819.pdf.
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La transplantation de myoblastes (TM) est une des thérapies potentielles des plus prometteuses pour la dystrophie musculaire de Duchenne (DMD). Une des limites de cette approche est le rejet des myoblastes du donneur par le système immunitaire de l’hôte. L’induction d’une tolérance immunologique envers les myoblastes greffés permettrait de contourner les effets secondaires conséquents à une immunosuppression soutenue, aujourd’hui indispensable à la survie de la greffe. Notre objectif est donc d'induire une tolérance immunologique via l’établissement d’un chimérisme mixte par un protocole non-myéloablatif, chez des souris dystrophiques. Le protocole testé a permis d'induire une tolérance périphérique transitoire au donneur ainsi que l'établissement de taux variables de chimérisme mixte. Cependant, il n’a pas permis d’induire une tolérance à la TM. Bien que nous n’avons pas obtenu les résultats escomptés quant à la TM, des améliorations, telle qu’une association à court terme à la rapamycine, pourraient être envisagées en vue d'une application en clinique.<br>Myoblast transplantation (MT) is one of the most promising potential therapies for Duchenne muscular dystrophy (DMD). One limitation of this approach is the rejection of the donor myoblast by the host immune system. Induction of donor-specific immune tolerance would avoid the toxicities of chronic immunosuppressive therapy that is currently required to prevent graft rejection. Our objective is to induce immunological tolerance through the establishment of mixed-chimerism using a non-myeloablative protocol, into DMD mice. Our results show that the tested protocol permits the induction of transient peripheral tolerance status to the donor. It also allows the establishment of variable rate of mixed-chimerism. However, this protocol failed to induce tolerance to MT. Although we did not obtain the expected results on the MT, improvements, such as association with a short-term rapamycin treatment, may be considered to enhance the outcome of the proposed protocol in perspective of clinical application for DMD patients.
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Judge, Luke Milburn. "Dissecting the signaling and mechanical functions of the dystrophin-glycoprotein complex in skeletal muscle /." Thesis, Connect to this title online; UW restricted, 2006. http://hdl.handle.net/1773/4989.
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Woolf, Peter James. "Cardiac calcium handling in the mouse model of Duchenne Muscular Dystrophy." University of Southern Queensland, Faculty of Sciences, 2003. http://eprints.usq.edu.au/archive/00001525/.
Full textAbstract:
The dystrophinopathies are a group of disorders characterised by cellular absence of the membrane stabilising protein, dystrophin. Duchenne muscular dystrophy is the most severe disorder clinically. The deficiency of dystrophin, in the muscular dystrophy X-linked (mdx) mouse causes an elevation in intracellular calcium in cardiac myocytes. Potential mechanisms contributing to increased calcium include enhanced influx, sarcoplasmic reticular calcium release and\or reduced sequestration or sarcolemmal efflux. This dissertation examined the potential mechanisms that may contribute to an intracellular calcium overload in a murine model of muscular dystrophy. The general cardiomyopathy of the mdx myocardium was evident, with the left atria from mdx consistently producing less force than control atria. This was associated with delayed relaxation. The role of the L-type calcium channels mediating influx was initially investigated. Dihydropyridines had a lower potency in contracting left atria corresponding to a redued dihydropyridine receptor affinity in radioligand binding studies of mdx ventricular homogenates (P<0.05). This was associated with increased ventricular dihydropyridine receptor protein and mRNA levels (P<0.05). The function of the sarcoplasmic reticulum in terms of release and also sequestration of calcium via the sarco-endoplasmic reticulum ATPase were investigated. A lower force of contraction was evident in mdx left atria in response to a range of stimulation frequencies (P<0.05) and concentrations of extracellular calcium (P<0.05). However, in the presence of 1 nM Ryanodine to block sarcoplasmic reticular calcium release, increased stimulation frequency caused similar forces to those obtained in control mice suggesting enhanced calcium influx via L-type calcium channels in mdx. Rapid cooling contractures showed a reduced contracture in mdx compared to control in response to cooling. This suggests some dysfunction in SR storage, which may be associated with the delayed relaxation time. Concentration-response curves to inhibitors of the sarco-endoplasmic reticulum showed no difference in function of the enzyme responsible for calcium uptake into the sarcoplasmic reticulum. Although sarco-endoplasmic reticulum ATPase mRNA was upregulated, no functional benefit was evident. This study indicates that a deficiency of dystrophin leads to upregulation of L-type calcium channels that contribute to increased calcium influx, with no functional change in sarcoplasmic reticular sequestration. Upregulation of the influx pathway is a potential mechanism for the calcium overload observed in mdx cardiac muscle.