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Kannebley, João Stein 1971. "Aspectos clínicos, radiológicos e neuroimagem em 12 pacientes com Gangliosidose GM1, formas juvenil e crônica." [s.n.], 2015. http://repositorio.unicamp.br/jspui/handle/REPOSIP/312528.
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Orientador: Carlos Eduardo SteinerDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: A gangliosidose GM1 é uma doença rara causada pela deficiência da enzima ?-galactosidase, decorrente de mutações no gene GLB1, acarretando o acúmulo de gangliosídeos, principalmente o GM1. É classificada em três formas dependendo da idade de início dos sintomas. Em todas ocorrem alterações esqueléticas e deterioração neurológica, sendo que na forma adulta predominam sinais extrapiramidais como distonia. No presente estudo descrevemos as características de 12 pacientes com gangliosidose GM1 nas formas juvenil e crônica de 10 famílias não aparentadas provenientes da região de Campinas, SP, e do sul do estado de Minas Gerais. Foram detalhados a história clínica e o exame físico, em especial o neurológico, bem como de aspectos radiológicos, ultrassonográficos, ecocardiográficos e de neuroimagem. Metade dos casos iniciou com queixas ósteo-articulares e outra metade com sintomas neurológicos, porém com a evolução todos apresentaram uma combinação de disostose múltipla e neurodegeneração. Opacificação de córnea e angioqueratomas foram vistos em um caso, cada. Outros sinais comumente associados às doenças de depósito lisossômico não foram vistos nesta casuística. Todos apresentaram baixa estatura, disostose múltipla, disartria e prejuízo nas atividades de vida diária, 10 tinham distonia e disfagia, nove atrofia muscular e oito sinais piramidais e alterações da movimentação ocular. Barra óssea e os odontoideum foram vistos em dois casos, sendo alterações previamente não descritas nessa condição. Exames de neuroimagem mostraram aumento do sistema ventricular e hipointensidade de sinal em globos pálidos em todos, além de deformidades vertebrais, hiperintensidade de sinal de putâmen e atrofia cortical na maioria. Alterações em tálamo, substância branca ou atrofia cerebelar não foram identificadas nessa série
Abstract: GM1 gangliosidosis is a rare disorder caused by deficiency in ?-galactosidase activity due to mutations in the GLB1 gene, leading to acumulation of gangliosides in multiple organs. Three main clinical forms have been described according to the age of onset. All present with skeletal deformities and neurologic deterioration, and in the adult form extrapyramidal signs including dystonia are frequent. In the present study we describe 12 subjects of 10 unrelated families from the region of Campinas and the southern state of Minas Gerais. Clinical information included detailed history, full neurologic examination, radiologic, ultrasonographic, echocardiographic, and neuroimaging description. Half of subjects presented initially with skeletal deformities, while the remaining opened clinical presentation with neurologic features. However, over time all presented dysostosis multiplex and neurodegeneration. Corneal clouding and angiokeratomas were seen in one individual each. Other features commonly described in lysosomal storage disorders were not found in this series. All subjects presented with short stature, dysostosis multiplex, dysarthria, and impairment of activities of daily living, 10 had extrapyramidal signs, nine had muscular atrophy, and eight had pyramidal signs and mild oculomotor abnormalities. A vertebral bone bar and os odontoideum were found in two patients, being previously undescribed in this condition. Neuroimaging revealed enlargement of the ventricular system and hypointensity of globus pallidus in all, besides vertebral deformities, putaminal hyperintensity, and cortical atrophy in most patients. Thalamic changes, abnormal white matter or cerebellar atrophy were not seen in this series
Mestrado
Genetica Medica
Mestre em Ciências Médicas
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Elliot-Smith, Elena. "GM1 gangliosidosis : therapy and pathogenesis." Thesis, University of Oxford, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.425028.
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Baptista, Marcella Bergamini de 1988. "Análise de mutações no gene GLB1 em pacientes com gangliosidose GM1 formas juvenil e crônica." [s.n.], 2013. http://repositorio.unicamp.br/jspui/handle/REPOSIP/308543.
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Orientador: Carlos Eduardo SteinerDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: Gangliosidose GM1 é uma doença autossômica recessiva rara, classificada em três formas clínicas de acordo com a idade de apresentação dos sintomas e a gravidade, provocada pela deficiência da enzima lisossômica ?-galactosidase que leva ao acúmulo, principalmente, do gangliosídeo GM1. A forma juvenil geralmente apresenta início entre sete meses e três anos de idade, com progressão lenta dos sinais neurológicos, dimorfismos menos graves que na forma infantil e deformidades ósseas. A forma crônica é caracterizada por apresentações clínicas mais leves e sintomas extrapiramidais. O gene codificador da enzima é o GLB1, no qual mais de 130 mutações foram descritas. No presente estudo foi realizada a caracterização molecular de 10 indivíduos de nove famílias não relacionadas diagnosticados com gangliosidose GM1, nas formas juvenil e crônica. Todas as famílias são originárias do interior do estado de São Paulo ou do sul do estado de Minas Gerais. Para a análise realizada foi possível identificar a mutação anteriormente descrita p.T500A, em sete das nove famílias estudadas, a inserção c.1717- 1722insG e a mutação p.R59H foram encontradas em duas famílias (a última segregou juntamente com o polimorfismo descrito IVS12+8T>C). As demais mutações descritas (p.F107L, p.L173P, p.R201H, p.G311R) foram encontradas em uma família cada. Uma alteração neutra (p.P152P) e duas mutações (p.I354S e p.T384S) são inéditas. Foi possível identificar a ocorrência de uma mutação de novo em uma família. Todas as mutações foram encontradas em heterozigose
Abstract: GM1 gangliosidosis is a rare autosomal recessive, classified in three clinical types according to age of onset and severity. The disease is caused by the deficiency of lysosomal enzyme ?-galactosidase that leads to the accumulation of GM1 ganglioside. The juvenile form usually shows an onset between seven months and three years of age, with slowly progressive neurological signs, less severe dysmorphisms than the infantile form and skeletal changes. The adult form is specified by a milder clinical manifestations and extrapyramidal signs. The lysossomal enzyme is coded by the GLB1 gene which more than 130 mutations have been decribed. In the present study it was genotyped 10 individuals of nine unrelated families originated from the States of São Paulo and Minas Gerais diagnosed with the juvenile and chronic forms of the disease. It was possible to find the previously described mutations p.T500A in seven of the nine families, c.1717-1722insG and p.R59H in two alleles (the latter also segregating with IVS12+8T>C), and p.F107L, p.L173P, p.R201H, and p.G311R in one familie each. One neutral alteration (p.P152P) and two mutations (p.I354S and p.T384S) are described for the first time. The occurrence of a de novo mutation was seen in one family. All patients presented as heterozygous compound
Mestrado
Ciencias Biomedicas
Mestra em Ciências Médicas
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Heinecke, Karie A. "Myelin abnormalities in the optic and sciatic nerves of mice with GM1-gangliosidosis." Thesis, Boston College, 2014. http://hdl.handle.net/2345/bc-ir:103611.
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Thesis advisor: Thomas N. SeyfriedGM1 gangliosidosis is a glycosphingolipid lysosomal storage disease caused by a genetic deficiency of acid b-galactosidase (β-gal), the enzyme that catabolyzes GM1 within lysosomes. Accumulation of GM1 and its asialo form (GA1) occurs primarily in the brain, leading to progressive neurodegeneration and brain dysfunction. Less information is available on the neurochemical pathology in optic nerve and sciatic nerve of GM1- gangliosidosis. Here we analyzed the lipid content and myelin structure in optic and sciatic nerve in 7 and 10 month old normal β-gal (+/?) and GM1-gangliosidosis β-gal (-/-) mice. Optic nerve weight was lower in the β-gal -/- mice than in unaffected β-gal +/? mice, but no difference was seen between the normal and the β-gal -/- mice for sciatic nerve weight. The concentrations of GM1 and GA1 were significantly higher in optic nerve and sciatic nerve in the β-gal -/- mice than in β-gal +/? mice. The content and composition of myelin-enriched cerebrosides, sulfatides, plasmalogen ethanolamines were significantly lower in optic nerve of β-gal -/- mice than in β-gal +/? mice, however cholesteryl esters were enriched in the β-gal -/- mice. No significant abnormalities in these myelin enriched lipids were detected in sciatic nerve of the β-gal -/- mice. The abnormalities in GM1 and myelin lipids in optic nerve of β-gal -/- mice were also associated with abnormalities in the X-ray diffraction pattern including myelin content in fresh nerves [M/(M +B)] and periodicity (d). With the exception of a slight reduction in myelin content, no abnormalities in the X-ray diffraction pattern were observed in sciatic nerve of β-gal -/- mice. The results indicate that neurochemical pathology is greater in optic nerve than in sciatic nerve of β-gal -/- mice
Thesis (MS) — Boston College, 2014
Submitted to: Boston College. Graduate School of Arts and Sciences
Discipline: Biology
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Kreutzer, Robert. "Molecular pathogenesis, differential transcription of enzymes forming the lysosomal multienzymic complex and microsatellite based genotyping in canine GM1-gangliosidosis." Giessen : DVG-Service, 2008. http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&doc_number=017137159&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA.
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Whalen, Michael. "Treating GM1 Gangliosidosis With Ex Vivo Hematopoietic Stem Cell Gene Therapy Without Using Total Body Irradiation: A Masters Thesis." eScholarship@UMMS, 2011. https://escholarship.umassmed.edu/gsbs_diss/558.
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GM1 gangliosidosis is an autosomal recessive lysosomal storage disease, caused by a deficiency in the enzyme β-galactosidase. The disease affects the CNS, liver, kidney, heart and skeletal system, leading to severe neurodegeneration and death. We propose to treat this disorder using ex vivo hematopoietic stem cell therapy. The effectiveness of this therapy requires the recruitment of transduced donor cells to the CNS. This is only found to occur after mice are conditioned with total body irradiation, due to the increase in CNS cytokine production and blood brain barrier permeability that occurs. As the use of total body irradiation in pediatric patients has been linked to future developmental problems, this myeloablation approach is often avoided in younger patients in favor of a conditioning regimen using the chemotherapy drugs, busulfan and cyclophosphamide. Whether donor cells can enter the CNS when a busulfan and cyclophosphamide conditioning regimen is used has not been determined. In this study we plan to quantify the cytokine and blood-brain barrier permeability increases necessary for donor cells to be recruited to the CNS after total body irradiation. We will then investigate whether busulfan and cyclophosphamide conditioning and/or the chronic neuroinflammation present in GM1 mice can produce similar conditions and facilitate the recruitment of donor hematopoietic stem cells to the CNS. Finally we will assess whether ex vivo hematopoietic stem cell gene therapy is still an effective therapy when busulfan and cyclophosphamide are used for myeloablative conditioning.
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Weismann, Cara M. "Approaches and Considerations Towards a Safe and Effective Adeno-Associated Virus Mediated Therapeutic Intervention for GM1-Gangliosidosis: A Dissertation." eScholarship@UMMS, 2014. http://escholarship.umassmed.edu/gsbs_diss/767.
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GM1 gangliosidosis is a lysosomal storage disorder caused by a deficiency in the catabolizing enzyme β-galactosidase (βgal). This leads to accumulation of GM1-ganglioside (GM1) in the lysosome inducing ER stress and cell death. GM1 gangliosidosis is primarily a disorder of the central nervous system (CNS) with peripheral organ involvement. In this work we report two major findings, 1) systemic treatment of GM1 gangliosidosis with an adenoassociated virus (AAV9) encoding mouse-βgal (mβgal) in a GM1 gangliosidosis mouse model (βGal-/-), and 2) an investigation into an intracranial injection of a therapeutic AAVrh8 encoding mβgal. Systemic treatment of GM1 gangliosidosis with AAV9 resulted in a moderate expression of enzyme in the CNS, reduction of GM1 storage, significant retention of motor function and a significant increase in lifespan. Interestingly, the therapeutic effect was more robust in females. Intracranial injections of AAVrh8 vector expressing high levels of βgal resulted in enzyme spread throughout the brain, significant retention of motor function and a significant increase in lifespan. Histological alterations were also found at the injection site in both βGal-/- and normal animals. We constructed a series of vectors with a range of decreasing enzyme expression levels to investigate the cause for the unanticipated result. Microarrays were performed on the injection site and we showed that a lower expressing AAVrh8-mβgal vector mitigated the negative response. Intracranial injection of this newly developed vector was shown to clear lysosomal storage throughout the CNS of βGal-/- mice. Taken together, these studies indicate that a combined systemic and fine-tuned intracranial approach may be the most effective in clearing lysosomal storage completely in the CNS while providing therapeutic benefit to the periphery.
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Kreutzer, Robert [Verfasser]. "Molecular pathogenesis, differential transcription of enzymes forming the lysosomal multienzymic complex and microsatellite based genotyping in canine GM1-gangliosidosis / by Robert Kreutzer." Gießen : DVG-Service, 2008. http://d-nb.info/997441550/34.
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Domingos, Priscila Perez. "Comparação dos efeitos do gangliosideo GM1 e do fator de crescimento neural (NGF) sobre a expressão de receptor de alta afinidade para NGF, TrkA e insulina em ilhotas pancreaticas isoladas de camundongos NOD (diabetico não obeso)." [s.n.], 2008. http://repositorio.unicamp.br/jspui/handle/REPOSIP/313486.
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Orientador: Ricardo de Lima ZollnerTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
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Resumo: O camundongo não obeso diabético (NOD) é caracterizado por desenvolver naturalmente diabetes mellitus tipo 1 (DM-1) com similaridade ao diabetes mellitus tipo 1 em humanos. A manifestação espontânea do diabetes neste modelo animal é caracterizado por infiltração progressiva das ilhotas de Langerhans por células mononucleares linfócitos T (CD4+ e CD8+) e destruição das células ß pancreáticas produtoras de insulina. O fator de crescimento neural (NGF) e algumas citocinas estão associados a regeneração neural, além de atuarem sobre células do sistema imune. Em adição a estes efeitos, NGF age na liberação de insulina pelas células betas das ilhotas pancreáticas, tornando-se foco de interesse com relação as suas propriedades moduladoras no processo inflamatório na ilhota pancreática. O gangliosídeo GM1 liga-se ao receptor de alta afinidade (TrkA) do NGF-ß, mimetizando seus efeitos. No presente trabalho, avaliamos a ação modulatória de GM1 e NGF em cultura de ilhotas pancreáticas, provenientes de camundongos NOD. Foram avaliados por meio de RT-PCR a expressão gênica de NGF-ß, TrkA e insulina e, por ensaio imunoenzimático, a concentração de citocinas IL-1ß, IL-12, TNF-a, INF-y e insulina. Nossos resultados sugerem ação moduladora similar entre GM1 e NGF sobre as ilhotas de NOD não diabéticos e pré-diabéticos. NGF e GM1 aumentam a expressão gênica de NGF e TrkA e diminuem a expressão gênica de insulina em NOD não diabéticos e pré-diabéticos. Além disso, aumentam a liberação de insulina e diminui a de citocinas inflamatórias IL-1ß, IL-12, TNF-a, IFN-y que caracterizam a resposta Th1.
Abstract: The non-obese diabetic mice (NOD) lineage is characterized by developing type 1 diabetes mellitus (DM-1) naturally, bearing a similarity to DM-1 in human beings. The spontaneous manifestation of diabetes is characterized by gradual infiltration in pancreatic islets by mononuclear cells lymphocytes T (CD4+ and CD8+) and destruction of the ß-cells producers of insulin. One consequence of this effect, is the release of neurotrophins trying modulate the insulin release by the ß cells of pancreatic islets. Thus, the neurotrophins have been the focus of interest in the modulation of the inflammatory process in the pancreatic islets. The ganglioside GM1 binds to the high affinity receptor (TrkA) of the NGF-ß, enhancing its effect. In the present work, we evaluate the immune modulation properties of GM1 and NGF in culture of pancreatic islets from NOD mice. The gene expression of NGF-ß, TrkA and insulin for immune enzymatic assay, the concentration of cytokines IL 1ß, IL-12, TNF-a, IFN-y and insulin were evaluated by RT-PCR and ELISA. Our results suggest similar modulation action between GM1 and NGF on islets of NOD non-diabetic and pre-diabetic. GM1 and NGF action increases the gene expression of NGF and TrkA and the decrease of insulin in mice NOD non-diabetic and pre-diabetic. Moreover, GM1 and NGF increase the insulin release and decrease inflammatory cytokines that characterize the Th1 reply.
Doutorado
Ciencias Basicas
Doutor em Clínica Médica
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Arthur, Julian. "Novel Therapies and Biochemical Insights for the GM1 and GM2 Gangliosidoses." Thesis, Boston College, 2011. http://hdl.handle.net/2345/3855.
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Thesis advisor: Thomas N. SeyfriedGangliosides are glycosphingolipids (GSLs) containing sialic acids that play numerous roles in neuronal maturation, apoptotic signaling, angiogenesis, and cell surface receptor activity. The GM1 and GM2 gangliosidoses are a series of autosomal recessive lysosomal storage disorders (LSDs) characterized by an inability to degrade these lipid molecules. GM1 gangliosidosis is caused by a mutation in the lysosomal hydrolase β-galactosidase, resulting in neuronal storage of ganglioside GM1 and asialo GA1. Tay-Sachs (TS) and Sandhoff Disease (SD) are GM2 gangliosidoses caused by mutations in either the α or β subunits, respectively, of the heterodimeric protein β- hexosaminidase A, resulting in the storage of ganglioside GM2 and asialo GA2. The accumulation of excess ganglioside in the central nervous system leads to abnormal intracellular vacuoles, neuronal loss, demyelination, ataxia, dementia, and premature death. In my studies, I have shown that accumulation of GM1 ganglioside may not coincide with secondary storage of cholesterol, by providing evidence that cholesterol-binding fluorescent molecule filipin reacted to GM1 ganglioside in the absence of cholesterol. In an effort to combat the early-onset gangliosidoses, I have explored the effects of combining Neural Stem Cells (NSCs) with Substrate Reduction Therapy (SRT) in juvenile Sandhoff mice. The analysis showed that SRT was more effective than NSCs in reducing stored GM2 and GA2 in young mice, and no synergy was observed. In adult GM1 gangliosidosis, Tay- Sachs, and Sandhoff mice, Adeno-Associated Viral (AAV) vector gene therapy was used to restore therapeutic levels of wild-type enzyme to the CNS. AAV therapy corrected ganglioside storage and ameliorated myelin-associated lipid loss in all tissues assayed, increasing motor performance and life in effected animals. Lastly, AAV therapy was also successful in a feline model of Sandhoff disease. These results in juvenile and adult model systems point the way towards multiple effective clinical therapies in the near future
Thesis (PhD) — Boston College, 2011
Submitted to: Boston College. Graduate School of Arts and Sciences
Discipline: Biology
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Kreutzer, Robert. "Charakterisierung des genetischen Defektes der GM1-Gangliosidose beim Alaskan Husky." Wettenberg : VVB Laufersweiler, 2005. http://deposit.ddb.de/cgi-bin/dokserv?idn=976072424.
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Müller, Gundi. "Die GM1-Gangliosidose beim Alaskan Husky unter besonderer Berücksichtigung der neuropathologischen Veränderungen /." Göttingen : Cuvillier, 2001. http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&doc_number=009411136&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA.
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Santamaría, Merino Raúl. "Anàlisi genètica i molecular de les malalties Gangliosidosi GM1 i Morquio B." Doctoral thesis, Universitat de Barcelona, 2007. http://hdl.handle.net/10803/1881.
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En aquesta tesi s'ha realitzat una aproximació genètica i molecular a les malalties Gangliosidosi GM1 i Morquio B. Aquestes dues malalties són causades per mutacions en un únic gen, el gen GLB1. Aquest gen codifica per la proteïna beta-galactosidasa lisosòmica, de manera que mutacions al gen GLB1 alteren la funcionalitat d'aquesta proteïna. Això pot conduir a l'acumulació dels diferents substrats que normalment són degradats per la beta-galactosidasa: el gangliòsid GM1, el queratà sulfat i diferents oligasacàrids proteics. En aquesta tesi es presenten els resultats de la cerca de mutacions en 49 pacients amb Gangliosidosi GM1 i 5 amb Morquio B. Els pacients estudiats provenien bàsicament d'Espanya i d'Argentina. Es van poder identificar 52 mutacions diferents de les que 32 no havien estat descrites prèviament. A més a més, per a la majoria de mutacions identificades es va poder establir una correlació entre la mutació trobada i un fenotip determinat de la malaltia. La mutació R59H va ser la mutació més prevalent a les poblacions analitzades, essent especialment prevalent als pacients d'ètnia gitana, on aquesta va ser l'única mutació descrita. A més a més, en aquests pacients la mutació R59H sempre es va trobar associada a un mateix haplotip, cosa que indicaria un origen únic del canvi R59H dins de la població gitana.Posteriorment, algunes de les mutacions identificades van ser expressades in vitro utilitzant com a sistema d'expressió les cèl.lules COS-7 transfectades amb Lipofectamina. D'aquesta manera es van expressar 15 variants mutades de la beta-galactosidasa. Les variants causants de la forma infantil (la forma més severa) van mostrar una activitat enzimàtica residual nul.la, mentre que 3 variants associades a formes més lleus (el tipus adult i la malaltia de Morquio B) van resultar en activitats residuals amb un rang del 7-15%. Per altra banda, 3 canvis que eren polimòrfics (no patogènics) van ser els que van presentar una activitat enzimàtica residual més elevada, al voltant del 30-60%. Així doncs, es va poder concloure que el sistema d'expressió emprat era un bon sistema per establir correlacions entre les activitats residuals de les variants mutades i el fenotip associat a cadascuna d'elles.
Finalment, es van dur a terme una sèrie d'experiments per entendre el mecanisme que regula el procés d'splicing alternatiu del gen GLB1. Aquest gen codifica dues proteïnes diferents (la beta-galactosidasa i l'EBP) gràcies a un mecanisme d'splicing alternatiu. Al transcrit de l'EBP, els exons 3, 4 i 6 són exclosos del transcrit madur. Diferents experiments van mostrar que el mecanisme d'NMD ("Nonsense-mediated decay") s'encarrega d'eliminar les combinacions d'exons errònies, fent que únicament els dos transcrits funcionals romanguin estables a la cèl.lula. Paral.lelament, mitjançant la cotransfecció de plasmidis que codificaven diferents proteïnes SR junt amb un minigèn construït amb els exons implicats en l'splicing alternatiu del gen GLB1, es va poder comprovar que les proteïnes SR tenien la capacitat de modificar la proporció en que es generaven les diferents combinacions d'exons en els transcrits obtinguts a partir del minigèn. Això indicaria que les proteïnes SR, que juguen un paper essencial en el procés d'splicing cel.lular, podrien tenir també una funció en la regulació de l'splicing alternatiu del gen GLB1.
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Sperb, Fernanda. "Gangliosidose GM1 : aspectos clínicos e moleculares da população brasileira e a busca de novas terapias para o tratamento da doença." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2012. http://hdl.handle.net/10183/54444.
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A deficiência hereditária da enzima lisossômica G-galactosidase, codificada pelo gene GLB1, causa duas doenças humanas clinicamente distintas, a Gangliosidose GM1 e Morquio B. Clinicamente, pacientes com Gangliosidose GM1 mostram graus variados de neurodegeneração e anormalidades esqueléticas, enquanto que os com Mórquio B apresentam displasia esquelética e opacidade de córnea, sem envolvimento do sistema nervoso central. Neste trabalho foi realizada a análise da freqüência populacional das mutações mais comuns no Brasil para Gangliosidose GM1, e a tentativa de comprovação da hipótese de efeito fundador destas mutações. Também foi realizada a pesquisa clínica e molecular de pacientes com Gangliosidose GM1 na tentativa de caracterizar os pacientes brasileiros, identificando novas mutações e traçando um panorama clínico e genético dessa população. Com a intenção de compreender os efeitos das novas mutações encontradas entre os pacientes brasileiros sobre a estrutura da proteína codificada por GLB1, modelos tridimensionais foram gerados através de ferramentas de bioinformática. Neste estudo foi possível predizer as conseqüências biológicas destas mutações, correlacionando às mesmas com os achados fenotípicos dos pacientes. Um esforço na busca de novas terapias para a doença também foi realizado, visto que não existe tratamento eficaz contra a Gangliosidose GM1. Para tanto, três terapias foram testadas em fibroblastos de paciente com a mutação mais comum encontrada na população brasileira: a terapia de tradução alternativa com o uso de geneticina e cloranfenicol, e a terapia de chaperonas farmacológicas, através do uso de galactose. Nenhuma das terapias foi eficaz no aumento da atividade enzimática da G-galactosidase, mas um aumento da expressão gênica pode ser observado para o gene GLB1.The inherited deficiency of the lysosomal enzyme G-galactosidase, encoded by the gene GLB1, causes two clinically distinct human diseases: GM1Gangliosidosis and Morquio B. Clinically, patients with GM1 Gangliosidosis show varying degrees of neurodegeneration and skeletal abnormalities, while Morquio B shows skeletal dysplasia and corneal opacity, without involving the central nervous system. This work was performed to analyze the population frequency of the most common mutations in Brazil for Gangliosidosis GM1, and the attempt to prove the hypothesis of a founder effect for these mutations. A clinical and molecular research in patients with Gangliosidosis GM1 was also performed, in an attempt to characterize Brazilian patients, identifying new mutations and drawing a picture of the clinical and genetic aspects of this population. Trying to understand the effects of new mutations found among Brazilian patients on the structure of the protein encoded by GLB1, threedimensional models were generated using bioinformatics tools. In this study it was possible to predict the biological consequences of these mutations, correlating them with the phenotypic findings of the patients. An effort in finding new therapies for the disease was also performed, since there is no effective treatment for GM1 Gangliosidosis. Therefore, three treatments were tested in fibroblasts from patients with the most common mutation found in Brazil: the alternative translation therapy using geneticin and chloramphenicol, and the pharmacological chaperone therapy, using galactose. None of these therapies was effective in increasing the enzyme activity of G-galactosidase, but an increase in gene expression could be observed in the GLB1 gene.
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Vieira, Matheus Barbosa. "Detecção de cinco novas mutações em pacientes brasileiros com gangliosidose GM1." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2006. http://hdl.handle.net/10183/6718.
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A Gangliosidose GM1 é um Erro Inato do Metabolismo (EIM) causado pela deficiência da enzima B-galactosidase ácida. Essa doença é caracterizada pelo acúmulo de metabólitos não degradados, principalmente gangliosídeo GM1, nos lisossomos de vários tipos celulares. Baseado na idade de início e na atividade residual da enzima, a Gangliosidose GM1 é classificada em três diferentes tipos: infantil, juvenil e adulto. O gene da B-galactosidase ácida (GLB1, GeneBank M27507) está situado no cromossomo 3 e possui mais de 60 kb, contendo 16 exons. Cerca de 50 mutações associadas à doença estão descritas na literatura. No sul do Brasil, há uma alta freqüência dessa doença (1:17.000 nascidos vivos). Neste trabalho, vinte pacientes diagnosticados no Hospital de Clínicas de Porto Alegre (Brasil) tiveram o gene GLB1 investigado por SSCP (Single Strand Conformational Polymorphism) usando DNA extraído de sangue periférico. Através desta triagem foram encontradas 52 alterações de mobilidade do DNA, indicando a presença de mutações. As amostras relativas aos exons 2 e 15 foram submetidas a sequenciamento direto com seqüenciador ABI31O(Applied Biosystens) utilizado kit BigDye 3.1. Cinco novas mutações no gene GLB1 (F63Y, R38G, Y36S, Y64F e R59C) e duas mutações já descritas (R59H e 1622-1627insG) foram encontradas. Este trabalho possibilitou a genotipagem completa de 6 pacientes e parcial de 5, e direcionou a investigação de mutações, contribuindo diretamente no diagnóstico da enfermidade e permitindo a realização de estudos de correlação genótipo/fenótipo destes pacientes.GM1 Gangliosidosis is a Iysosomal storage disease caused by r3- galactosidase deficiency. As a result of this defect there is a huge accumulation of GM1 ganglioside in tissues of affected patients. Gangliosides are glycosphingolipids present in high concentration in neural tissues. The localization of these lipids explain in part the neurodegeneration present in patients. The r3-galactosidasegene (GLB1-Gene Bank M27507) is located on chromosome 3 and spands more than 60 kb and it is formed by 16 exons. Over than 45 mutations were found in this gene up to now. In southern Brazil the high frequency of GM1 Gangliosidosis (1:17.000 live born) justify the aim of this work, that is to genotype those patients with GM1 Gangliosidosis, by, fist screening they DNA by SSCP (Single Strand Conformational Polimorphism) and than, sequencing in automated apparatus. The screening of 16 exons from 20 patiens gave us the information that 52 mobility changes of DNA Single Strand were found, suggesting possibility of mutations. Samples from exons 2 and 15 were submitted to direct sequencing in ABI310 (Applied Biosystems) using Big Dye3.1 terminator Kit. Five new mutations were found in GLB1 gene (F63Y, R38G, Y36S, Y64F and R59C) and two mutations described previously (R59H and 1627insG). This investigation gave support to complete genotype 6 patients with GM1 Gangliosidosis, partial genotype 5 patients and gave a good support for future analysis in GLB1 gene to correlate genotype and phenotype easily.
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MENA, CHANTAL. "Approche clinique et paraclinique du diagnostic des encephalopathies metaboliques progressives : a propos d'un cas de gangliosidose a gm 1 de type ii." Nantes, 1989. http://www.theses.fr/1989NANT114M.
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Kreutzer, Robert [Verfasser]. "Charakterisierung des genetischen Defektes der GM1-Gangliosidose beim Alaskan Husky / Robert Kreutzer." Wettenberg : VVB Laufersweiler, 2005. http://d-nb.info/976072424/34.
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Ribeiro, Maria Gil Roseira. "Biochemical and genetic studies on GM2-Gangliosidosis : Tay-Sachs disease and variants." Tese, Universidade do Porto. Reitoria, 1995. http://hdl.handle.net/10216/10290.
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Ribeiro, Maria Gil Roseira. "Biochemical and genetic studies on GM2-Gangliosidosis : Tay-Sachs disease and variants." Doctoral thesis, Universidade do Porto. Reitoria, 1995. http://hdl.handle.net/10216/10290.
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Finck, Sonja. "Gangliosidose generalisee a gmi type i : a propos d'une observation avec avance staturale et hypersecretion d'hormone de croissance." Université Louis Pasteur (Strasbourg) (1971-2008), 1989. http://www.theses.fr/1989STR1M063.
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Bourgoin, Christophe. "Transfert de gènes dans les modèles animaux de gangliosidoses à GM2." Paris 7, 2003. http://www.theses.fr/2003PA077139.
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Altaleb, Naderah. "Assessing the potential of rAAV9 systemic gene therapy for GM2 gangliosidoses using a Sandhoff mouse model." Nature Publishing Group, 2014. http://hdl.handle.net/1993/30287.
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The infantile GM2 gangliosidoses are severe neurodegenerative disorders, caused by a defect in the β-hexosaminidase system. They are characterized by lysosomal accumulation of the substrate, GM2 ganglioside, which results in severe neuronal damage and death in the early years of life. Sandhoff mice deficient in both major hexosaminidase isozymes, Hex A and Hex B, mimic the disease severity in the human condition including the motor deterioration, histopathological findings, and premature death. To investigate the utility of systemic adeno-associated virus 9 (AAV9)-based gene delivery in treating GM2 gangliosidoses, we evaluated the therapeutic outcome of a single intravenous injection of recombinant AAV9 encoding the complementing Hexb gene in a Sandhoff mouse model. We showed prolonged survival, preserved motor function, and reduced GM2 ganglioside accumulation as well as inflammation when systemic AAV9 therapy was administered to 1-2 days old mice. However, the formation of liver or lung tumours accompanied the positive therapeutic effect.
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Rossi, Thiago. "Estudo do efeito do gangliosideo GM1 sobre os nervos perifericos do camundongo NOD (Non Obese Diabetic)." [s.n.], 2007. http://repositorio.unicamp.br/jspui/handle/REPOSIP/311769.
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Orientador: Ricardo de Lima ZollnerDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
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Resumo: A linhagem de camundongos NOD (non obese diabetic) desenvolve espontaneamente diabetes mellitus tipo 1 (DM-1) com marcante similaridade ao observado em humanos, que se estabelece entre 12ª e 24ª semana de vida. Os gangliosideos são glicoesfingolipídeos de membrana que contém ácido siálico em sua composição e estão presentes na maioria das células dos vertebrados sendo particularmente abundantes no sistema nervoso. Gangliosídeos exógenos são capazes de acelerar a regeneração de nervos periféricos danificados, porém tem sido relacionados com síndromes neuropáticas periféricas como a síndrome de Guilláin Barret onde os pacientes apresentam anticorpos anti-gangliosídeos especificamente contra o gangliosídeo GM1. Entretanto os mecanismos ainda permanecem controversos. Nossos resultados sugerem que administração de GM1 na dose de 100mg/kg/dia em camundongos NOD e Balb/C fêmeas a partir da 4ª semana de vida não é capaz de provocar neuropatia clínica e que animais diabéticos apresentaram maior imunoreatividade para GM1 nos nervos periféricos com presença de marcação para NGF somente em camundongos Balb/C. Os animais diabéticos tratados com GM1 demonstraram queda na atividade nervosa, em contraste os camundongos Balb/C tratados com GM1 apresentaram aumento significativo na atividade nervosa
Abstract: The strain of NOD mice (non obese diabetic) spontaneously develops diabetes mellitus type 1 (DM-1) similarity to the observed in humans. In this model, the diabetes manifestation occurs between 12th and 24th weeks of life, with presence of pancreas-specific autoantibodies. The gangliosides are glycosphingolipids of membrane that contains sialic acid in their composition and are present in the majority of cells from vertebrates and are particularly abundant in the nervous system. Exogenous gangliosides are capable to increase regeneration in damaged peripheral nerves. However, the gangliosides are related with peripheral neuropathics syndromes as the syndrome of Guilláin Barret in which the patients specifically present antibodies against gangliosides GM1, however these mechanisms still remain controversial. Our results suggest that administration of GM1 in the dose of 100mg/kg/day in female NOD and Balb/C mice at the 4th week of life is not capable to provoke clinical peripheral neuropathy and that diabetic animals present major immunoreactivity for GM1 in peripheral nerves with the presence of immunoreactivity to NGF only in Balb/C mice. Diabetic animals treated with GM1 showed lower nervous activity when compared to Balb/C mice, which presented significant increase
Mestrado
Ciencia Basica
Mestre em Clinica Medica
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Golebiowski, Diane L. "Overcoming Toxicity from Transgene Overexpression Through Vector Design in AAV Gene Therapy for GM2 Gangliosidoses." eScholarship@UMMS, 2009. http://escholarship.umassmed.edu/gsbs_diss/895.
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GM2 gangliosidoses are a family of lysosomal storage disorders that include both Tay-Sachs and Sandhoff diseases. These disorders result from deficiencies in the lysosomal enzyme β-N-acetylhexosaminidase (HexA). Impairment of HexA leads to accumulation of its substrate, GM2 ganglioside, in cells resulting in cellular dysfunction and death. There is currently no treatment for GM2 gangliosidoses. Patients primarily present with neurological dysfunction and degeneration. Here we developed a central nervous system gene therapy through direct injection that leads to long-term survival in the Sandhoff disease mouse model. We deliver an equal mixture of AAVrh8 vectors that encode for the two subunits (α and β) of HexA into the thalami and lateral ventricle. This strategy has also been shown to be safe and effective in treating the cat model of Sandhoff disease. We tested the feasibility and safety of this therapy in non-human primates, which unexpectedly lead to neurotoxicity in the thalami. We hypothesized that toxicity was due to high overexpression of HexA, which dose reduction of vector could not compensate for. In order to maintain AAV dose, and therefore widespread HexA distribution in the brain, six new vector designs were screened for toxicity in nude mice. The top three vectors that showed reduction of HexA expression with low toxicity were chosen and tested for safety in non-human primates. A final formulation was chosen from the primate screen that showed overexpression of HexA with minimal to no toxicity. Therapeutic efficacy studies were performed in Sandhoff disease mice to define the minimum effective dose.
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Golebiowski, Diane L. "Overcoming Toxicity from Transgene Overexpression Through Vector Design in AAV Gene Therapy for GM2 Gangliosidoses." eScholarship@UMMS, 2016. https://escholarship.umassmed.edu/gsbs_diss/895.
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GM2 gangliosidoses are a family of lysosomal storage disorders that include both Tay-Sachs and Sandhoff diseases. These disorders result from deficiencies in the lysosomal enzyme β-N-acetylhexosaminidase (HexA). Impairment of HexA leads to accumulation of its substrate, GM2 ganglioside, in cells resulting in cellular dysfunction and death. There is currently no treatment for GM2 gangliosidoses. Patients primarily present with neurological dysfunction and degeneration. Here we developed a central nervous system gene therapy through direct injection that leads to long-term survival in the Sandhoff disease mouse model. We deliver an equal mixture of AAVrh8 vectors that encode for the two subunits (α and β) of HexA into the thalami and lateral ventricle. This strategy has also been shown to be safe and effective in treating the cat model of Sandhoff disease. We tested the feasibility and safety of this therapy in non-human primates, which unexpectedly lead to neurotoxicity in the thalami. We hypothesized that toxicity was due to high overexpression of HexA, which dose reduction of vector could not compensate for. In order to maintain AAV dose, and therefore widespread HexA distribution in the brain, six new vector designs were screened for toxicity in nude mice. The top three vectors that showed reduction of HexA expression with low toxicity were chosen and tested for safety in non-human primates. A final formulation was chosen from the primate screen that showed overexpression of HexA with minimal to no toxicity. Therapeutic efficacy studies were performed in Sandhoff disease mice to define the minimum effective dose.
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Arfi, Audrey. "Transfert de gènes dans le modèle murin de la maladie de Sandhoff à l'aide de vecteurs lentiviraux." Paris 7, 2005. http://www.theses.fr/2005PA077126.
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Mugnaini, Julia. "Estudio de las bases moleculares de la Fibrosis Quística y la enfermedad de Sandhoff : Ensayos IN VITRO en modelos de mutaciones intrónicas del gen hexb." Doctoral thesis, Mugnaini J. Estudio de las bases moleculares de la Fibrosis Quística y la enfermedad de Sandhoff : Ensayos IN VITRO en modelos de mutaciones intrónicas del gen hexb [Internet]. Universidad Nacional de Córdoba, 2018 [citado el 13 de febrero de 2020]. Disponible en: https://rdu.unc.edu.ar/handle/11086/6799, 2018. http://hdl.handle.net/11086/6799.
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Tesis - Doctor en Ciencias de la Salud - Universidad Nacional de Córdoba. Facultad de Ciencias Médicas. Secretaría de Graduados en Ciencias de la Salud, 2018163 h. : gráf, tabl., 29 cm
During the period from 1970-2017, 151 patients were diagnosed with cystic fibrosis and 110 patients with Sandhoff disease in CEMECO, making these diseases the two most diagnosed according to the local registry of patients. Objective 1: To contribute to the molecular charaterization of CFTR and HEXB genes and to integrate this knowledge into the multidisciplinary study of cystic fibrosis and Sandhoff disease, including a perspective from the genome to phenome level.
Durante el período 1970-2017, en CEMECO se han diagnosticado 151 pacientes con fibrosis quística y 110 pacientes con enfermedad de Snadhoff, convirtiéndose éstas en las enfermedades metabólicas con mayor registro local de pacientes. Objetivo general 1: Contribuir a la caracterización molecular de los genes CFTR Y HEXB e integrarlo al estudio multidisciplinar de las enfermedades fibrosis quística y de Sandhoff, dede una perspectiva que abarque desde el genoma al fenoma.
2020-11-06
Fil: Mugnaini, Julia. Universidad Nacional de Córdoba. Facultad de Ciencias Médicas.; Argentina.
Fil: Mugnaini, Julia. Provincia de Córdoba. Hospital de Niños de Córdoba; Argentina.
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Chen, Wei Ju, and 陳威儒. "The observation of cell membrane damage caused by the interaction between oligomer Amyloid-Beta 1-42 and GM1 gangliosidosis in lipid raft." Thesis, 2013. http://ndltd.ncl.edu.tw/handle/99444689395390143039.
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碩士長庚大學
光電工程研究所
101
Alzheimer’s disease (AD) is a progressive, neurodegenerative disease. It is characterized by the functional impairment and loss of neurons that results in a progressive decline in memory and other cognitive functions, leading to dementia. Currently without a cure, AD and related disorders will inevitably reach epidemic proportions in a few years. Recent studies have shown that the oligomeric forms of Aβ correlate more strongly with the actual diseased state than either fibril (plaque) or monomers. Thus there must be a mechanism(s) for Aβ oligomers to form, and unfortunately resulting in neurotoxicity. Our working hypothesis is that a highly structured, functional membrane construct, the lipid raft, plays an important role in: a) accumulating Aβ molecules, either in small aggregate forms or influences oligomerization of monomers, and b) membrane integrity is compromised to facilitate osmotic imbalances and/or transport of Aβ oligomers across the membrane.We utilized an ultrasensitive,label-free detection method, the dual-channel paired, surface plasmon wave detector system with ~pM sensitivity, to characterize the interaction between Aβ protein and the supported membrane constructs, starting on lipid bilayer constructs.
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Pereira, Cátia Sofia de Oliveira. "Lipid - specific T cells in fabry disease, gaucher disease and GM2 gangliosidosis." Tese, 2016. https://hdl.handle.net/10216/87863.
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Pereira, Cátia Sofia de Oliveira. "Lipid - specific T cells in fabry disease, gaucher disease and GM2 gangliosidosis." Doctoral thesis, 2016. https://hdl.handle.net/10216/87863.
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Gomes, Madalena de Vasconcelos. "Gangliosidose GM1 no cão de água português: contribuição para o estudo da doença em Portugal." Master's thesis, 2019. http://hdl.handle.net/10437/9690.
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Orientação interna: Margarida Alves ; orientação externa: Rui Pedro LouroA Gangliosidose GM1 é uma doença autossómica recessiva associada à diminuição da atividade da enzima beta-galactosidase 1 (GLB1), devido a mutações no gene GLB1, que levam à acumulação de gangliosídeos GM1 nos lisossomas. Esta acumulação resulta em manifestações clínicas neurológicas. Na raça Cão de Água Português os sinais clínicos têm início a partir dos quatro meses e envolvem, principalmente, sinais de disfunção cerebelar, tais como, tremores da cabeça, dismetria, ataxia e nistagmo. É uma doença fatal e de rápida evolução para a qual não existe qualquer tipo de tratamento. O conhecimento da existência da doença e a realização de testes genéticos, por parte dos criadores é o primeiro passo para a sua prevenção. O presente estudo teve como objetivo obter informação sobre o conhecimento da doença por parte de criadores e proprietários de cães da raça Cão de Água Português e também sobre a realização do teste genético para detecção da presença da mutação c.200G>A no gene GLB aos seus exemplares. O trabalho foi realizado em 70 cães, todos eles registados no Clube Português de Canicultura. Todos os criadores tinham conhecimento da doença e sabiam da existência do teste genético, sendo que, apenas, dois de três o realizavam. Nenhum dos proprietários conhecia a doença. Dos 70 cães em estudo, apenas 28 tinham sido submetidos ao teste genético, revelando serem homozigóticos para a ausência da mutação. Os resultados obtidos evidenciam a falta de conhecimento sobre a doença por parte dos proprietários de cães da raça Cão de Água Português e a necessidade de sensibilizar os criadores para a realização dos testes genéticos e para a importância de informar os novos proprietários sobre a doença.
GM1 gangliosidosis is an autosomal recessive disorder which involves a decrease of beta-galactosidase 1 enzyme (GLB1) activity, due to a mutation in the GLB1 gene, leading to accumulation of GM1 gangliosides in lysosomes. This accumulation results in clinical neurological manifestations. In the Portuguese Water Dog breed, the clinical signs begin at four months of age and involve, mainly, signs of cerebellar dysfunction: head tremors, dysmetria, ataxia, and nystagmus. It is a fatal and fast evolving disease for which there is no treatment. The knowledge about the existence of the disease and the genetic testing by breeders, is the first step to its prevention. This study aimed to obtain information about the knowledge of breeders and owners of dogs from the Portuguese Water Dog breed about the diasease and to evaluate if the breeders test their dogs for the presence of the c.200G>A mutation in the GLB1 gene. The study envolved 70 dogs, all of them registered in the Clube Português de Canicultura (Portuguese Kennel Club). All the tree breeders were all aware about the disease and the existence of the genetic test, but, only two out of three of them performed it on a regular basis. None of the owners knew the disease. Only 28 dogs, out of the 70 in study, were tested for this disease, being homozygous for the absence of the mutation. The results obtained showed the lack of knowledge about the disease by the owners of the Portuguese Water Dog breed and the need for greater education of breeders so that they understand the importance of genetic testing and to inform new owners about the disease.
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Maegawa, Gustavo Henrique Boff. "Juvenile GM2 Gangliosidosis: A Model for Investigation of Small-molecule Therapies for Lysosomal Storage Diseases." Thesis, 2008. http://hdl.handle.net/1807/16802.
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Juvenile GM2 gangliosidosis (jGM2) is a group of inherited neurodegenerative diseases caused by deficiency of lysosomal β-hexosaminidase A (Hex A) resulting in GM2 ganglioside accumulation in brain. Like many other lysosomal storage diseases (LSDs), no specific treatment currently exists. In order to establish clinical outcomes for the investigation of potential therapies for jGM2, I collected comprehensive information on the natural history of the condition by studying retrospective and prospectively a cohort of 21 patients with the disease, and reviewing previously published reports of 134 patients. Several symptoms at disease onset, symptom latencies, and the survival curve were described. Genotype-phenotype correlations and neuroradiological findings were also studied. Based on pre-clinical results in animal models, we studied substrate reduction therapy (SRT), with miglustat, in a phase I/II clinical trial to assess its pharmacokinetics (PK), safety, tolerability in infantile and jGM2. Miglustat showed a PK profile similar to the one found in adult patients. The drug was found to be safe and well-tolerated in patients with jGM2, with diarrhea and weight loss being the most common drug-related adverse events. The analysis of efficacy showed that SRT was unable to arrest the full neurological progression of the condition; however, relative stabilization of cognitive function was noted, which was consistent with brain MRI findings. Because of the limited efficacy obtained with SRT, enzyme-enhancement therapy was considered to be an attractive alternative therapy for the late onset forms of GM2 gangliosidosis. Screening of a FDA-approved library of approved therapeutic compounds resulted in the identification of pyrimethamine, as a potential pharmacological chaperone for mutant forms of Hex A. Relative enhancements of enzyme activity and protein levels were observed in patient cells treated with therapeutic concentrations of drug. Applying the same principles, ambroxol was identified as a potential PC for mutant glucocerebrosidase (GCC), the lysosomal enzyme that when deficient causes Gaucher disease (GD). Significant increases of residual mutant GCC were observed in cultured patients cells with type 1 GD. In conclusion, principles developed in the course of studies on jGM2 were shown to be useful for the investigation of novel small-molecule therapies for LSDs, associated with significant neurodegeneration.
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Petroulakis, Emmanuel. "Molecular characterization of [beta]-hexosaminidase A deficiency in a late-onset GM2 gangliosidosis Type I patient." 1996. http://hdl.handle.net/1993/19322.
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