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1
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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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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Messaed, Christiane. "Investigation of molecular mechanisms underlying Oculopharyngeal Muscular Dystrophy (OPMD)." Thesis, McGill University, 2007. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=111879.
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Oculopharyngeal Muscular Dystrophy (OPMD) is a late-onset dominant/recessive myopathy caused by the expansion of a polyalanine repeat in exon 1 of the PABPN1 gene. The expression of expanded PABPN1 (expPABPN1) triggers the formation of insoluble nuclear aggregates within muscle fiber nuclei of OPMD patients. These aggregates are enriched in poly(A)RNA and sequester molecular chaperones, ubiquitin and proteasome subunits. In addition to these cellular components, we first identified two novel PABPN1 interacting partners, hnRNPA1 and hnRNPA/B that also localized to the insoluble expPABPN1 aggregates. However, only hnRNPA1 was observed in inclusions of OPMD patients' muscle fiber nuclei. Following this finding, we next established the involvement of the ubiquitin-proteasome pathway in the clearance of misfolded expPABPN1 and provided more insights into the beneficial role of molecular chaperones in OPMD. The inhibition of proteasome correlated with an increase in the aggregation of expPABPN1, suggesting a possible proteasome impairment in OPMD. Conversely, the overexpression of Hsp70 and Hsp40 coincided with a decrease in nuclear aggregates concomitant with a reduced cellular toxicity, suggesting the therapeutic potential of manipulating molecular chaperones levels. Finally, we demonstrated that soluble forms of expPABPN1 are the primary toxic species in OPMD. In the presence of endogenous HSPs, a decrease in expPABPN1 aggregation correlated with an increased cellular toxicity. A defect in polyadenylation or ubiquitination significantly increased expPABPN1 solubility and cell death. Using live-cell imaging, we observed that nuclear aggregates prolonged the survival of expPABPN1-expressing cells, which led us to speculate that protein aggregates are subnuclear structures that preserve cellular homeostasis by depleting the expPABPN1 from the nuclear soluble pool. We propose that the polyalanine expansion in expPABPN1 could enable aberrant protein-protein interactions that would compromise the cellular function of nuclear factors and the expression of genes essential for muscle integrity and differentiation. For instance, expPABPN1 might compromise the function of hnRNP proteins and lead to altered mRNA processing and nucleocytoplasmic export, which can be detrimental to the cell.
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Clapp, Jannine. "Investigating the molecular genetics of FSH muscular dystrophy." Thesis, University of Nottingham, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.435765.
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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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Cockburn, David James. "Analysis of DMD translocations." Thesis, University of Oxford, 1991. http://ora.ox.ac.uk/objects/uuid:ab53825b-b18e-4f60-954a-4ea9e0435126.
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Duchenne and Becker muscular dystrophies (DMD, BMD) are allelic X-linked diseases which affect approximately one in 3500 male newborns. They are caused by mutations in a gene positioned on the short arm of the X chromosome at Xp21. The first indication of the location of this gene was the description of rare females expressing DMD and who were found to have constitutional X;autosome translocations with an X chromosome breakpoint at this site. There are now 24 such females known worldwide. They express DMD as a consequence of preferential inactivation of the normal X chromosome. In order to contribute to the understanding of the aetiology of mutations causing DMD and the aetiology of constitutional translocations, two types of study have been performed here. Firstly, the detailed mapping of the X chromosome breakpoints of DMD-associated X;autosome translocations has been investigated. The results of this study have been compared with data on the physical distribution of mutations causing DMD in male patients. Secondly, one translocation, an X;l translocation with an autosomal breakpoint at Ip34, has been selected for more detailed investigation and the DNA sequence has been determined at the site of the rearrangement. Translocation breakpoint mapping studies were performed by somatic cell hybrid analysis. Hybrids were karyotyped and this information was used to construct a hybrid panel for the purpose of determining the autosomal localisations of anonymous DNA probes. The mapping of seven probes using this panel is described. The work described in this thesis revealed that the distribution of translocation breakpoints within the DMD gene appears to be random and may differ from the distribution of mutations in male patients. The X;l translocation whose breakpoints are cloned and sequenced was found to involve two expressed loci, one coding for dystrophin on the X chromosome and one for the leukocyte antigen related protein on chromosome 1. Sequence data revealed that a deletion of four to seven nucleotides from the X chromosome and a duplication of two to five nucleotides are associated with the translocation. The possible involvement of trinucleotides adjacent to the breakpoints, and of a LINE, a SINE and a stretch of potential Z-DNA within 1 kb of the X chromosome or the chromosome 1 breakpoint, is discussed.
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Brais, Bernard. "Oculopharyngeal muscular dystrophy : from phenotype to genotype." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape11/PQDD_0002/NQ44369.pdf.
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Van, der Merwe Annelize. "Genetic heterogeneity in South African facioscapulohumeral muscular dystrophy (FSHD) families." Pretoria : [s.n.], 2006. http://upetd.up.ac.za/thesis/available/etd-10262005-110841/.
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Kaspar, Rita Wen. "Genotype-Phenotype Association Analysis of Dilated Cardiomyopathy in Becker Muscular Dystrophy." The Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=osu1243469474.
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Montanaro, Federica. "The role of dystroglycan in muscular dystrophy and synaptogenesis." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape7/PQDD_0020/NQ55361.pdf.
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Tyers, Lynn. "Skin cells as a tool in genetic diagnosis of Duchenne muscular dystrophy." Master's thesis, University of Cape Town, 2016. http://hdl.handle.net/11427/22731.
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Duchenne muscular dystrophy (DMD) is the most common and severe of the dystrophies, with an incidence of 1 in 3500 live male births, worldwide. Becker Muscular dystrophy (BMD) has a lower incidence of approximately 1 in 17500 births, a milder progression and longer life expectancy. Many advancements have been made in the development of gene-based therapies for the treatment of D/BMD, however, these treatments require genetic confirmation of the disease which continues to present a significant diagnostic challenge. The current standard for RNA-based analysis requires obtaining an invasive, often distressing, muscle biopsy. This dissertation investigated the utility of human autologous epidermal melanocyte and dermal fibroblast cell cultures for use as a tool for genetic confirmation of D/BMD from a much less invasive shave skin biopsy. Methodologies included immunohistochemical, immunocytochemical, Western blot, qPCR analysis and cDNA sequencing. The results suggest that melanocytes and fibroblasts express the full length muscle isoform of dystrophin, although at differing levels, and that melanocytes could potentially be used as an alternative for the genetic confirmation of D/BMD.
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Chen, Hung-Chih. "Functions of Caveolin-1 and Caveolin-3 in muscular dystrophy." Thesis, University of Birmingham, 2014. http://etheses.bham.ac.uk//id/eprint/4739/.
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Duchenne muscular dystrophy (DMD) is an X chromosome-linked disease caused by the absence of the sarcolemmal protein dystrophin. The skeletal muscles of DMD have disrupted dystrophin-glycoprotein complex (DGC) and impaired sarcolemma integrity. In this study, we show that clonally derived dystrophin-deficient myoblasts PD50A are differentiation impaired. Coculture with osteoblasts improves the differentiation efficiency of PD50A myoblasts. We also establish that supplementation of combinations of IGF-1/IGF-2, IGF-1/LIF and IGF- 2/LIF in cultured PD50A myoblasts ameliorates the differentiation impairment. We establish that there are elevated levels of Cav-3 and Cav-1 proteins in dystrophin-deficient myoblasts and mdx mouse embryos and that Cav-3 and Cav-1 form heterooligomers in adult skeletal muscles. We show that overexpression of Pax7 suppresses Cav-3 in dystrophin-deficient myoblasts. Using a genetic mouse model (mdx/cav3\(^{+/-}\)) embryo we further establish that immunohistochemistry staining of Cav-1 and Cav-3 coincides with the mouse heart development. The DGC of skeletal muscles plays a role in signal transduction and mechanical response. Here we show that AKT/mTOR and IGF-2/p57\(^{kip2}\) (but not ERK) signalling pathways are upregulated in dystrophin-deficient myoblasts and mouse embryos. Using atomic force microscope we show that Cav-1 helps maintain the stiffness of dystrophindeficient myotubes while Cav-3 help maintain that of dystrophin-deficient myoblasts. This study suggests that Cav-1 and Cav-3 have both compensatory and compromising roles in mdx.
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Haravuori, Henna. "Molecular genetics of tibial muscular dystrophy (TMD) and a novel distal myopathy." Helsinki : University of Helsinki, 2003. http://ethesis.helsinki.fi/julkaisut/laa/haart/vk/haravuori/.
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Booler, Helen. "Pathogenetic mechanisms in the dystroglycanopathies pathogenesis." Thesis, Royal Veterinary College (University of London), 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.669190.
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Khudai, Chandni. "A Descriptive Study on the Effect of Carrier Status on Mothers’ Wellbeing and Adaptation to Duchenne and Becker Muscular Dystrophy." University of Cincinnati / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1343068081.
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Winchester, Catherine Louisa. "Expression of myotonic dystrophy candidate proteins." Thesis, Imperial College London, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.265141.
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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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Sirsi, Shashank Ramesh Lutz Gordon J. "Treatment of Duschenne Muscular Dystrophy with exon skipping antisense oligonucleotides using novel polyethylenimine carriers /." Philadelphia, Pa. : Drexel University, 2007. http://hdl.handle.net/1860/1869.
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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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Giesige, Carlee Rae. "Mouse model characterization and in vivo testing of gene therapies for Facioscapulohumeral Muscular Dystrophy." The Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu153193150617187.
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Taylor, Peter John Medical Sciences Faculty of Medicine UNSW. "Molecular genetic analysis of a New South Wales muscular dystrophy cohort." Publisher:University of New South Wales. Medical Sciences, 2008. http://handle.unsw.edu.au/1959.4/43309.
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Duchenne muscular dystrophy (DMD) is an X-linked lethal condition associated with high morbidity and mortality. There is currently no cure for this disease. Several gene-based therapeutic approaches for treating DMD are currently under development but all are dependent on the knowledge of the causative dystrophin gene mutation. A combined mutation detection approach consisting of a quantitative PCR based analysis and DNA sequencing of the dystrophin gene resulted in a mutation etection rate of 96% in the New South Wales (NSW) DMD cohort. The proportion of exon duplication mutations was twice that generally reported for similar patient opulations. The clinical utility of the combined mutation protocol for DMD carrier testing clarified the carrier status of an additional one-third (33%) of female relatives compared to a conventional approach of biochemical, pedigree and linkage studies. The generally accepted view that two-thirds of mothers of isolated cases of DMD are themselves mutation carriers is challenged. Although this assumption is valid for duplication and DNA sequence mutations, it is not valid for deletion mutations in the NSW cohort. The incidence of new cases of DMD in the New South Wales population was educed from approximately 1 in 3594 live male births to 1 in 6022 live male births over a 25 year period, indicative of a significant effect of the combination of genetic counselling and improved methods of carrier detection over that period. In a study of a cohort of boys with DMD, who had both psychological and mutational analysis, it was shown that mutations affecting the shorter, C-terminal isoforms of dystrophin are associated with decreased mean intellectual function. A hypothesis is presented that mutations within the long 5' untranslated region of the Dp140 isoform are unlikely to significantly affect expression of this brain-expressed isoform. During the course of studying the NSW DMD cohort a family was identified which exhibited X-linkage and a unique clinical presentation involving episodes of severe and prolonged muscle weakness. A novel variant in the pyruvate dehydrogenase E1 alpha subunit (PDHA 1) was identified. The phenotypic effect of this variant is not proven but a body of evidence implicates this as likely to be causative of the observed phenotype.
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Tabebordbar, Mohammadsharif. "Improving Stem Cell-Based Therapy and Developing a Novel Gene Therapy Approach for Treating Duchenne Muscular Dystrophy (DMD)." Thesis, Harvard University, 2016. http://nrs.harvard.edu/urn-3:HUL.InstRepos:26718751.
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Genetic mutations in muscle structural genes can compromise myofiber integrity, causing repeated muscle damage that ultimately exhausts muscle regenerative capacity and results in devastating degenerative conditions such as Duchenne Muscular Dystrophy (DMD), Congenital Muscular Dystrophy (CMD) and different forms of Limb Girdle Muscular Dystrophy (LGMD). Gene supplementation and autologous stem cell transplant have been put forward as promising, though still unproven, therapeutic avenues for combatting these genetic muscle diseases. Both strategies aim to compensate expression of the missing or mutated protein. For cell therapy, autologous muscle stem cells (satellite cells) from dystrophic muscles undergo in vitro expansion and gene correction and then are transplanted into diseased tissue, where they fuse with resident myofibers to deliver a functional copy of the gene. One of the major obstacles for the autologous adult stem cell transplantation is that adult satellite cells account for a very rare population in muscle and they need to be expanded in culture, while retaining their engraftment potential, to generate sufficient number of cells for gene correction and transplantation. I tackled this problem by developing a culture condition that allows engraftable mouse satellite cells to expand in culture. This study also provides evidence for the feasibility of in vitro expansion, gene correction and transplantation of dystrophic satellite cells to restore DYSTROPHIN expression in dystrophic muscle.
In gene therapy, engineered gene products are delivered directly to muscle fibers as transgenes carried by viral vectors, such as Adeno Associated Viruses (AAVs). Viral- mediated delivery of a normal copy of the mutated genes into dystrophic muscle fibers holds big promise as a therapeutic avenue for Muscular Dystrophies. However, considering the indispensible role of satellite cells in muscle regeneration, an effective and long-term therapy for genetic muscle diseases requires restoration of gene expression in both dystrophic muscle fibers and satellite cells. Conventional gene therapy approaches lack the potential for long-term restoration of the mutated gene expression in satellite cells. In order to address this limitation, this study provides the proof of concept evidence for the use of a novel gene editing approach, which allows irreversible correction of the mutations in both dystrophic skeletal muscle fibers and satellite cells.Biology, Molecular and Cellular
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Albuquerque, Marco Antonio Veloso de. "Distrofia muscular de cinturas em crianças: caracterização clínica, histológia e molecular." Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/5/5138/tde-03012014-154533/.
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Introdução: As distrofias de cinturas representam um grupo de miopatias progressivas, geneticamente determinadas, envolvendo 16 formas de herança autossômica recessiva e oito dominantes, sendo as formas recessivas mais comuns, particularmente em crianças. Caracterizam-se por fraqueza muscular progressiva de predomínio proximal em cinturas escapular e pélvica, existindo desde formas graves de início na infância a formas leves de início em adultos. A biópsia muscular, com estudo histológico e imunoistoquímico, é fundamental para o diagnóstico, porém o exame molecular é o teste padrão ouro para o diagnóstico de certeza. Objetivos: Determinar a freqüência dos diferentes subtipos de distrofia de cinturas em crianças na nossa população, descrevendo os aspectos clínicos, histológicos e moleculares. Resultados: Fizeram parte deste estudo 39 crianças provenientes do ambulatório de doenças neuromusculares do HC-FMUSP, sendo a proporção entre o sexo feminino e masculino de 3:1. A idade de início da doença variou de dois a 13 anos, com média de 7,5 anos. Os sinais e sintomas na apresentação clínica incluíram: quedas frequentes (22 casos), dificuldades em subir escadas (13 casos), marcha digitigrada (2 casos) e dificuldades para se levantar do chão (2 casos). Os níveis de CK foram elevados em todos os pacientes, sendo maiores naqueles com diferlinopatia e algumas formas de sarcoglicanopatias. Dentre os 39 pacientes, 37 foram classificados como LGMD. Destes, 15 (40,5%) receberam o diagnóstico de sarcoglicanopatia (LGMD2C-F), cinco (13,5%) de disferlinopatia (LGMD2B), cinco (13,5%) de calpainopatia, dois (5,5%) de LGMD1B, dois (5,5%) de LGMD2I, um (2,5%) de caveolinopatia (LGMD1A), e em sete (19%) não foi possível identificar o subtipo específico. A biópsia muscular mostrou um padrão distrófico em todos os casos, sendo mais acentuado nas sarcoglicanopatias e na LGMD2I. A presença de inflamação foi incomum na LGMD2B, e a presença de fibras lobuladas foi um achado marcante na LGMD2A. Conclusões: O diagnóstico do subtipo específico de LGMD em crianças é um desafio. Este estudo em crianças brasileiras provenientes de um centro de doenças neuromusculares de um grande hospital da rede pública mostrou alta frequência de sarcoglicanopatias, seguida por LGMD2A e LGMD2B. Já a LGMD2I parece ser incomum no BrasilBackground: Limb-girdle muscular dystrophies (LGMD) are a heterogeneous group of genetic muscular dystrophies, involving 16 autosomal recessive subtypes and eight autosomal dominant subtypes. Autosomal recessive dystrophy is far more common than autosomal dominant dystrophy, particularly in children. The clinical course in this group is characterized by progressive proximal weakness, initially in pelvic and after in shoulder-girdle musculature, varying from very mild to severe degree. Significant overlap of clinical phenotypes, with genetic and clinical heterogeneity, constitutes the rule for this group of diseases. Muscle biopsies are useful for histopathologic and immunolabeling studies, and DNA analysis is the gold standard to establish the specific form of muscular dystrophy. Objectives: The aim of this study was to characterize the clinical, histological and molecular aspects in children with LGMD who attend a big public neuromuscular centre in our country to determine the frequency of different forms. Results: Thirty seven patients were classified as LGMD and included in this analysis. The study period extended from 2009-2012. The female to male ratio was 3:1. The age of onset ranged from two to 13 years, mean 7,5 years. Onset in the first decade was seen in 90%. The initial clinical signs included: frequent falls (22 cases), difficulty in climbing stairs (13 cases), walk on tip toes (2 cases), difficulty in rising from the floor (2 cases) and difficulty on walking (1 case). The serum CK levels were high in all cases. Among the 37 patients, 15 (40,5%) were classified as sarcoglycanopathies (LGMD2C-F), five (13,5%) as dysferlinopathy (LGMD2B), five (13,5%) as calpainopathy (LGMD2A). Mutations in LMNA gene (LGMD1B), FKRP gene (LGMDI) and caveolin gene (LGMD 1C) were identified in two (5,5%), two (5,5%) and one patient (2,5%), respectively. In seven of 37 cases (19%) it was impossible to determine specific diagnosis. Calf hypertrophy, scapular winging and scoliosis were the most characteristic signs in sarcoglycanopathies. In LGMD2I calf hypertrophy is also observed. Atrophy of posterior compartment of thighs is frequent in children with LGMD2B and could suggest the diagnosis. In LGMD2A winging of scapulae and contractures in Achilles tendons were important findings. Muscle biopsy showed a dystrophic pattern in all cases, more intense in sarcoglycanopathies and LGMD2I. Differently from adult\'s patients, inflammation changes in dysferlinopaties were uncommon. Lobuled fibers were characteristic changes in calpainopathies in children. Conclusions: A definitive diagnosis among various subtypes of LGMD in children is challenging. Our series was a large study on LGMD in Brazilian children and showed high frequency of sarcoglycanopathies followed by LGMD2A, LGMD2B, LGMD2I, LGMD1B and LGMD1C
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O'Reilly, Sean W. P. "RNAi Screening of the Kinome Identifies PACT as a Novel Genetic Modifier of Foci Integrity in Myotonic Dystrophy type 1." Thèse, Université d'Ottawa / University of Ottawa, 2014. http://hdl.handle.net/10393/30639.
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Myotonic Dystrophy type 1 (DM1), the most common form of adult muscular dystrophy (~1:8000) currently has no effective treatment. In DM1, expansion of a tri-nucleotide repeat in the 3' UTR of the DMPK gene results in DMPK mRNA hairpin structures, aggregating as insoluble ribonuclear foci. The resulting mis-regulation of important splicing factors, causes the inclusion of fetal exons in dozens of transcripts that contribute to the disease phenotype. In order to identify novel gene targets and kinase signalling pathways for potential therapeutics we have performed a high-throughput RNAi. RNA foci were visualized and quantified by in-situ hybridization. From our screen, we have identified a novel gene, PACT, as a modulator of foci integrity and that PACT knockdown can induce MBNL1 protein levels. The identified signalling complex represents a valid target for DM1 therapeutics. Our data further emphasizes the utility of RNAi screens in identifying disease-associated genes.
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Gladstone, Amy R. "Assessing the Genetic Counseling Needs of Parents who have Adopted a Child with Duchenne or Becker Muscular Dystrophy." University of Cincinnati / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1367924226.
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Ghosh, Arkasubhra. "Rational design of split gene vectors to expand the packaging capacity of adeno-associated viral vectors." Diss., Columbia, Mo. : University of Missouri-Columbia, 2007. http://hdl.handle.net/10355/4712.
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Thesis (Ph. D.)--University of Missouri-Columbia, 2007.The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Vita. "December 2007" Includes bibliographical references.
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Hoogerwaard, Edo Marc. "Duchenne and Becker muscular dystrophy neurological, cardiological and genetic studies in carriers and patients /." [S.l. : Amsterdam : s.n.] ; Universiteit van Amsterdam [Host], 2000. http://dare.uva.nl/document/55600.
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Acharyya, Swarnali. "Elucidating molecular mechanisms of muscle wasting in chronic diseases." Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1180096565.
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Packer, Davin R. "Leveraging the Extracellular Matrix to Create Novel Gene Therapies for the Congenital Muscular Dystrophies." The Ohio State University, 2021. http://rave.ohiolink.edu/etdc/view?acc_num=osu1618248650165864.
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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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Pogue, Robert. "Genetic analysis as part of an integrated strategy for diagnosis in autosomal recessive limb-girdle muscular dystrophy." Thesis, University of Newcastle Upon Tyne, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.299052.
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Hamanaka, Kohei. "Clinical, muscle pathological, and genetic features of Japanese facioscapulohumeral muscular dystrophy 2 (FSHD2) patients with SMCHD1 mutations." Kyoto University, 2016. http://hdl.handle.net/2433/216182.
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Final publication is available at http://dx.doi.org/10.1016/j.nmd.2016.03.001Kyoto University (京都大学)
0048
新制・課程博士
博士(医学)
甲第19928号
医博第4148号
新制||医||1017(附属図書館)
33014
京都大学大学院医学研究科医学専攻
(主査)教授 萩原 正敏, 教授 羽賀 博典, 教授 松田 秀一
学位規則第4条第1項該当
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Davis, Rohit Michael. "THE ASSESSMENT AND DEVELOPMENT OF FOLLISTATIN AS A GENE THERAPY AND ITS POTENTIAL ORTHOPEDIC APPLICATIONS." Case Western Reserve University School of Graduate Studies / OhioLINK, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=case1346854771.
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Kergourlay, Virginie. "Mise au point d'outils novateurs pour l'identification de mutations pathogènes : le cas des dysferlinopathies." Thesis, Aix-Marseille, 2014. http://www.theses.fr/2014AIXM5044.
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Le diagnostic des maladies génétiques est difficile à émettre. En effet, il est souvent difficile de déterminer comment une mutation va entrainer la pathologie. Le but de cette thèse est de développer des outils permettant de répondre à cette interrogation. Les mutations peuvent entrainer des anomalies à différents niveaux, différentes outils ont ainsi été développées en parallèle afin de pouvoir détecter différents types d'anomalies. Ces outils ont été développés en utilisant comme modèle une maladie génétique appartenant à la famille des myopathies, entrainant une dégénérescence des muscles des patients. Les travaux de cette thèse ont permis de confirmer le caractère délétère de certaines mutations en démontrant des anomalies dans un mécanisme appelé « épissage » qui permet la transmission de l'information contenue dans le génome. Les mutations en empêchant cette transmission vont ainsi être responsables de la maladieDiagnosis of genetic diseases is a difficult task. Indeed, it is often difficult to determine if mutations detected in patients will be responsible of the disease. The aim of this thesis is to develop tools allowing answering on this question. Mutations can have deleterious effects to several levels, thus different tools have been develop in parallel in order to detect different kind of abnormalities. These tools have been developed using as model a genetic disease belonging to the family of myopathy, leading to a degeneration of patients muscles. These thesis works have confirmed the deleterious effect on some mutations in a mechanism named "splicing" which allow transmission of the genome's information. Mutations preventing the transmission will thus be responsible of the disease
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Triandafillou, Joan. "Control of brown adipose tissue growth and function in rats and hamsters normalities in genetic models of human disease (obesity muscular dystrophy)." Thesis, University of Ottawa (Canada), 1985. http://hdl.handle.net/10393/4969.
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Henderson, Alex. "Consent, choice and children in research : exploring decision making by parents of children with Duchenne muscular dystrophy considering participation in genetic research projects." Thesis, University of Newcastle Upon Tyne, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.485599.
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Background: Informed consent is a concept that is fundamental to the ethical inclusion of individuals in medical research projects. Theoretical and ethical analyses of consent has focused on important criteria including voluntariness, competence, provision of information, recommendation, understanding, decision making al!d authorisation. Study aims: (l) To explore the meaning of the concept of informed consent to parents who are contemplating including their sons in research projects, which are designed to develop and trial novel genetic treatments; (2) To assess the ways in which these parents engage in the consent process. Discussion: This thesis draws on qualitative interview data on the process ofconsent as experienced by parents of children with Duchenne muscular dystrophy. The results from an interpretative phenomenological analysis ofthe interviews indicate that there is significant dissociation between how parents are expected to think and choose, and how they actually behave in real life when ml)king consent decisions for their children. Many ofthe criteria which are used'for assessing adequacy of consent appear unrealistic, impossible or irrelevant to parents. This incongruence seems to result from a model, based on a principle-led form ofrational reasoning, which tends to abstract the process of consent from its clinical and social setting. There is a risk that a strict focus on a narrow analysis of consent, concentrating on elements such as competence, voluntariness, etc., can lead to consent becoming devoid ofmeaning to individuals. In tum, this threatens parents' participation in decision-making and provides some explanation for why many patients, parents, clinicians and researchers feel cynical, irritated, or despondent about consent. A more sophisticated understanding of how these decisions are made is important to ensure that ethical decisions about paediatric research participation can be made.
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Loggenberg, Kelly. "An investigation into the level of genetic knowledge of parents of sons with Duchenne Muscular Dystrophy and their satisfaction with the genetic counselling service at Red Cross War Memorial Children's Hospital." Master's thesis, University of Cape Town, 2006. http://hdl.handle.net/11427/3419.
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Aupy, Philippine. "Le développement préclinique des tcDNA pour la Dystrophie Musculaire de Duchenne Evaluating the impact of variable phosphorothioate content in tricyclo-DNA antisense oligonucleotides in a Duchenne Muscular Dystrophy mouse model Identifying and avoiding tcDNA-ASO sequence specific toxicity for the development of DMD exon 51 skipping therapy Long term efficacy of AAV9-U7snRNA mediated exon 51 skipping in mdx52 mice The use of tricyclo-DNA for the treatment of Genetic Disorders Exon-skipping advances for Duchenne Muscular Dystrophy." Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLV083.
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La Dystrophie Musculaire de Duchenne est une maladie génétique mortelle qui touche un garçon sur 3500. Elle se manifeste par une faiblesse musculaire progressive conduisant à une perte de la marche autour de l’âge de 10 ans, puis des problèmes respiratoires et cardiaques. Elle est due à des mutations dans le gène DMD conduisant à une absence de la protéine dystrophine. Il n’existe à l’heure actuelle aucun traitement satisfaisant. L’une des stratégies thérapeutiques les plus prometteuses pour cette maladie consiste à moduler l’épissage de l’ARN pré-messager. Cette stratégie appelée aussi « saut d’exon » utilise principalement des oligonucléotides antisens qui vont permettre de restaurer le cadre de lecture et ainsi entrainer la production de protéine.Le laboratoire Biothérapie des Maladies du Système Neuromusculaire a développé une nouvelle chimie d’oligonucléotide antisens, les tricyclo-DNA (tcDNA), ayant fait leur preuve pour effectuer un saut de l’exon 23 efficace dans des modèles murins de la DMD. En effet, les chercheurs de l’équipe ont pu démontrer la présence de saut d’exon et de restauration de dystrophine dans l’ensemble de la musculature et dans le système nerveux central, permettant d’obtenir une amélioration fonctionnelle. Lors de ma thèse, je me suis intéressée au développement pré-clinique d’un tcDNA ciblant l’exon 51 humain, puisqu’il s’agit de l’exon permettant de traiter la plus grande proportion de patients (13%).La première partie de mon projet a été consacrée à l’amélioration de la tolérabilité des tcDNAs à travers deux approches : la modification de la séquence et la modification du design de la molécule. En effet, la cause principale de la toxicité des tcDNAs est la formation de structures homodimériques associée à la présence de liens phosphorothioates (PS). Cette première étude a permis, d’une part, de démontrer qu’une modification de la séquence entraine une élimination des structures homodimériques et permet ainsi d’obtenir une meilleure tolérabilité de la molécule. D’autre part nous avons pu mettre en évidence qu’une diminution du contenu en liens PS permet de limiter l’apparition d’une toxicité à long terme sans impacter significativement l’efficacité.La deuxième partie de mon projet de thèse a été consacrée à l’optimisation de l’efficacité des tcDNAs. Pour cela deux approches ont été investiguées : d’une part l’amélioration de la biodisponibilité de la molécule et d’autre part l’optimisation de la séquence cible. Nous avons ainsi pu démontrer que la conjugaison d’un acide gras à un tcDNA entraine une amélioriation significative de sa biodistribution et de l’efficacité du tcDNA. En parallèle, un criblage de nombreuses séquences ciblant différentes régions de l’exon 51 a permis de sélectionner une séquence candidate présentant une efficacité nettement supérieure à celle de la séquence initiale. Cette séquence, conjuguée à un acide palmitique, a démontrée des résultats extremement encourageants pour les futurs essais cliniques et est actuellement en phase finale de développement précliniqueDuchenne Muscular Dystrophy is a fatal genetic disorder affecting 1/3500 newborn males. It is characterized by progressive muscle weakness causing loss of ambulatory functions and respiratory and cardiac failures. This disease is due to mutations in the DMD gene leading to complete loss of protein expression. There is currently no satisfactory treatment but one of the most promising therapeutic strategy is splicing modulation. This strategy also called “exon skipping” is achieved through the use of antisense oligonucleotides allowing a restoration of the reading frame, and thus leading to protein rescue.The laboratory Biothérapie des Maladies du Système Neuromusculaire has developped a new chemistry of antisense oligonucleotide, tricyclo-DNA (tcDNA). They have demonstrated the therapeutic potential of tcDNA in different mouse models of DMD. Indeed, after systemic treatment significant exon 23 skipping and dystrophin restoration were found in all tested muscles as well as in the central nervous system, leading to functional improvement. During my phD project, I worked on the pre-clinical development of a tcDNA targeting human exon 51, which could be applicable to a large proportion of DMD patients (13%).The first part of my project was dedicated to the improvement of tcDNA tolerability through the modification of the sequence itself and the modification of the chemical design. Indeed, the major cause of tcDNA toxicity is the formation of homodimeric structure associated with the presence of phosphorothioates linkages (PS). In this study, we were able to demonstrate that modification of the toxic sequence impairs homodimerization, thus suppressing toxicity. Moreover, we have demonstrated that a decrease in the PS content prevent the apparition of long term toxicity without impairing significatively exon skipping efficacy but.The second part of my project focused on the optimisation of tcDNA efficacy through improvement of their biodisponibility and optimisation of the targeted sequence. We first demonstrated that fatty acid conjugation to tcDNA significantly improves biodistribution and efficacy. In parallel, we screened numerous sequences targeting different regions of the exon 51 and selected a novel sequence with a significantly higher efficacy than the initial sequence. This novel tcDNA sequence, once conjugated with palmitic acid demonstrated extremely encouraging results for the treatment of DMD and we are currently finalizing its development for future clinical trials
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Silva, Marly Conceição. "Diagnóstico da cardiomiopatia na distrofia muscular progressiva por ressonância magnética cardiovascular - correlação com tratamento, prognóstico e preditores genéticos." Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/5/5131/tde-01112013-093410/.
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Introdução: Distrofia muscular progressiva nas formas de Duchenne (DMD) e Becker (DMB) são doenças caracterizadas por progressiva degeneração musculoesquelética e substituição por tecido fibrogorduroso. O envolvimento cardíaco está presente em 80% dos pacientes, apresenta curso clínico silencioso e é diagnosticado tardiamente pelos métodos tradicionais. Objetivos: 1. Investigar a progressão da fibrose miocárdica pela ressonância magnética cardíaca (RMC), em ensaio clínico randomizado para tratamento ou não com IECA, de pacientes com DMD e DMB e fração de ejeção ventricular esquerda (FEVE) preservada, por um período de 02 anos. 2. Investigar se há mutações genéticas específicas que sejam preditoras do acometimento miocárdico diagnosticado pela RMC. 3. Comparar os achados do ECG, radiografia de tórax e ecocardiograma com os da RMC. Métodos: Entre 1/6/2009 e 1/6/2012 foram incluídos 76 pacientes com diagnóstico de DMD e DMB. Todos os pacientes realizaram duas RMCs com intervalo médio de 2,05±0,11 anos, com técnicas de cine ressonância para avaliação da função ventricular e realce tardio miocárdico para avaliação da fibrose miocárdica. A fibrose miocárdica foi quantificada por software específico para obtenção do percentual da massa de fibrose do VE com análise semi automática, utilizando os desvios padrões da média dos valores de intensidade do sinal do miocárdio normal. Os valores acima de 5 desvios padrões da média do miocárdio normal foram considerados como fibrose miocárdica. Os 42 pacientes com fibrose miocárdica e FEVE normal foram randomizado em 2 grupos, com 21 deles recebendo tratamento com IECA e 21 sem qualquer tratamento para cardiomiopatia. Após 2 anos, novas RMCs foram realizadas para avaliar a evolução da fibrose e a FEVE. Resultados: Notou-se fibrose miocárdica em 72,3% dos pacientes, sendo que 55,6 % não apresentavam disfunção sistólica. Verificou-se uma correlação positiva significativa entre idade e percentual de fibrose na RMC basal (r=0,338, p=0,014) e seguimento (r=0,315, p=0,006). Os pacientes randomizados e tratados com IECA apresentaram menor evolução do percentual de fibrose do que os randomizados não tratados (3,1±7,4% versus 10,0±6,2% respectivamente, p=0,001). Na análise linear multivariada, verificamos que pertencer ao grupo tratado diminui a progressão do percentual de fibrose (y=-4,51x+29,63 ajustado por idade, CK e percentual de fibrose basal, p=0,039) e indica uma tendência de menor probabilidade de apresentar fração de ejeção do VE < 50% na RMC seguimento (OR= 3,18, p= 0,102, por regressão logística). Os pacientes com mutação nos exons menores que 45 do gene da distrofina apresentaram maior percentual de fibrose que os com mutação dos exons maiores ou iguais ao 45 na RMC basal (27,9±18,4% versus 12,1±13,4%, respectivamente, p=0,006) e seguimento (33,1±21,1% versus 18,8±16,9%, respectivamente, p=0,024). A avaliação conjunta por métodos tradicionais (radiografia de tórax, ECG e ecocardiografia) apresentou baixa sensibilidade de 47,3% e valor preditivo negativo de 34,1% para o diagnóstico do envolvimento cardíaco na DMD e DMB, em pacientes com FEVE normal e fibrose miocárdica na RMC. Conclusões: O ensaio clínico randomizado, por um período de 2 anos, em pacientes com DMD e DMB, com fibrose miocárdica diagnosticada pela RMC e FEVE preservada, demonstrou significativa maior progressão da fibrose miocárdica nos pacientes que não fizerem uso de IECA. Existe uma correlação significativa entre o local de mutação no gene da distrofina e o acometimento cardíaco. O ECG, o eco e radiografia de tórax apresentaram baixa sensibilidade e baixo valor preditivo negativo para detecção do envolvimento cardíaco precoce nos pacientes com DMD e DMBIntroduction: Duchenne and Becker muscular dystrophies (DMD and BMD) are diseases characterized by progressive skeletal muscle degeneration and replacement by fibro fatty tissue. Cardiac involvement is frequent, as high as 70 - 80% of patients, and often develops clinically silent, without any evident early clinical signs. Traditional diagnostic methods (ECG, chest x-ray and echocardiography) are only able to diagnose cardiac involvement at a later stage. Objectives: 1. To investigate the progression of myocardial fibrosis by cardiac magnetic resonance (CMR), in a randomized clinical trial for treatment with ACE inhibitors, in patients with DMD or BMD and preserved left ventricular ejection fraction (LVEF), for a period of 02 years. 2. To investigate whether there are specific genetic mutations that are predictive of myocardial involvement detected by CMR. 3. To compare the findings of ECG, chest radiography and echocardiography with those found by CMR. Methods: Between 01/06/2009 and 01/06/2012 76 patients with DMD and BMD were included. All patients underwent two CMRs with a mean interval of 2.05±0.11 years, using cine resonance for function evaluation and myocardial delayed enhancement technique for myocardial fibrosis detection. Myocardial fibrosis was quantified by specific software for obtaining fibrosis mass, as percentage of LV mass, using semi-automatic fibrosis analysis and standard deviations of the mean values of signal intensity of the normal myocardium. A value of five standard deviations above the mean of a normal myocardium were considered myocardial fibrosis. The 42 patients with myocardial fibrosis and normal LVEF were randomized into 2 groups, with 21 of them receiving ACE inhibitor treatment and 21 no treatment for cardiomyopathy. After 2 years, new CMRs were performed to evaluate fibrosis extent and LVEF. Results: Myocardial fibrosis was noted in 72.3% of the patients, 55.6% showed no systolic dysfunction. There was a significant positive correlation between age and myocardial fibrosis at the CMR baseline (r=0.338, p=0.014) and follow-up (r=0.315, p=0.006). Patients randomized and treated with ACE inhibitors had lower evolution of myocardial fibrosis than those who were randomized and untreated (3.1±7.4% vs.10.0±6.2%, respectively, p=0.001). Using multivariate regression analysis, we found that belonging to the treated group decreases the progression of myocardial fibrosis (y=-4.51x+29.63 adjusted for age, CK and baseline myocardial fibrosis, p=0.039) and indicated a trend for lower probability of presenting LVEF<50% at follow-up CMR (OR= 3.18, p= 0.102, by logistic regression). Patients with mutations in exons less than 45 had greater extent of myocardial fibrosis than patients with mutations in exons greater than or equal to 45 in CMR at baseline (27.9±18.4% vs. 12.1±13.4%, respectively, p=0.006) and at follow-up (33.1±21.1% vs. 18.8±16.9%, respectively, p=0.024). Conclusions: In this 2-year follow-up randomized clinical trial in patients with DMD and BMD with preserved LVEF, myocardial fibrosis diagnosed by CMR, showed significantly greater progression in patients not receiving ACE inhibitors therapy. There was a significant correlation between the site of mutation in the dystrophin gene and cardiac involvement. ECG, echocardiography and chest radiography showed low sensitivity and low negative predictive value for early detection of cardiac involvement (myocardial fibrosis by CMR) in patients with DMD and BMD
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Franco, Carolina Rosa. "Caracterização do diagnóstico clínico e detecção no gene da distrofia muscular de Duchenne/Becker no Rio Grande do Sul por PCR quantitativo em tempo real." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2007. http://hdl.handle.net/10183/12031.
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A Distrofia Muscular de Duchenne/Becker (DMD/BMD) é a doença neuromuscular mais freqüente em crianças, afetando uma em cada 3.500 nascidos vivos do sexo masculino (DMD), e um em cada 20.000 (BMD). A criança nasce aparentemente saudável, com o aparecimento gradual e progressivo dos sintomas desde o primeiro ano de vida. A perda da habilidade de caminhar se dá entre os sete e 12 anos de idade, com sobrevivência rara acima dos 30 anos; e a BMD, de forma mais amena, com os mesmos sintomas aparecendo mais tardiamente. O diagnóstico se baseia nas características clínicas e na investigação genética de deleções e duplicações no gene da distrofina. Um teste preciso ainda é necessário para a identificação de mulheres portadoras. O PCR quantitativo em tempo real seria um bom ensaio para a determinação deste status.O objetivo deste trabalho foi identificar as mulheres portadoras de deleções no gene da distrofina através de PCR quantitativo em tempo real e apresentar informações diagnósticas sobre a população de meninos com DMD/BMD do RS. Informações pertinentes a 123 meninos com diagnostico clínico foram incluídos neste estudo. Após análise dos exames de DNA nos meninos estudados, os exons 47, 48 e 50 se mostraram mais frequentemente deletados na nossa população, confirmando que o segundo "hotspot" gênico é o que mais sofre alterações. Cinco mulheres com filhos com deleções nos exons 45, 47 e 51 foram testadas para estabelecimento do seu status de portadora ou não-portadora. A comparação direta dos exons específicos em relação aos mesmos em outras mulheres, determinou, com uma fácil visualização, a confirmação de três mulheres portadoras e duas não-portadoras, sendo um método preciso e efetivo. É uma abordagem prática e importante para uma utilização em casos de duplicações neste mesmo gene e em outros que necessitem deste tipo de quantificação exata.Duchenne/Becker Muscular dystrophy (DMD/BMD) is the most frequent neuromuscular disorder in children, affecting one in every 3,500 born male boys (DMD), and one in every 20,000 (BMD). The child is born apparently healthy, with a gradual and progressive appearance of the symptoms during the first year of life. Between the ages of seven to 12, the child demonstrates a loss of the ability to walk, with rare survival above 30 years; and BMD, a milder form, with similar symptoms delayed. The diagnosis is based on the clinical characteristics and a genetic investigation of deletions and duplications in the dystrophin gene. A precise test is still necessary for the identification of carrier women. A quantitative real-time PCR would be a good assay for the determination of this status. The main goals of this study were to identify the carrier women of deletions in the dystrophin gene through the quantitative real-time PCR and to present the diagnostic information available for the population of boys with DMD/BMD in RS. Information pertaining to 123 boys with a clinical diagnosis was included in this study. After the analysis of the boy´s DNA exams, exons 47, 48, and 50 were the most frequently deleted in our population, confirming that the second genetic hospot suffers most of the alterations. Five women that bore children with deletions in exons 45, 47, and 51 were tested for the establishment of their carrier or non-carrier status. A direct comparison of the specific exons to the same ones in other women determined, with an easy visualization, the confirmation of three carrier women and two non-carrier, being a precise and effective method. It is a practical and important approach for the use in cases of duplication in this same gene and in others that may need an exact quantification.
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Geng, Yan. "Molecular genetic studies of the mouse dystrophin gene." Thesis, University of Cambridge, 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.239374.
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Clement, E. "Congenital muscular dystrophy in 2010." Thesis, University College London (University of London), 2011. http://discovery.ucl.ac.uk/1318071/.
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Congenital Muscular Dystrophies (CMDs) are a heterogeneous group of conditions that usually present in the first months of life with weakness and hypotonia. Extramuscular manifestations are common and may include brain, skin and eye abnormalities. CMDs are relatively rare disorders and despite the major progress made over the last 2 decades in identifying, mapping and investigating these conditions, there remains a lot to be learned. Little is known about the relative frequency of the various forms of CMD in the UK population. Experience had shown that founder mutations are common in different ethnic populations and epidemiological studies performed in other countries are of limited value in this regard. Since 2001, the Dubowitz Neuromuscular Centre (DNC) has been the National Commissioning Group UK Centre for CMD. As such we are in the privileged position to have access to a large number of UK patients with CMD. I analysed a cohort of 214 CMD referrals to the DNC between 2001 and 2008 with a view to reporting the diagnostic outcome and the frequency of the various forms of CMD encountered in our patient population. The second part of the thesis is concerned with the dystroglycanopathies, a recently described group of CMDs associated with aberrant glycosylation of alpha dystroglycan. To date, 7 genes have been identified, some of which give rise to multiple dystroglycanopathy phenotypes. I studied the genotype-phenotype relationship in a large group of dystroglycanopathy patients, reporting new clinical phenotypes and establishing the mutation frequency in this group. I also report in detail the spectrum of MRI brain changes seen in 27 dystroglycanopathy patients. In summary, this work reports the diagnostic outcome in the largest cohort of UK CMD cases studied and refines the genotype-phenotype correlation in patients with dystroglycanopathies.
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Holst, Holst. "The history of muscular dystrophy." Thesis, University of British Columbia, 1989. http://hdl.handle.net/2429/27477.
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The muscular dystrophies, Duchenne muscular dystrophy being the most common type, are a group for which there is no apparent pathology to the spinal motor neurons concomitant to progressive muscular degeneration. After this fact was established during the nineteenth century through postmortem examination, Charcot divided muscular disease into the "Great Classes" of myopathy and neuropathy. Erb's study of the histopathology brought a further division between the two before death and therefore the muscle biopsy became a tool for differential diagnosis. He also discovered that the response of muscle in myopathy and neuropathy to the application of electric current differed. While the response of myopathic muscle was progressively diminishing and equally so to the application of either galvanic or alternating current, neuropathic muscle maintained its ability to contract upon the application of galvanic current during the course of the disease.
As well as the animating power of the nervous system by way of the anterior nerves, its trophic effect upon the muscle was evident by loss of volume upon interruption of its influence. Even though the absence of a lesion involving the spinal motor neurons or descending motor tracts was a constant in muscular dystrophy, there remained some reluctance to accept myopathy as being independent of the nervous system. According to the maintenance of the contractile response to galvanic current in neuropathy Erb suggested that there was a nerve centre other than that of the anterior cornua of the spinal cord which supplied the trophic influence. When he found histological features which were typical of myopathy in poliomyelitis he was convinced that muscular dystrophy was the result of a trophic disturbance. However, this theory was not sustainable because there was no anatomical evidence for a special trophic centre.
In 1970 McComas again proposed that a neurogenic phenomenon was responsible for the pathogenesis of the muscular dystrophies. It was the re-emergence of a neurogenic hypothesis for muscular dystrophy which was the purpose of my exercise. In order to answer the question as to why a trophic theory reappeared I followed the research and theory regarding muscular dystrophy over time.
The powerful effect of the somatic innervation upon muscle metabolism as determined by cross innervation experiments during the 1960's, set the stage for the reassertion of a trophic disturbance in muscular dystrophy. In addition, the division between myopathy and neuropathy had become less.distinct by 1970 in terms of histology, serum enzymes and the intramuscular innervation. Histological features considered to by typical of myopathy were seen in the biopsies of Charcot-Marie-Tooth disease and Kugelberg-Welander spinal muscular atrophy. As well, abnormally elevated serum levels of creatine phosphokinase which was characteristic of muscular dystrophy, were measured in these neuropathies. Changes in the intramuscular innervation of myotonic dystrophy and the animal model for muscular dystrophy also brought into question the myopathicity of muscular dystrophy.
By 1970 the types of muscular dystrophy had been classified according to clinical and genetic criteria and were thus known to be genetically distinct diseases. A unifying hypothesis is always desireable and therefore, mental deficiency according to clinical assessment in Duchenne and myotonic dystrophy, the latter being an "impure" dystrophy, were considered to be supportive of the neurogenic hypothesis. "Hypertrophic paraplegia of infancy of cerebral origin" was the original title of what became known as Duchenne dystrophy. The frequent occurrence of mental retardation was the foundation of the name but with knowledge concerning the profound influence of the nerve upon the metabolism of the muscle, the alleged cerebral defect in Duchenne dystrophy favoured the neuropathicity of dystrophy even more.Medicine, Faculty of
Cellular and Physiological Sciences, Department of
Graduate
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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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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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Bakir, Hadil. "Studies on muscular dystrophy associated genes." Thesis, Durham University, 2007. http://etheses.dur.ac.uk/2143/.
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Muscular dystrophy is a collective group of genetic disorder that results in progressive wasting of skeletal muscle. Dysferlin, the gene responsible for Limb Girdle Muscular Dystrophy type 2B (LGMD2B) and Miyoshi Myopathy (MM) was found to be a member of a newly identified protein family named the ferlins. Recent work has suggested that dysferlin is necessary for efficient calcium sensitive membrane resealing therefore is involved in membrane repair, a mechanism which if defective results in progressive muscle wasting. In this project, the involvement of other genes that could possibly be associated with muscular dystrophy is investigated. Myoferlin, a member of the ferlin protein family is highly homologous to dysferlin and is also a plasma membrane protein with six C2 domains and a C-terminus transmembrane domain. To date no disease has been associated with mutations in the myoferlin gene but its high similarity to dysferlin means that it could be a potential muscular dystrophy associated gene. Results obtained from this study strongly suggest that myoferlin like dysferlin is enriched at plasma membrane disruption sites and during myoblast differentiation, two processes which involve the fusion of two opposed bilayers, a process vital in membrane repair. In addition, a fifth member of the ferlin protein family is reported in this project and the primary results obtained are consistent with it being a potential muscular dystrophy associated gene. Finally, a group of MM affected families that were previously excluded for mutations in their dysferlin gene were analysed for muscular dystrophy associated genes other than dysferlin.
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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.Cataloged from PDF version of thesis.
Includes bibliographical references (pages 75-78).
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.
by Sisir Koppaka.
S.M.
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Beers, Leanne. "Living With Muscular Dystrophy: Sexual Education." ScholarWorks, 2018. https://scholarworks.waldenu.edu/dissertations/4908.
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Sexual pleasure and intimacy are fundamental and innate human needs. Individuals with physical disabilities often find it difficult to meet these needs because of such factors as impaired mobility and lack of knowledge about sexual health. People with physical disabilities are often seen as asexual and not capable of having sex, and sexuality is often not considered a concern among this population. These misconceptions can result in individuals with physical disabilities not receiving basic sex education or advice and guidance when issues arise. Not receiving this attention may impede disabled individuals' sexual potential and personal relationships. This study's focus was on the unique challenges individuals with muscular dystrophy (MD) face regarding sexual pleasure and intimacy. Humanistic psychology and the human rights theory provided the theoretical framework for this study. Using a qualitative multiple case study approach, 4 individuals with MD were asked what sexual education, if any, they received, and if they did receive sexual education, whether it met their needs. Data were analyzed using open and axial coding. Key findings were that there is an overarching theme of sexual silence and lack of sex education for people with MD. These findings can help inform efforts to provide more inclusive education for people with MD and individuals with other types of physical disabilities. Study findings contribute to social change by showing the importance of the need for more inclusive sexual education. Providing such education will better meet the basic human needs of an often undeserved and stigmatized population and end the silence that individuals with physical disabilities have regarding sexual health and intimacy.
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Wallace, Lindsay M. "Gene Therapy for Facioscapulohumeral Muscular Dystrophy." The Ohio State University, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=osu1338315498.
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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.
Full textAbstract:
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.