Tesi: "Mucopolysaccharidosis I"

1

Pereira, Cátia Daniela Isaías. "Lymphocyte populations in Mucopolysaccharidosis patients". Master's thesis, Universidade de Aveiro, 2015. http://hdl.handle.net/10773/15580.

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Mestrado em Biomedicina molecular
As doenças de sobrecarga lisossomal (DSLs) constituem um grupo de distúrbios metabólicos raros maioritariamente causados por mutações em hidrolases lisossomais, que conduzem à acumulação anormal de diferentes substratos macromoleculares no interior do lisossoma. Este trabalho é focado nas mucopolissacaridoses (MPSs), um grupo de DSLs resultantes da atividade deficiente de enzimas envolvidas no catabolismo dos glicosaminoglicanos. A MPS II é caraterizada pela perda de atividade da enzima iduronato-2-sulfatase, levando ao armazenamento intralisossomal de sulfato de dermatano e sulfato de heparano. A MPS VI é definida pela acumulação de sulfato de dermatano dentro do lisossoma, devido a uma deficiência na atividade enzimática de arilsulfatase B. O lisossoma é um compartimento celular importante para o funcionamento normal do sistema imunitário. Em diversos modelos de DSLs, foram anteriormente descritas alterações nas células do sistema imunitário. Os principais objetivos do presente trabalho eram: (i) estudar as várias populações leucocitárias – incluindo células T e seus subconjuntos, células natural killer (NK), células B e suas subpopulações, e monócitos – no sangue periférico de doentes com MPS II e MPS VI; (ii) produzir linhas de células B transformadas pelo vírus Epstein–Barr (EBV) destes pacientes, assim como avaliar a eficácia na sua produção e determinar o seu fenótipo. A caraterização do sistema imunitário nas doenças MPS II e MPS VI revelou um decréscimo significativo na frequência de células NK e monócitos em doentes com MPS VI, mas não em doentes com MPS II, em comparação com indivíduos controle. Em contraste, não foram identificadas alterações na percentagem de células T, células natural killer T invariantes (iNKT) e células B nos grupos de doentes com MPS II e MPS VI, comparando com o grupo controlo. A análise detalhada do estado de memória de células T auxiliares e células T citotóxicas revelou desequilíbrios nos fenótipos naïve e de memória em ambos os compartimentos de células T em doentes com MPS VI, mas não em doentes com MPS II, em comparação com indivíduos controle. As linhas de células B transformadas pelo EBV foram produzidas com sucesso nos dois grupos de doentes com MPS, mas a eficácia na sua produção foi superior no caso dos doentes com MPS VI, comparando com os indivíduos controle e doentes com MPS II. O fenótipo predominante das linhas de células B transformadas pelo EBV era similar entre ambos os grupos de doentes com MPS e o grupo controlo, o qual foi avaliado como sendo correspondente à subpopulação de células B de memória duplamente negativas. Em conclusão, este trabalho permitiu caraterizar melhor o sistema imunitário nestas duas doenças raras.
Lysosomal storage diseases (LSDs) constitute a group of rare metabolic disorders mostly caused by mutations in lysosomal hydrolases, which conduce to abnormal accumulation of different macromolecular substrates inside the lysosome. This work is focused on the mucopolysaccharidoses (MPSs), a group of LSDs arising from the deficient activity of enzymes involved in the catabolism of glycosaminoglycans. The MPS II is characterized by loss of activity of the enzyme iduronate-2-sulfatase, leading to the intralysosomal storage of dermatan sulfate and heparan sulfate. The MPS VI is defined by the accumulation of dermatan sulfate within the lysosome, owing to a deficiency in the enzymatic activity of arylsulfatase B. The lysosome is an important cellular compartment for the normal functioning of the immune system. In several models of LSDs, alterations in the immune system cells were previously described. The main aims of the present work were: (i) to study the various leukocyte populations – including T cells and their subsets, natural killer (NK) cells, B cells and their subpopulations, and monocytes – in the peripheral blood of MPS II and MPS VI patients; (ii) to produce Epstein–Barr virus (EBV)- -transformed B cell lines from these patients, as well as to evaluate the efficacy in their generation and determine their phenotype. The characterization of the immune system in MPS II and MPS VI diseases revealed a significant decrease in the frequency of NK cells and monocytes in MPS VI patients, but not in MPS II patients, in comparison with control subjects. In contrast, no alterations were identified in the percentage of T cells, invariant natural killer T (iNKT) cells, and B cells in the groups of MPS II and MPS VI patients comparing with the control group. The detailed analysis of the memory state of helper T cells and cytotoxic T cells revealed imbalances in the naïve and memory phenotypes in both T cell compartments in MPS VI patients, but not in MPS II patients, as compared with control subjects. The EBV-transformed B cell lines were successfully produced in the two MPS patient groups, but the efficacy in their generation was higher in the case of MPS VI patients when comparing with control subjects and MPS II patients. The predominant phenotype of EBV-transformed B cell lines was similar between both groups of MPS patients and the control group, which was assessed as corresponding to the double-negative memory B cell subpopulation. In conclusion, this work allowed to better characterize the immune system in these two rare diseases.

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2

Lutzko, Carolyn Mary. "Gene therapy for canine mucopolysaccharidosis type I". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape7/PQDD_0006/NQ41221.pdf.

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3

Litjens, Tom. "The molecular genetics of mucopolysaccharidosis type VI /". Title page, contents and abstract only, 1994. http://web4.library.adelaide.edu.au/theses/09PH/09phl776.pdf.

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4

Scott, Hamish Steele. "The molecular genetics of mucopolysaccharidosis type I /". Title page, contents and summary only, 1992. http://web4.library.adelaide.edu.au/theses/09PH/09phs426.pdf.

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5

Lopes, Nuno Duarte Ribeiro. "iNKT cells in mucopolysaccharidosis type II patients". Master's thesis, Universidade de Aveiro, 2013. http://hdl.handle.net/10773/11621.

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Mestrado em Biomedicina Molecular
A Mucopolissacaridose tipo II (MPS II) é uma Doença de Sobrecarga Lisossomal (LSD) pertencente às mucopolissacaridoses. É caracterizada pela acumulação de sulfato de heparan e dermatan devido à deficiência na enzima lisossomal Iduronato 2-Sulfatase. O lisossoma é um compartimento importante para a atividade dos linfócitos iNKT (iNKT). Os linfócitos iNKT são linfócitos T restritos a lípidos envolvidos na infeção, autoimunidade e vigilância tumoral. Estudos anteriores em modelos de murganhos de LSDs demonstraram uma redução do número de linfócitos iNKT assim como alterações nas subpopulações de linfócitos iNKT. Apesar destes resultados, investigação similar em doentes humanos foi ainda pouco abordada. Aqui, analisamos pela primeira vez os linfócitos iNKT de doentes com MPS II. Os dados foram recolhidos através da análise por citometria de fluxo de Células Mononucleares do Sangue Periférico de doentes com MPS II. Os doentes com MPS II não apresentavam diferenças nos linfócitos iNKT totais nem nas subpopulações de linfócitos iNKT. Fenotipicamente, não foram encontradas, nestas células, alterações na expressão de marcadores de ativação e de linfócitos NK. Uma vez que a ativação de linfócitos iNKT requer o funcionamento do lisossoma das células apresentadoras de antigénios, analisámos as suas frequências e fenótipos. Foram encontradas reduções significativas nos monócitos de doentes e não foram encontradas alterações nas restantes células. Não foram encontradas alterações fenotípicas nas células apresentadoras de antigénios. A comparação dos resultados apresentados nesta tese com os resultados previamente obtidos no nosso laboratório para outras LSD sugere que o desenvolvimento dos linfócitos iNKT é influenciado pela natureza das moléculas acumuladas. Descrevemos ainda pela primeira vez alterações na percentagem de monócitos no sangue de doentes com MPS II.
Mucopolysaccharidosis type II (MPS II) is a Lysosomal Storage Disorder (LSD) belonging to the group of mucopolysaccharidoses. It is characterised by the accumulation of heparan and dermatan sulfate due to deficiency of the lysosomal enzyme Iduronate 2-Sulfatase. The lysosome is an important compartment for the activity of invariant Natural Killer T cells (iNKT). iNKT cells are lipid-specific T cells that were shown to be important in infection, autoimmunity and tumour surveillance. Previous studies in mouse models of LSDs have shown a decrease in iNKT cell numbers and alterations in iNKT cell subsets. In spite of these findings, similar research in human patients has been poorly addressed. Herein, we analysed for the first time iNKT cells from Mucopolysaccharidosis type II patients. Data was acquired through flow cytometry analysis of Peripheral Blood Mononuclear Cells from MPS II patients. MPS II patients did not present differences in total iNKT cells neither in iNKT cell subsets. Phenotypically, no differences have been found in the expression of activation and NK cells markers. Since iNKT cell activation requires a functioning lysosome of antigen presenting cells, we analysed their frequency and phenotype. We have found a significant reduction in monocytes from patients and no differences in the other cells. Furthermore, no phenotypical alterations have been found in antigen presenting cells. The comparison of the results presented in this thesis with the results previously obtained by our laboratory in other LSD suggests that iNKT cell development is influenced by the nature of the accumulated molecules. We also described for the first time alterations in the percentage of monocytes in the peripheral blood of MPS II patients.

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6

Maia, Maria da Luz Galante. "Lipid specific T cells in Mucopolysaccharidosis VI patients". Master's thesis, Universidade de Aveiro, 2012. http://hdl.handle.net/10773/10388.

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Mestrado em Biologia Molecular e Celular
Doenças de sobrecarga lisossomal (DSL) são um grupo de doenças metabólicas hereditárias causadas pela acumulação de moléculas não degradadas nos lisossomas, devido sobretudo a defeitos em enzimas lisossomais. Mucopolissacaridoses são DSL caracterizadas pela acumulação de glicosaminoglicanos anteriormente designados mucopolissacarídeos. O foco deste trabalho é a Mucopolissacaridose tipo VI (MPS VI), que resulta da defeciência de uma hidrolase lisossomal (Arylsulfatase B) responsável pela degradação do sulfato de dermatan, o que leva á acumulação desta macromolécula nos doentes. O lisossoma é um organelo importante na apresentação de antigénios lipídicos ás células T. A apresentação de antigénios lipídicos é mediada por moléculas CD1 existentes nas células apresentadoras de antigénios. A ligação do antigénio lipídico ás moléculas CD1 das células apresentadoras leva á activação das células T restritas a CD1 (NKT). Existem cinco isoformas de moléculas CD1 (a, b, c, d, e), mas apenas quatro são capazes de apresentar antigénios (a, b, c, d). Um dos locais na célula onde a associação das moléculas CD1 com os antigénios lipídicos ocorre é o lisossoma, portanto a apresentação de antigénios lipídicos pode estar afectada em doentes com DSL. Células NKT são um grupo heterogéneo de células T que partilham propriedades das células T e das células natural killer . Em humanos existem três subpopulações de células iNKT dependendo da expressão de CD4 e CD8: CD4+ (apenas expressam CD4), CD8+ (apenas expressam CD8) e duplas negativas (DN) que não expressam nenhumas das duas moléculas. Em estudos prévios foi observado em modelos animais de várias DSL uma diminuição na percentagem de células iNKT. Em doentes de Fabry e Gaucher não foram encontradas alteraçoes. O objectivo deste trabalho é estudar os linfócitos incluindo as células iNKT, as células dendríticas (como células apresentadoras de antigénios) e apresentação de antigénios lipídicos em doentes com MPS VI. Não foram encontradas alterações na percentagem de células iNKT assim como nas suas subpopulações entre doentes com MPS VI e indivíduos controlos. Curiosamente encontramos um aumento na percentagem de linfócitos B em doentes com MPS VI quando comparados com indivíduos controlo. Para determinar o fenótipo das células dendríticas três doentes foram analisados, encontramos para alguns destes doentes uma diminuição na expressão das moléculas CD1a, CD11c e HLA-DR (MHC-class II), mas para tirar mas conclusões mais doentes precisam ser analisados. Três doentes com MPS VI foram analisados para testar a capacidade das suas células dendríticas apresentarem antigénios lipídicos pela molécula CD1b. Não foram encontradas alterações na capacidade destes doentes apresentarem o antigénio lipídico GM1 pela molécula CD1b. Pela primeira vez foram realizados ensaios de apresentação de antigénios lipídicos em doentes com MPS.
Lysosomal storage diseases (LSD) are a group of hereditary metabolic disorders caused by accumulation of undegraded molecules in the lysosome, mainly due to the impairment of the function of lysosomal enzymes. Mucopolysaccharidoses are LSDs characterized by the accumulation of glycosaminoglycans previously designated Mucopolysaccharides. The focus of this work is the Mucopolysaccharidosis type VI (MPS VI), which is a disorder caused by a deficiency in a lysosomal hydrolase (Arylsulfatase B) responsible for the dermatan sulfate degradation, that leads to an accumulation of this macromolecule in the patients. Lysosome is an important organelle in the presentation of lipid antigen to T cells. Lipid antigen presentation is mediated by CD1 molecules existent in the antigen presenting cells. The binding of lipid antigens and the presenting cells containing CD1 molecules lead to activation of T cells that respond to those molecules. There are five isoforms of CD1 molecules (a, b, c, d, e), but only four are antigen presenting (a, b, c, d). One of the cell locations where the association of the CD1 molecules and lipid antigens occurs is the lysosome, so that means that antigen presentation could be affected in LSDs patients. NKT cells are a heterogeneous group of T cells that share properties with T cells and natural killer cells. In humans there are three subpopulations depending on the expression of CD4 and CD8 molecules: CD4+ (only express CD4), CD8+ (only express CD8) and double negative (DN) that do not express any of them. In previous studies a decrease in the percentage of iNKT cells were observed in mouse models of several LSDs. However in patients with Fabry and Gaucher diseases no alterations were found. The aim of this work is to study the lymphocytes including the iNKT cells, the dendritic cells (as antigen presenting cells) and the lipid antigen presentation in MPS VI patients. We found no alterations in the percentage of the iNKT cells and in their subsets between MPS VI patients and control subjects. Interestingly we found an increase in the percentage of the B lymphocyte population in MPS VI patients when compared with control subjects. For dendritic cells phenotype three patients were analyzed, we found for some of them a decrease of the expression of CD1a, CD11c and HLA-DR (MHC-class II) however, more patients need to be study before conclusions can be drawn. In lipid antigen presenting assays, three patients were tested for the capacity of their dendritic cells to present lipid antigens by CD1b molecule. We found no alterations in patients’ capacity to present the lipid antigen GM1 by CD1b molecule. Studies regarding the lipid antigen presentation were for the first time performed in MPS.

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7

O'Leary, H. A. ngharad E. S. G. "Heparan sulphate inhibits haematopoietic stem cell homing in mucopolysaccharidosis I". Thesis, University of Manchester, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.528510.

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8

Heppner, Jonathan Michael. "Early disruption of the extracellular matrix in murine mucopolysaccharidosis I". Thesis, University of British Columbia, 2015. http://hdl.handle.net/2429/54160.

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Progressive skeletal and connective tissue disease is a major clinical burden in Mucopolysaccharidosis type I (MPS I). Although enzyme replacement therapies are available and improve some aspects of the disease, bone and joint disease is recalcitrant. The underlying pathogenic mechanisms of MPS I skeletal and connective tissue disease, and the basis of the recalcitrance to therapy, remain unknown. The classical view of MPS I describes somatic disease as the direct result of glycosaminoglycan (GAG) accumulation; however, it is now clear that many lysosomal storage disorders involve more complex pathogenic mechanisms than simple GAG storage. In order to understand the pathogenic mechanisms underlying skeletal and connective tissue disease in MPS I, I have used proteomic and genome wide expression studies of the femoral head growth plate cartilage, and functional studies of the murine MPS I model knee joint to identify early pathogenic events. Three and five-week-old mice were used; thus these studies represent a previously-unexamined time point at which underlying pathogenic mechanisms may be discovered. Unbiased iTRAQ differential proteomic and multiple reaction monitoring mass spectrometry approaches identified significant decreases in six key structural and signalling extracellular matrix proteins (biglycan, type I collagen, fibromodulin, lactotransferrin, proline/arginine-rich end leucine-rich repeat protein, and SERPINF1). Genome-wide expression studies in five-week growth plate cartilage revealed fourteen significantly deregulated mRNAs (Adamts4, asporin, chondroadherin, type II collagen, type IX collagen, hyaluronan and proteoglycan link protein, lumican, matrillin 1, matrix metalloproteinase 3, osteoglycin, osteomodulin, prolyl 4-hydroxylase, alpha polypeptide II, proline/arginine-rich end leucine-rich repeat protein, and member RAS oncogene family 32). The involvement of members of the small leucine repeat proteoglycan family (asporin, chondroadherin, osteoglycin, osteomodulin, and proline/arginine-rich end leucine-rich repeat protein) in MPS I disease pathogenesis is novel and intriguing, as these proteins are associated with the pathogenesis of osteoarthritis. Functional studies of the MPS I mouse knee joint suggested that early disruption of the extracellular matrix may predispose skeletal and connective tissues to late-stage degeneration. These results imply that biomechanical failure of chondro-osseous tissue may underlie skeletal and joint disease in MPS I. This represents a novel finding which has clear therapeutic implications.
Medicine, Faculty of
Medical Genetics, Department of
Graduate

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9

Crawley, Allison Catherine. "Enzyme replacement therapy in a feline model of mucopolysaccharidosis type VI /". Title page, contents and abstract only, 1998. http://web4.library.adelaide.edu.au/theses/09PH/09phc9107.pdf.

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10

Gliddon, Briony Lee. "Enzyme replacement therapy in a murine model of mucopolysaccharidosis type IIIA /". Title page, contents and abstract only, 2002. http://web4.library.adelaide.edu.au/theses/09PH/09phg5595.pdf.

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11

Bitencourt, Fernanda Hendges de. "Aspectos farmacoeconômicos associados à terapia de reposição enzimática para mucopolissacaridoses tipo I, II e VI : um estudo com ênfase em intervenções médicas". reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2013. http://hdl.handle.net/10183/71291.

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Introdução: As mucopolisaccaridoses tipo I (MPS I), tipo II (MPS II) e tipo VI (MPS VI) são doenças lisossômicas (DL) para as quais está disponível a terapia de reposição enzimática (TRE) com laronidase, idursulfase e galsufase, respectivamente. Objetivo Primário: Analisar a frequência anual de intervenções médicas (número de consultas, internações, cirurgias, exames solicitados, medicamentos prescritos, equipamentos de uso crônico e outras formas de terapia) em uma amostra de pacientes brasileiros com MPS I, II e VI e, desta forma, contribuir para o conhecimento dos aspectos farmacoeconômicos relacionados a essas doenças. Metodologia: Estudo exploratório, retrospectivo, de base hospitalar, baseado em revisão de prontuário, com amostragem por conveniência, e que foi realizado em duas etapas (etapas 1 e 2). Um instrumento específico para a coleta de dados de ambas as etapas foi construído pela equipe do estudo, que é multidisciplinar. Os desfechos de interesse foram as frequências anuais de intervenções médicas (consultas, exames, cirurgias, internações, medicamentos utilizados, outras formas de terapia). A etapa 1 consistiu em estudo pré-experimental, realizado no Serviço de Genética Médica do Hospital de Clínicas de Porto Alegre (SGM-HCPA), e que comparou as variáveis de interesse, para o mesmo grupo de pacientes, entre o período pré e pós-TRE. Os critérios de inclusão dessa etapa foram: ter diagnóstico confirmado de MPS I; estar em acompanhamento regular no SGM-HCPA desde o diagnóstico; estar em TRE por pelo menos um ano; e não ter participado de ensaio clínico envolvendo TRE ou ter realizado transplante de células-tronco hematopoiéticas. A etapa 2 foi transversal, multicêntrica (centros incluídos: SGMHCPA, Departamento de Genética Médica da Universidade Estadual de Campinas - UNICAMP, Pontifícia Universidade Católica de Campinas – PUC-Campinas, e Departamento de Pediatria da Universidade Estadual do Rio de Janeiro - UERJ), e comparou as variáveis de interesse entre grupos diferentes de pacientes (aqueles recebendo TRE e aqueles não recebendo TRE). Para essa etapa, foram considerados somente os dados relativos a 2010, sendo os seguintes os critérios de inclusão dos pacientes: ter diagnóstico confirmado de MPS I, II e VI; não estar participando de nenhum ensaio clínico envolvendo TRE ou ter realizado transplante de células-tronco hematopoiéticas; estar em TRE por pelo menos 12 meses antes do início da coleta, ou em acompanhamento por pelo 12 meses antes do início da coleta. Resultados: Etapa 1 - Nove pacientes (graves=3; atenuados=6) com MPS I foram incluídos no estudo, com mediana de idade de diagnóstico de 4,4 anos. Somente o número de cirurgias/ano/paciente foi dependente do tempo de doença (p=0,0004) e da gravidade do fenótipo (p=0,014). Com relação às comparações pré e pós-TRE, as variáveis que apresentaram diferença significativa (média do número/ano/paciente) foram: exames (pré-TRE=10,2+2,7; pós-TRE=22,5+2,1; p=0,005) e internações (pré-TRE=0,05+0,04; pós-TRE=0,30+0,11; p=0,013). Para as demais variáveis, não foi encontrada associação. Etapa 2 - Trinta e quatro pacientes com MPS I (n=12), II (n=17) e VI (n=5) foram incluídos no estudo. Desses, sete não utilizavam TRE (grupo “sem TRE") e 27 faziam uso de tratamento específico (grupo “com TRE"). Não foi encontrada correlação significativa entre tempo de doença e as variáveis estudadas. Considerando a amostra total, foi encontrada diferença entre o grupo “sem TRE” e o grupo “com TRE” em relação à mediana de internações hospitalares e de cirurgias realizadas [1(0-2) vs. 0 (0-1), p=0,015; e 0 (0-2) vs. 0 (0-0), p=0,040, respectivamente]. Para as crianças/adolescentes (<18 anos), não foi encontrada diferença estatística entre os grupos. Os pacientes com comprometimento cognitivo utilizavam mais medicamentos que os demais (p=0,024). Encontrou-se correlação negativa entre as variáveis duração da TRE e número anual de internações (r= -0,504; p=0,007). Discussão/ Conclusões: Este é um dos primeiros estudos a avaliar aspectos relacionados à farmaconomia da TRE para as MPS. De acordo com os resultados obtidos na etapa 2, verifica-se que, desconsiderando-se o custo associado às infusões, o custo do tratamento de pacientes com MPS parece ser menor para aqueles pacientes que utilizam a TRE do que para os pacientes que fazem somente tratamento sintomático. Entretanto, de acordo com a etapa 1 do estudo, a TRE parece não impedir a evolução da doença, pelo menos em relação à MPS I, e, assim, a cada ano de vida do paciente ocorreria um incremento do custo associado ao tratamento. Estudos adicionais, com maior tamanho amostral, deverão ser realizados para confirmar nossos achados.
Introduction: The mucopolysaccharidoses type I (MPS I), II (MPS II) and VI (MPS VI) are lysosomal disorders (LSD) for which enzyme replacement therapy (ERT) with laronidase, idursulfase and galsulfase, respectively, are available. Principal objective: To analyze the annual frequency of medical interventions (number of medical appointments, hospital admissions, surgical procedures, exams performed, medications prescribed, ancillary therapies and the use of medical devices) in a sample of Brazilian patients with MPS I, II and VI, and thus, contribute to the understanding of some pharmacoeconomic aspects related to these diseases. Methodology: Retrospective, exploratory, hospital-based study, based on medical records review, with convenience sampling, which was conducted in two steps (steps 1 and 2). A specific data collection instrument for both steps was designed by the study team, which is multidisciplinary. The chosen outcomes were: annual frequencies of medical interventions (medical appointments, exams, surgical procedures, hospital admissions, medications used and ancillary therapies). Step 1 was a pre-experimental study conducted at the Medical Genetics Service of Hospital de Clínicas de Porto Alegre (SGM-HCPA), and compared the variables of interest between the pre and post-ERT periods for the same group of patients. The patient inclusion criteria were: a biochemical diagnosis of MPS I and regular follow-up at SGM-HCPA since diagnosis; ERT for at least 1 year; no enrollment in any clinical trials involving ERT, and no history of hematopoietic stem cell transplantation. Step 2 was a cross-sectional and multicentric estudy (Centers included: SGM-HCPA), the Department of Medical Genetics of Universidade Estadual de Campinas - UNICAMP, Pontifícia Universidade Católica de Campinas - PUC-Campinas, and the Department of Pediatrics at Universidade Estadual do Rio de Janeiro – UERJ, which compared the variables of interest between different groups of patients (those receiving and those not receiving ERT). For this step only data from 2010 were considered. The inclusion patient criteria were: a biochemical diagnosis of MPS I, II or VI; no enrollment in any clinical trials involving ERT, and no history of hematopoietic stem cell transplantation, to be on ERT for at least 12 months before the start of data collection or to undergo regular follow-up for at least 12 months before the start of data collection. Results: Step 1 – Nine MPS I patients (severe=3; attenuated phenotype=6) were included in the study with median age at diagnosis was 4.4 years. Only the number/year/patient of surgeries was found to be dependent on length of disease (p=0.0004) and on severity of phenotype (p=0.014). Regarding pre- and post-ERT comparisons, the variables for which a significant difference was detected (mean number/year/patient) were exams (pre-ERT, 10.2±2.7; post-ERT, 22.5±2.1; p=0.005) and hospital admissions (pre-ERT, 0.05±0.04; post-ERT, 0.30±0.11; p=0.013). For the other variables, no association was found. Step 2: Thirty-four patients with MPS I, II and VI were included (I=12, II=17, VI=5). From them, 27 on ERT (“ERT group”) and 7 receiving supportive care only (“non-ERT group”). There were no significant correlation between length of disease and any of the variables of interest. There were significant between-group differences in the median number of hospital admissions and surgical procedures, both of which were higher in the non-ERT group [1(0-2) vs. 0 (0-1), p=0,015; e 0 (0-2) vs. 0 (0-0), p=0,040, respectively]. There were no significant between-group differences when only children and adolescents (<18 years) were taken into account. Patients with cognitive involvement used more medications than the others (p=0.024). A correlation was detected between time on ERT and the hospital admissions variable (r= -0.504; p=0.007). Discussion/conclusions: This was one of the first studies to evaluate aspects related to pharmacoeconomics of ERT for MPS. According to the results of step 2, and not acknowledging the costs associated with recombinant enzyme infusions, patients with MPS who undergo ERT generate less cost to SUS than patients on symptomatic treatment. On the other hand, according to the results of step 1, ERT seems not to stop the disease progress, at least in respect to MPS I, and thus, for each year of a patient life occurred an increase in cost associated with treatment. Additional studies with larger sample size are needed to confirm our findings.

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Zarrinkalam, Krystyna. "Characterisation of osteoblast function in a feline model of mucopolysaccharidosis type VI". Title page, contents and introduction only, 2001. http://web4.library.adelaide.edu.au/theses/09PH/09phz38.pdf.

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Addenda slip inserted in back. Includes bibliographical references (leaves 178-231). To further the understanding of the molecular mechanisms that contribute to the skeletal pathology of mucopolysaccharidosis type VI and to investigate the production of organic matrix by mucopolysaccharidosis VI osteoblasts

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13

Langford-Smith, Alexander William Walker. "Lentiviral vector mediated haematopoietic stem cell gene therapy for mucopolysaccharidosis type IIIA". Thesis, University of Manchester, 2012. https://www.research.manchester.ac.uk/portal/en/theses/lentiviral-vector-mediated-haematopoietic-stem-cell-gene-therapy-for-mucopolysaccharidosis-type-iiia(89f8e108-58f3-42bb-8b80-0e0a1fe45fd7).html.

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Mucopolysaccharidosis type III (Sanfilippo) is comprised of four phenotypically similar lysosomal storage disorders (MPS IIIA-D) caused by the deficiency of enzymes that catabolise heparan sulphate (HS). Progressive accumulation of HS results in abnormal behaviour, progressive cognitive and motor impairment and death in mid-teens. There are currently no treatments for MPS III. To assess the effect of novel therapeutics in the mouse models of MPS III it is necessary to examine the effect on primary storage of HS, secondary storage and behaviour. The reported behaviour of MPS IIIA and B mice is conflicting therefore we developed a one-hour open field test, performed at the same time of day during a period of hyperactivity observed in a previous circadian rhythm study of MPS IIIB mice. At 8 months of age MPS IIIB mice were hyperactive, with increased rapid exploratory behaviour and a reduction in immobility time. The MPS IIIA mice presented with the same behavioural phenotype as the MPS IIIB mice and were significantly hyperactive at 4 and 6 months of age and also displayed a reduced sense of danger. The hyperactivity and reduced sense of danger observed in the mice is consistent with the patient phenotype. Whilst haematopoietic stem cell transplant (HSCT) is the standard therapy used to treat the similar HS storage disorder MPS I Hurler, it is ineffectual in MPS IIIA. We hypothesise that HSCT failure in MPS IIIA is due to insufficient enzyme production in the brain by donor-derived microglial cells. By increasing expression of N-sulphoglucosamine sulphohydrolase (SGSH) we may be able to treat MPS IIIA. Therefore we compared the effect of HSCT using normal haematopoietic stem cells (WT-HSCT) to lentiviral overexpression of SGSH in normal cells (LV-WT-HSCT) or MPS IIIA cells (LV-IIIA-HSCT) in MPS IIIA mice, using the behavioural tests developed.SGSH activity in the brain of MPS IIIA recipients was not significantly increased by WT-HSCT, but was significantly increased by LV-IIIA-HSCT and LV-WT-HSCT. HS was significantly reduced by all transplants but the best treatment was LV-WT-HSCT. Neuroinflammation, indicated by the number of microglia in the brain, was significantly reduced by all treatments but remains significantly elevated. GM2 gangliosides were significantly reduced by WT-HSCT and LV-WT-HSCT and were no longer significantly elevated, but LV-IIIA-HSCT had no significant effect. Critically LV-WT-HSCT corrected the behaviour at 4 and 6 months of age whilst the other treatments had no significant effect. LV-WT-HSCT and WT-HSCT reduced GM2 gangliosides and neuroinflammation equally but only LV-WT-HSCT corrected behaviour and primary HS storage, suggesting they are the important factors in MPS IIIA pathology. LV-WT-HSCT corrects the neurological phenotype in MPS IIIA mice and is a clinically viable approach to treat MPS IIIA and other neuropathic lysosomal storage disorders.

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Lehtonen, Annukka. "Social functioning and behaviour in mucopolysaccharidosis type I and other developmental genetic disorders". Thesis, University of Manchester, 2017. https://www.research.manchester.ac.uk/portal/en/theses/social-functioning-and-behaviour-in-mucopolysaccharidosis-type-i-and-other-developmental-genetic-disorders(e048920a-f3b8-4a9d-aebf-349ee3da411f).html.

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This thesis investigates the behavioural phenotype, especially social functioning, in mucopolysaccharidosis type IH (MPS IH) and reviews research in social information processing in developmental genetic disorders in general. MPS IH is a developmental genetic disorder that causes severe physical symptoms and intellectual disabilities. Paper 1 presents a systematic literature review that aimed to review research on social information processing in genetic developmental disorders. Searches identified 23 articles and a quality assessment classified 15 of these as high quality. These articles were included in the review. The results showed that social information processing was impaired in sex chromosome aneuploidies, Turner syndrome, neurofibromatosis 1 (NF1), and Williams syndrome (WS). The findings suggest that problems with social information processing are part of the phenotype of several different developmental genetic disorders. In addition, social outcomes were lower than those of control children or in comparison to norms in NF1, deletion syndromes and WS. Thus, it is important to consider the potential social impairment in children with developmental genetic disorders when planning the care of these children and their families. Paper 2 is an empirical study investigating the behavioural phenotype in MPS IH with particular focus on social functioning and sleep. Participants were 22 children with MPS IH (mean age 9 years 4 months). Nine control children with intellectual disabilities were recruited as well, but due to the small size of the control group, the scores of the children with MPS IH were compared to questionnaire norms instead of the control group. The results indicated that 23 percent of children with MPS IH scored in the severe range on social functioning difficulties. Thus, children with MPS IH were more than 30 times more likely to score in the severe range than typically developing children. Children with MPS IH did not exhibit significantly more behaviour problems, but they scored higher than the norms on social, thought and attention problems and rule-breaking behaviour. They were also markedly impaired in all the competence areas (social, activities, school). The results indicate that these problems are part of the behavioural phenotype in MPS IH. They should therefore be considered in the design of clinical care of individuals with MPS IH and their families in terms of support and follow-up and for example facilitation of ASD diagnoses where appropriate. Paper 3 is a critical appraisal and reflection on the research process of both the literature review and empirical study, considering issues such as the quality ratings used in the literature review and the reasons for the small control sample in the empirical study. The implications of the decision to use norms rather than the control group as a comparison are discussed. This paper also considers the significance of the findings for the research in the field and the clinical care provided to children with developmental genetic disorders, MPS IH especially.

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15

Motas, Mallol Sandra. "Gene therapy for the treatment of neurologic and somatic mucopolysaccharidosis type II (hunter syndrome)". Doctoral thesis, Universitat Autònoma de Barcelona, 2016. http://hdl.handle.net/10803/390961.

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La Mucopolisacaridosis tipus II (MPSII), o síndrome de Hunter, és una malaltia d’acumulació lisosòmica d’herència recessiva lligada al cromosoma X i està causada per la deficiència de l’Iduronat-2-sulfatasa (IDS), enzim que actua en la via de degradació dels glicosaminoglicans (GAGs) heparan sulfat (HS) i dermatan sulfat (DS). Aquests GAGs no degradats s’acumulen als lisosomes de manera patològica, causant disfunció cel·lular. La forma més severa i també més prevalent de la MPSII es caracteritza per una neurodegeneració crònica i progressiva del sistema nerviós central (SNC) acompanyada de disfunció multisistèmica. Com a conseqüència, els pacients de MPSII solen morir durant la segona dècada de vida. Actualment, la única opció terapèutica disponible pels pacients amb Hunter és la teràpia de substitució enzimàtica (TSE), la qual consisteix en la infusió setmanal de l’enzim recombinant. No obstant, degut a la presència de la barrera hemato-encefàlica, la TSE no és efectiva en la correcció del deteriorament neurològic, a més de presentar altres inconvenients. Per tant, el desenvolupament d’una teràpia eficient pel tractament de la patologia neurodegenerativa característica de la MPSII és una necessitat mèdica no coberta. La teràpia gènica in vivo basada en l’administració de vectors virals derivats dels virus adeno-associat (AAV) representa una alternativa atractiva pel tractament d’aquesta malaltia, ja que ofereix la possibilitat d’obtenir benefici terapèutic de per vida després d’una única administració del producte terapèutic. Així doncs, la present tesi doctoral s’ha centrat en el desenvolupament d’una estratègia de teràpia gènica per a la MPSII basada en l’administració de vectors directe al líquid cefaloraquidi (LCR) amb la finalitat de tractar simultàniament tant la patologia neurologia com la somàtica de la malaltia. Mitjançant un procediment poc invasiu, es van administrar vectors AAV de serotip 9 (AAV9) que contenien el gen murí Ids (AAV9-Ids) al LCR de ratolins MPSII de 2 mesos d’edat, els quals ja presentaven una patologia ben establerta tant a nivell del SNC com a nivell somàtic. Transcorreguts 4 i 8 mesos després de l’administració, es va avaluar l’eficàcia del tractament en contrarestar la patologia de la MPSII. A nivell del SNC, l’augment d’activitat enzimàtica IDS obtinguda mitjançant el tractament va donar lloc a la completa correcció de les lesions lisosomals característiques a la MPSII. El tractament també va donar lloc a la correcció de la disfunció lisosomal del SNC, a la normalització de l’expressió gènica del cervell i a la eradicació de la neuroinflamació característica de la malaltia. A més, mitjançant l’administració al LCR, vectors AAV9-Ids també van transduir el fetge, convertit aquest òrgan en una font de la proteïna terapèutica a nivell perifèric. En conseqüència, l’enzim IDS produït al fetge de ratolins MPSII tractats va donar lloc a la correcció de la patologia somàtica. A més, la reversió de la patologia observada en aquells teixits somàtics no transduits pel vector AAV9-Ids va evidenciar el mecanisme de correcció creuada aconseguit mitjançant l’enzim IDS circulant. A banda d’aquests efectes, el tractament també va comportar una normalització de les alteracions de comportament característiques de la malaltia, així com també un augment significatiu de la supervivència dels ratolins MPSII. L’eficàcia obtinguda mitjançant l’administració de vectors AAV9 que contenien la seqüència codificant humana IDS també es va avaluar en ratolins MPSII. Després de 1,5 mesos de tractament, es va observar un increment en l’activitat IDS al cervell, fetge i sèrum, fet que va donar lloc a la correcció del contingut de GAGs tant a nivell del SNC com a nivell somàtic. Conjuntament, els resultats obtinguts en aquest treball recolzen la translació clínica de l’aproximació de teràpia gènica basada en l’administració al LCR de vectors AAV9-IDS pel tractament de pacients de Hunter amb afectació neurològica.
Mucopolysaccharidosis type II (MPSII), or Hunter syndrome, is an X-linked recessive lysosomal storage disease (LSD) caused by the deficiency in Iduronate-2-sulfatase (IDS), an enzyme involved in the stepwise degradation of the glycosaminoglycans (GAGs) heparan sulfate (HS) and dermatan sulfate (DS). The pathological accumulation of undegraded HS and DS in the lysosomes leads to cell dysfunction, causing severe neurologic and somatic disease. The most severe and most prevalent form of Hunter syndrome is characterized by chronic and progressive neurodegeneration of the central nervous system (CNS) and multisystem dysfunction; patients usually die during the second decade of life. To date, weekly intravenous enzyme replacement therapy (ERT) constitutes the only approved therapeutic option for MPSII. However, the inability of recombinant IDS to efficiently cross the blood-brain barrier (BBB) limits the efficacy of ERT in treating neurological symptoms. The therapy has several other drawbacks. Thus, an efficient therapy for the treatment of the neurodegeneration of MPSII disease represents a highly unmet medical need. In vivo gene therapy with adeno-associated vectors offers the possibility of lifelong therapeutic benefit following a single administration. Therefore, the present work was focused on the development of a new gene therapy approach for MPSII based on the delivery of vectors to the cerebrospinal fluid (CSF) and aimed at counteracting simultaneously the neurological and somatic pathology characteristic of the disease. Adeno-associated virus serotype 9 vectors (AAV9) containing the murine Ids gene were administered through a minimal invasive procedure to the CSF of 2-month-old MPSII mice, which already presented established pathology. The efficacy of AAV9-Ids vectors to counteract MPSII pathology after a single intra-CSF injection was evaluated 4 and 8 months after treatment. AAV9-mediated Ids gene transfer led to a significant increase in IDS activity throughout the encephalon, which resulted in full reversion of lysosomal storage lesions. In addition, correction of lysosomal dysfunction in the CNS, normalization of brain transcriptomic signature and disappearance of neuroinflammation were achieved after gene transfer. Moreover, after AAV9-Ids delivery to the CSF, vectors also transduced the liver, providing a peripheral source of the therapeutic protein that corrected storage pathology in visceral organs of treated MPSII mice. The reversion of the pathology in non-transduced somatic organs provided evidence of cross-correction by circulating enzyme. Importantly, AAV9-Ids treatment also resulted in normalization of behavioural deficits and considerably prolonged the survival of treated MPSII mice. The efficacy of the intra-CSF administration of AAV9 vectors containing the human IDS coding sequence was also evaluated in MPSII mice. One and a half months after gene transfer, a significant increase in IDS activity was documented throughout the encephalon, an in the liver and serum of treated MPSII mice. Consequently, pathological GAG content was reduced, or even normalized, in the CNS and in most somatic tissues of MPSII mice that received the vectors. Altogether, the results obtained in the present work provide a strong proof of concept that supports the clinical translation of the intra-CSF AAV9-IDS gene therapy for the treatment of Hunter patients with cognitive impairment.

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Sorrentino, Nicolina Cristina. "Systemic AAV-mediated gene therapy approach to treat CNS pathology in Mucopolysaccharidosis type IIIA". Thesis, Open University, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.594745.

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Mucopolysaccharidosis type IIIA (MPS-IIIA) is a severe neurodegenerative lysosomal storage disorder (LSD) inherited as an autosomal recessive trait and caused by sulfamidase deficiency. Using somatic gene transfer, we demonstrated therapeutic efficacy of a novel low-invasive gene therapy approach to treat the brain pathology in MPS-IIIA. The therapeutic strategy is based on a chimeric sulfamidase engineered with both the signal peptide (sp) from the highly secreted iduronate-2-sulfatase (IDS) linked to its N-terminal end and the blood-brain barrier (BBB)-binding domain of apolipoproteinB (ApoB-BO) linked to its C-terminal end. These modifications allow the enzyme (i) to be highly secreted from the liver and (ii) to efficiently cross the BBB. A single intravascular administration of vectors, based on adena-associated virus (AAV) serotype 8, was performed in one-month old MPS-IIIA mice to efficiently target the liver and convert it in a factory organ for sustained systemic release of high levels of the modified sulfamidase. We show that while the 10Ssp replacement results in higher enzyme secretion, the addition of the ApoB-BO allows efficient BBB transcytosis and restoration of sulfamidase activity in the brain of treated MPS-IIIA mice to ~ 12-15% of the normal levels. This, in turn, results in reduction of pathological vacuolization,

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17

Mauri, Victor [Verfasser]. "Trehalose mediated enhancement of glycosaminoglycan degradation in the lysosomal storage disorder Mucopolysaccharidosis III / Victor Mauri". Köln : Deutsche Zentralbibliothek für Medizin, 2014. http://d-nb.info/1047324342/34.

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Yamashita, Takafumi. "C-type natriuretic peptide restores growth impairment under enzyme replacement in mice with mucopolysaccharidosis VII". Kyoto University, 2020. http://hdl.handle.net/2433/258994.

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Mahon, Louise. "Objective assessment of sleep in neurodevelopmental disorders : a study of children with mucopolysaccharidosis type III". Thesis, University of Manchester, 2012. https://www.research.manchester.ac.uk/portal/en/theses/objective-assessment-of-sleep-in-neurodevelopmental-disorders-a-study-of-children-with-mucopolysaccharidosis-type-iii(35869dbd-15ba-44d7-a710-72adb2b04cd3).html.

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This thesis, which focuses on sleep disturbance in people with neurodevelopmental disabilities, is divided into three sections. Paper one is a systematic review of the extant literature on objective studies of sleep in neurodevelopmental genetic disorders. Twenty papers met inclusion criteria and were subject to quality assessment, of which five were found to be high-quality, thirteen were medium-quality and two were low-quality. Studies were grouped by disorder and although there was some disparity across investigations, generally there was agreement about specific sleep difficulties in each disorder which seem to be part of the behavioural phenotypes. Overall a lack of total sleep, diminished REM sleep, and fragmented, less efficient sleep are prevalent across the disorders. Paper two is an empirical study which employed actigraphy to assess sleep in children with mucopolysaccharidosis type III (MPS III) and typically developing children. Parents completed a sleep diary, a sleep questionnaire and took saliva samples from their child. Actigraphic findings showed that MPS III patients had lengthened sleep onset latencies and greater daytime sleep than controls, but night-time sleep duration was within the normal range. In the MPS III group, some sleep problems correlated with age and progression of the disorder. Analysis of saliva samples revealed that children with MPS III had abnormal melatonin concentrations. Questionnaire responses demonstrated that children with MPS III had more sleep difficulties in all domains compared to controls. Implications for the management of sleep difficulties are discussed. Paper three is a critical appraisal of the research process which includes personal reflections on designing and conducting this research and a discussion of the principal issues which arose. Strengths and limitations of the research, ideas for further research and implications for clinical practice are considered.

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Yogalingam, Gouri. "Molecular characterisation of feline MPS VI and evaluation of gene therapy /". Title page, contents and abstract only, 1998. http://web4.library.adelaide.edu.au/theses/09PH/09phy54.pdf.

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21

Sergijenko, Ana. "Improved lentiviral vectors for haematopoietic stem cell gene therapy of Mucopolysaccaridosis type IIIA". Thesis, University of Manchester, 2012. http://www.manchester.ac.uk/escholar/uk-ac-man-scw:176449.

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Mucopolysaccharidosis type IIIA (MPS IIIA) is caused by mutations in the N-sulphoglucosamine sulphohydrolase (SGSH) gene, leading to cellular accumulation of heparan sulphate and progressive neurodegeneration in patients. One of the proposed treatment methods is haematopoietic stem cell (HSC) gene therapy, which should result in an excess of SGSH produced in the peripheral organs and brain. The pre-clinical feasibility of this approach was demonstrated by our group in a mouse model of MPS IIIA. However, the overall efficiency of this method was limited and a number of approaches to solving these issues were addressed in this project in order to bring this therapy closer to clinical application. Our first aim was to optimise transduction of HSCs using cytokines, bovine serum albumin (BSA), and chemicals, such as MG132, genistein and valproic acid. Addition of BSA with cytokines improved cell viability, addition of MG132/ BSA/ cytokines improved transduction, but also caused cellular toxicity, while addition of genistein was inefficient. Addition of valproic acid with cytokines resulted in increased number of colony forming units. Next, we generated clinically applicable third generation pCCL lentiviral vector backbones with the eGFP reporter gene driven by one of ubiquitous hPGK or myeloid specific hCD11b and hCD18 internal human promoters, and optimised production of lentiviral vectors to increase titre and reduce production cost. These lentiviral vectors were used to transduce lineage depleted HSCs and transplanted into WT mice. Full chimerism and over 80% transduction were achieved with an average of 5 vector copy numbers/ cell. The hCD11b promoter resulted in the highest eGFP expression in monocytes and B cells in blood, but was weaker than the hPGK in T cells. The hCD18 promoter was more monocyte-specific but weak. Significant numbers of GFP-positive microglial cells were present in the brain from all groups, with an average of 25% transduced CD11b-positive cells in perfused mice. We subsequently codon-optimised (CO) the SGSH gene significantly improving enzyme activity, and transduced lineage depleted WT cells with one of hCD18.SGSH-CO, hCD11b.SGSH-CO, or hPGK.SGSH-CO lentiviral vectors, or MPS IIIA cells with either hCD11b.SGSH-CO or hPGK.SGSH-CO lentiviral vectors. These transduced cells were transplanted into MPS IIIA mice and outcomes were measured 6 months later. Only treatment with the hCD11b.SGSH-CO-LV transduced WT or MPS IIIA HSCs corrected abnormal behaviour of MPS IIIA mice. However, all treatments resulted in complete GAG storage clearance in the periphery and brain, and significantly elevated enzyme activity in the brain, liver and spleen to 7-11%, 60-75%, and 170-250% of WT enzyme activity respectively. A fine threshold of over 8.6% brain enzyme activity appeared to be required for behavioural correction in MPS IIIA mice. Further assessment of treated mice for the amount of secondary storage, HS sulphation patterning, neuroinflammation and longevity are still required for complete therapeutic assessment. However, it appears that neurological correction of the MPS IIIA mouse using MPS IIIA cells is feasible using a clinically-relevant pCCL vector with the hCD11b promoter and the codon-optimised SGSH gene.

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Mumford, Rachel Anne. "Circadian rhythms, sleep and behaviour in intellectual and developmental disabilities : a systematic review of sleep and challenging behaviour and actigraphic assessment of circadian functioning in MPS III (Sanfilippo syndrome)". Thesis, University of Manchester, 2013. https://www.research.manchester.ac.uk/portal/en/theses/circadian-rhythms-sleep-and-behaviour-in-intellectual-and-developmental-disabilities-a-systematic-review-of-sleep-and-challenging-behaviour-and-actigraphic-assessment-of-circadian-functioning-in-mps-iii-sanfilippo-syndrome(a42b0492-2049-4cf6-9eae-8a7c6fdcf36a).html.

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Sleep disturbance and behavioural difficulties are both prevalent problems in the intellectual and developmental disability population and can have a significant impact on quality of life for the individual and their family. This thesis investigated sleep, behaviour and circadian rhythm functioning in children with intellectual and developmental disabilities, and is presented in three sections. The first two papers have been prepared in accordance with the author guidelines of the journals proposed for submission, excluding tables and figures for ease of reading. The first paper is a systematic review of the literature examining the relationship between sleep disturbance and challenging behaviour in children with intellectual and developmental disabilities. 15 studies were included in the review and overall there were consistent findings of an association between the presence of sleep disruption and increased behavioural difficulties. A causal relationship could not be inferred due to the cross-sectional methodology of studies. Other factors, such as parental wellbeing, child level of intellectual disability and comorbidity of physical health conditions, need to be considered to understand the complexity of this relationship. Children with the neurodevelopmental disorder mucopolysaccharidosis type III (MPS III or Sanfilippo syndrome) present with high rates of sleep disturbance and challenging behaviour. The second paper investigates circadian rhythm functioning and activity levels in children with MPS III, compared to typically developing controls. Objective measurement of circadian rhythm and activity levels was obtained through actigraphic recording for 7-10 days. Children with MPS III had increased fragmentation of circadian rhythm, less stability of rhythm in relation to external cues and a differential pattern of activity across the day compared to controls. Overall, results were indicative of a disruption of circadian rhythm function in children with MPS III. The implications for clinical practice and future research are discussed. The third paper provides a critical appraisal of the overall research process, including further consideration of the strengths and limitations, implications for clinical practice, wider context of the research and personal reflections. An account of the project that was originally proposed with the MPS III population is also presented, alongside reflections on its termination.

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Dierenfeld, Ashley Dawn. "Enzyme replacement therapy treatment from birth increases therapeutic efficacy and generates tolerance to enzyme in canine mucopolysaccharidosis type I". [Ames, Iowa : Iowa State University], 2009. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:1473198.

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Cross, Elaine. "Behavioural phenotypes in the mucopolysaccharide disorders". Thesis, University of Manchester, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.566569.

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This thesis investigated behaviour and behavioural phenotypes in the Mucopolysaccharide (MPS) disorders. The MPS disorders are a group of rare lysosomal storage disorders which are characterised by a period of normal development followed by gradual cognitive and/or physical decline.Paper 1 describes a systematic review of the extant literature on cognitive, motor, social, linguistic and behavioural presentation in all of the MPS disorders. 25 papers were reviewed and the methodology they employed was assessed. Sleep disturbance was found to be part of the behavioural phenotype of MPS III. In MPS I and II fearfulness and sleep problems occurred in most cases. In MPS II participants with the mild form were found to have relatively normal development and few or no behavioural problems, while those with the severe form had behavioural problems, delayed speech, delayed development and limited motor function. High rates of challenging behaviour, most commonly associated with aggression, hyperactivity, orality, unusual affect and temper tantrums were consistently observed in children with MPS III.Paper 2 describes an empirical study investigating the behavioural phenotype of MPS III, Sanfilippo syndrome. Parents of 20 children with MPS III, 5 adults with MPS III and 25 children with Intellectual Disability (ID) completed questionnaires relating to their son/daughter’s behaviour and adaptive skills. The frequency of challenging behaviours displayed by children aged 2-9 years with MPS III and ID were high but not significantly different. Behaviours associated with hyperactivity, orality, body movements and inattention were seen significantly more frequently in 2-9 year olds with MPS III than ID. The frequency of challenging behaviours displayed by children with MPS III and their adaptive skills was found to decrease with age. Children age 10-15 years with MPS III displayed significantly fewer problem behaviours than children of the same age with ID. It is recommended that parents with a child with MPS III aged 2-9 years are offered clinical services to support them with managing challenging behaviour while those with a child of 10 years or over are offered support with managing health concerns and end of life care.The third Paper, provides an evaluation of the strengths and limitations of the literature review and the empirical study. The findings and clinical implications from both studies are discussed. The process of conducting research into rare, life limiting, genetic syndromes is reflected upon and recommendations for replication and further research are made.

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Bicalho, Cibele Gomes. "Avaliação do comprometimento auditivo em pacientes com mucopolissacaridose". reponame:Repositório Institucional da FIOCRUZ, 2015. https://www.arca.fiocruz.br/handle/icict/10849.

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Fundação Oswaldo Cruz. Centro de Pesquisas Gonçalo Moniz. Salvador, BA, Brasil
Introdução: Mucopolissacaridose (MPS) é um conjunto de doenças raras causadas pela deficiência de enzimas lisossômicas levando ao acúmulo de glicosaminoglicanos (GAG) em órgãos e tecidos, responsáveis pelo quadro clínico multissistêmico, crônico e progressivo. O comprometimento auditivo é frequente. Objetivo: Avaliar manifestações auditivas de pacientes com MPS. Metodologia: Estudo descritivo, série de casos do comprometimento auditivo de pacientes com MPS. Foi realizada avaliação retrospectiva através de revisão de prontuário e avaliação prospectiva de dezembro de 2012 a outubro de 2014. Foram analisados a primeira e a última avaliação otorrinolaringológica (ORL) e audiológica realizada. Resultados: A principal queixa auditiva foi a hipoacusia. Aperdaauditiva estava presente em quase todos os pacientes, sendo que a perda auditiva condutiva foi a mais frequente, especialmente nos pacientes com MPS VI. Conclusão: A perda auditiva é muito frequente em pacientes com MPS, devendo o acompanhamento audiológicoser realizado precocemente.
Introduction: Mucopolysaccharidosis (MPS) is a set of rare diseases caused by deficiency of lysosomal enzymes leading to accumulation of glicosaminoglicanos (GAG) in tissues and organs responsible for the multisystemic clinical, chronic and progressive symptons. Objective: Todescribe the profile of otorhinolaryngological clinical examination and audiology tests of patients with MPS disease. Methods:Study of case series. The evaluation was performed, at the beginning, in 31 patients with MPS I, II, IIIA, IV and VI. Results: The most common hearing complaint was hearing loss and it was confirmed by audiology tests in almost 100% of patients, mostly with condutive hearing loss. Conclusions: It is important to evaluate the complaints, physical examination and audiology tests in MPS disease. Otorhinolaryngologist should be part of professional group that follow these patients in order to better monitor their hearing and provide early hearing rehabilitation.

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Roy, Elise. "Cell disorders in lysosomal storage diseases". Phd thesis, Université René Descartes - Paris V, 2012. http://tel.archives-ouvertes.fr/tel-00683248.

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Mucopolysaccharidosis type IIIB (MPSIIIB) is a lysosomal storage disease (LSD) characterized by accumulation of heparan sulfate oligosaccharides (HSO), which results in progressive mental retardation, neurodegeneration and premature death in children. The underlying mechanisms are poorly understood. Coming to a better understanding of the pathophysiology of MPSIIIB has become a necessity to assess the efficacy of gene therapy treatment regarding loss of neuronal plasticity, and to define the best conditions for treatment. To address the link between HSO accumulation and downstream pathological events, new cell models of MPSIIIB were created. First, induced pluripotent stem cells (iPSc) were generated from fibroblasts of affected children, followed by differentiation of patient-derived iPSc into a neuronal progeny. Second, a HeLa cell model was created in which expression of shRNAs directed against a-N-acetylglucosaminidase (NAGLU), the deficient enzyme in MPSIIIB, is induced by tetracycline. Success in the isolation of these different models was pointed by the presence of cardinal features of MPSIIIB cell pathology. Studies in these models showed that: I) HSO excreted in the extracellular matrix modifies cell perception of environmental cues, affecting downstream signalling pathways with consequences on the Golgi morphology. II) Accumulation of intracellular storage vesicles, a hallmark of LSDs is due to overexpression of the cis-Golgi protein GM130 and subsequent Golgi alterations. It is likely that these vesicles are abnormal lysosomes formed in the cis- and medial-Golgi which are misrouted at an early step of lysosome biogenesis, giving rise to a dead-end compartment. III) Other cell functions controlled by GM130 are affected, including centrosome morphology and microtubule nucleation. These data point to possible consequences on cell polarization, cell migration and neuritogenesis.

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Abily-Donval, Lénaïg. "Exploration des mécanismes physiopathologiques des mucopolysacharidoses et de la maladie de Fabry par approches "omiques" et modulation de l'autophagie. Urinary metabolic phenotyping of mucopolysaccharidosis type I combining untargeted and targeted strategies with data modeling Unveiling metabolic remodeling in mucopolysaccharidosis type III through integrative metabolomics and pathway analysis". Thesis, Normandie, 2019. http://www.theses.fr/2019NORMR108.

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Les pathologies lysosomales sont des maladies liées au déficit quantitatif ou qualitatif d’une hydrolase ou d’un transporteur à l’origine d’une atteinte multiviscérale potentiellement sévère. Certaines de ces pathologies sont accessibles à des traitements mais ces thérapeutiques sont uniquement symptomatiques et ne guérissent pas les patients. Même si le phénomène de surcharge peut expliquer entre autres la symptomatologie observée, la physiopathologie de ces maladies est complexe et non précisément connue. Une meilleure connaissance de ces pathologies pourrait permettre d’améliorer leur prise en charge globale. L’objectif de ce travail était dans un premier temps d’appliquer des techniques « omiques » dans deux groupes de maladies : les mucopolysaccharidoses et la maladie de Fabry. Cette étude a permis la mise en place d’une méthodologie métabolomique non ciblée basée sur une stratégie analytique multidimensionnelle comportant la spectrométrie de masse à haute résolution couplée à la chromatographie liquide ultra-haute performance et la mobilité ionique. Dans les mucopolysaccharidoses, l’étude des voies métaboliques a mis en évidence des modifications dans le métabolisme de plusieurs acides aminés et du système oxydatif du glutathion. Dans la maladie de Fabry, des modifications ont été observées dans l’expression de l’interleukine 7 et du facteur de croissance FGF2. La deuxième partie du travail s’est intéressée à la modulation de l’autophagie dans la maladie de Fabry. Notre étude a montré une diminution du flux autophagique avec un retard d’adressage de l’enzyme au lysosome dans les cellules Fabry. L’inhibition de l’autophagie permet de diminuer l’accumulation du substrat accumulé (Gb3) et améliore l’efficacité de l’enzymothérapie substitutive. En conclusion ce travail a permis une meilleure compréhension des mécanismes physiopathologiques des pathologies lysosomales et a montré la complexité du fonctionnement du lysosome. Ces données permettent d’espérer l’amélioration des stratégies thérapeutiques et diagnostiques dans ces maladies
Lysosomal diseases caused by quantitative or qualitative hydrolase or transporter defect induce multiorgan features. Some specific symptomatic treatments are available but they do not cure patients. Pathophysiological bases of lysosomal disease are poorly understood and cannot be due to storage only. A better knowledge of these pathologies could improve their management. The first aim of this study was to apply “omics” strategies in mucopolysaccharidosis and in Fabry disease. This thesis allowed the implementation of an untargeted metabolomic methodology based on a multidimensional analytical strategy including high-resolution mass spectrometry coupled with ultra-high-performance liquid chromatography and ion mobility. Analysis of metabolic pathways showed a major remodeling of the amino acid metabolisms as well as oxidative stress via glutathione metabolism. In Fabry disease, changes were observed in expression of interleukin 7 and FGF2. The second study focused on modulation of autophagy in Fabry disease. In this work, we have shown a disruption of the autophagic process and a delay in enzyme targeting to the lysosome in Fabry disease. Autophagic inhibition reduced accumulation of accumulated substrate (Gb3) and improved the efficiency of enzyme replacement therapy. This work allowed a better knowledge of the physiopathological mechanisms implicated in lysosomal diseases and showed the complexity of lysosome. These data could ameliorate management of these disease and are associated with hope for patients

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Bochernitsan, Aline Nemetz. "Mucopolissacaridose IVA : análise molecular e caracterização de haplótipos intragênicos no gene Galns". reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2015. http://hdl.handle.net/10183/139801.

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Introdução: Mucopolissacaridose IVA é uma doença lisossômica, autossômica recessiva, causada pela deficiência da enzima N-acetilgalactosamina-6-sulfatase. É uma doença rara e a incidência varia de 1:76.000 a 1:640.000 recém-nascidos vivos. Até o momento 319 diferentes mutações causadoras da doença já foram identificadas, o que demonstra a ampla variabilidade genética. Objetivo: Caracterizar o genótipo de pacientes com MPS IVA, analisar 6 polimorfismos intragênicos e identificar os haplótipos presentes em nossos pacientes, através do estudo molecular do gene GALNS. Métodos: O estudo foi realizado em 45 pacientes provenientes das regiões Nordeste, Sudeste, e Sul do Brasil, com diagnóstico bioquímico confirmado para MPS IVA. A análise molecular foi realizada através de PCR seguida de sequenciamento, pelo método de Sanger, a fim de identificar as mutações causadoras da doença. Para o estudo de haplótipos foram analisados 6 polimorfismos intragênicos através de PCR em Tempo Real, pelo método Taqman, em pacientes e controles. Resultados: A análise do gene GALNS, nos 45 pacientes, permitiu a identificação de 18 diferentes mutações, e a caracterização de 6 haplótipos distintos. Das 18 mutações encontradas, 5 apresentaram uma alta frequência (p.Ser341Arg, p.Arg386Cys, p.Gly301Cys, p.Arg94Leu e p.Gly116Ser), além disso, foram encontradas 4 novas mutações em outros três pacientes (p.Gly115Arg, p.Asn45Gly, p.Thr394Ala e c.759-2A>G). Dentre as mutações encontradas com maior frequência, a mutação p.Ser341Arg foi identificada em um maior número de pacientes, sendo a maioria proveniente da região Nordeste. Além disso, todos os pacientes com esta mutação apresentaram um único haplótipo. Conclusão: Os resultados obtidos permitiram a identificação de 18 mutações dentre elas 4 novas mutações. A alta frequência da mutação p.Ser341Arg no Nordeste do Brasil, principalmente no estado da Paraíba nos leva a inferir um possível efeito fundador da doença. Esta mutação foi observada somente na população brasileira e todos os pacientes com mutação em homozigose apresentaramum único haplótipo. Estas análises são importantes para identificar portadores nas famílias, para diagnóstico pré-natal, e também como forma de identificar uma origem comum em mutações frequentes em determinadas populações.
Background: Mucopolysaccharidosis IVA is an autosomal recessive lysosomal disease, caused by deficiency of N-acetilgalactosamina-6-sulfatase. It is a rare disease and the incidence ranges from 1: 76,000 to 1:640,000 live births. To date 319 mutations have been identified in this gene, demonstrating the wide variability of disease causing mutations. Objective: Analyze and characterize the genotype of patients with MPS IVA, through molecular analysis of GALNS. Methods: Molecular analysis of 45 patients with confirmed biochemical diagnosis for MPS IVA was performed. Mutation analysis was performed by PCR followed by Sanger sequencing. Haplotype analysis was performed using 6 intragenic polymorphisms by Real-Time PCR. Results: In this study we found 18 different mutations among 45 Brazilian patients and identified 5 common mutations (p.Ser341Arg, p.Arg386Cys, p.Gly301Cys, p.Arg94Leu e p.Gly116Ser). Four novel mutations were also identified through molecular analysis, including: p.Gly115Arg, p.Asn45Gly, p.Thr394Ala e c.759-2A>G. Patients are distributed in Northeast, Southeast and South regions of Brazil. Six different haplotypes were identified among patients. The p.Ser341Arg mutation showed the highest frequency, and most patients are located in the Northeast, additionally, all patients with this mutation show the same haplotype.Conclusion: These analyzes are important to identify carriers in families, for prenatal diagnosis, and in order to identify the mutation origin when certain recurrent mutation is associated with the same haplotype. In this study, we observed a high frequency of p.Ser341Arg mutation in Northeast, mainly in the state of Paraíba. This mutation was detected with higher frequency among patients, and showed only a haplotype. This mutation is unique for the Brazilian population and thus, we could suggest that a possible founder effect for this mutation could exist.

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Pagès, i. Pi Gemma. "Intrathecal administration of AAVrh10 coding for β‐glucuronidase corrects biochemical and histological hallmarks of mucopolysaccharidosis type VII mice and improves behavior and survival". Doctoral thesis, Universitat Autònoma de Barcelona, 2015. http://hdl.handle.net/10803/300733.

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La mucopolisacaridosi tipus VII (MPS VII) és una malaltia monogènica molt rara inclosa en el grup de malalties lisosòmiques. Està causada per la manca d’activitat β-‐ glucuronidasa, un enzim lisosòmic involucrat en la via de degradació de glicosaminoglicans. Aquesta alteració congènita causa una disfunció del sistema lisosòmic que provoca una acumulació anormal als lisosomes i la disrupció de l’homeòstasi de la cèl·lula. La malaltia presenta diferents graus de severitat clínica que van des de la mort prenatal fins a pacients amb formes lleus i una esperança de vida de 20 o 30 anys. Entre els casos que presenten un inici postnatal de la malaltia, la forma més severa de MPS VII es caracteritza per hepatomegàlia, esplenomegàlia, anomalies esquelètiques, desenvolupament tardà i retard mental, entre altres símptomes. Actualment els tractaments per als pacients de MPS VII són intervencions per pal·liar els símptomes de la malaltia, però no disposen de cap tractament curatiu. La teràpia gènica és una estratègia prometedora de cara a trobar una cura per a malalties monogèniques. Entre els vectors de teràpia gènica disponibles, els virus adeno-‐associats (AAV) presenten certes característiques que els fan molt atractius per a la teràpia gènica: permeten la transducció tant de cèl·lules en divisió com quiescents, proporcionen una expressió del transgèn a llarg termini, no poden replicar-‐se de manera autònoma sense un virus accessori i, a més, les infeccions naturals dels AAV no són patogèniques. Diferents serotips d’AAV s’han utilitzat com a vectors de teràpia gènica en estudis preclínics. Entre ells, els serotips AAV9 i AAVrh10 són els que presenten una capacitat de transducció més gran, així com una gamma més àmplia de tipus cel·lulars que poden transduir, especialment al sistema nerviós central. El serotip AAVrh10 no és d’origen humà. Per això, el fet d’utilitzar-‐lo com a vector de teràpia gènica podria evitar la neutralització per part dels factors immunològics específics contra AAV, factors que són presents en el sèrum humà després d’infeccions d’AAV naturals. Tanmateix, el reconeixement creuat per part d’anticossos generats contra AAV2, el serotip humà més comú, podrien interferir en el resultat de la teràpia. En aquest treball es proposa una estratègia de teràpia gènica per a MPS VII basada en una única injecció intratecal d’un vector AAVrh10 que conté el gen de la β-‐ glucuronidasa, testada en ratolins MPS VII adults joves. Es mostra que l’administració del vector al líquid cefaloraquidi (LCR) per punció lumbar, una tècnica molt poc invasiva, permet la transducció d’estructures del sistema nerviós central (SNC) utilitzant una dosi de vector més baixa que mitjançant injecció intravenosa. A més, el drenatge del vector del LCR cap al torrent sanguini comporta la transducció d’òrgans somàtics com el fetge. Això genera una font de β-‐glucuronidasa que aconsegueix una activitat enzimàtica en sèrum comparable a la de ratolins sans. L’expressió sostinguda de l’enzim recombinant per part de les cèl·lules transduïdes, així com la correcció creuada deguda a la secreció de l’enzim, aconsegueixen la correcció de les característiques bioquímiques i histopatològiques de la malaltia, tant al SNC com als òrgans somàtics. Aquesta correcció a nivell cel·lular condueix a una millora significativa de les capacitats físiques, cognitives i emocionals dels ratolins MPS VII i aconsegueix doblar la seva esperança de vida.
Mucopolysaccharidosis type VII (MPS VII) is an ultrarare monogenic lysosomal storage disease. It is caused by the lack of β-‐glucuronidase activity, a lysosomal enzyme involved in the degradation pathway of glycosaminoglycans. This inborn genetic alteration causes a dysfunction of the lysosomal system that entails abnormal lysosomal storage and disruption of cell homeostasis. The disease presents a range of clinical severity among patients, from death in utero to a life expectancy of up to 20 or 30 years for the milder forms. The severe form of MPS VII among cases with postnatal disease onset is characterized by hepatosplenomegaly, skeletal abnormalities, developmental delay and mental retardation, among other symptoms. Currently, the only treatments for MPS VII patients are interventions to alleviate the symptoms, but no curative treatment is available. Gene therapy is a promising therapeutic approach to find a cure for monogenic diseases. Among the available gene delivery vectors, adeno-‐associated viruses (AAVs) present several features that make them attractive for gene therapy strategies: they are able to transduce dividing and quiescent cells, they provide long term expression of the transgene, they are not able to autonomously replicate without a helper virus, and wild type AAV infections are not pathogenic. Different AAV serotypes have been used as gene therapy vectors in preclinical studies. Among them, AAV9 and AAVrh10 are the serotypes which show greater transduction capacity and a broader range of cell-‐type specific tropism, particularly in the central nervous system. The use of AAVrh10, a non-‐human serotype, may avoid the neutralization by anti-‐AAV immune factors present in human sera after natural AAV infections. However, cross-‐reactivity with antibodies raised against AAV2, the most common human AAV serotype, may still interfere in the therapeutic outcome. In this work, we propose a gene therapy strategy for MPS VII based on a single intrathecal injection of an AAVrh10 coding for the β-‐glucuronidase gene, tested in young adult MPS VII mice. We show that vector delivery to the CSF by lumbar puncture, a poorly invasive technique, allows the transduction of CNS structures using a lower vector dose than by intravenous delivery. In addition, the drainage of the vector from the CSF to the bloodstream results in transduction of somatic organs such as liver, thus providing a systemic β-‐glucuronidase source that achieves serum enzymatic activity comparable to wild type mice. The sustained recombinant enzyme expression by AAV-‐transduced cells, and the cross-‐correction provided by enzyme secretion, attains the correction of biochemical and histopathological hallmarks of the disease in CNS and somatic organs. This correction at the cellular level leads to a significant improvement of physical, cognitive and emotional characteristics of MPS VII mice and a doubling of the MPS VII mouse life span.

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Morini, Sandra Regina. "Caracterização do sistema musculo-esqueletico em individuos com mucopolissacaridose Tipo II : alguns aspectos cineticos e consequencias funcionais". [s.n.], 2007. http://repositorio.unicamp.br/jspui/handle/REPOSIP/308545.

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Orientador: Carlos Eduardo Steiner
Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
Made available in DSpace on 2018-08-10T08:47:23Z (GMT). No. of bitstreams: 1 Morini_SandraRegina_M.pdf: 2171982 bytes, checksum: 43545a3cec722564439f5853d48c9de2 (MD5) Previous issue date: 2007
Resumo: A mucopolissacaridose tipo II (MPS II) é uma doença de depósito lisossômico rara causada pela deficiência da atividade da enzima iduronato-2-sulfatase. Essa enzima é responsável pelo catabolismo de dois Glicosaminoglicanos (GAGs) diferentes, o sulfato de dermatan e o sulfato de heparan. O acúmulo lisossômico desses GAGs causa disfunção de células, tecidos e órgãos, sendo que o envolvimento do Sistema Músculo-esquelético se deve ao acúmulo essencial em articulações e no tecido conectivo. A MPS II abrange muitos aspectos e dois fenótipos são reconhecidos, o leve e o grave, que representam os dois pontos extremos de um vasto espectro da gravidade clínica. O objetivo desse estudo foi caracterizar o Sistema Músculo-esquelético de uma amostra de sujeitos com MPS II, relacionando as conseqüências biomecânicas e funcionais. Foram encontradas alterações biomecânicas, principalmente em articulações dos membros superiores, que interferiram em algumas atividades funcionais dos sujeitos do estudo. Através da goniometria, observou-se uma defasagem nas amplitudes de movimentos de várias articulações, especialmente em ombros e cotovelos. Os sujeitos apresentaram perda de força muscular em diversos grupos musculares, principalmente flexores e extensores dos dedos das mãos e pronadores e supinadores do antebraço. Foram observadas algumas alterações posturais características e disostose múltipla em todos os indivíduos. Tais alterações contribuíram para os déficits encontrados nas atividades de vida diária. As escalas PEDI e FIM foram aplicadas e os resultados demonstraram uma relação de maiores déficits em tarefas ligadas com as funções de membros superiores, tais como: pentear os cabelos, vestir uma camiseta e amarrar os sapatos
Abstract: Mucopolysaccharidosis type II (MPS-II) is a rare lysosomal storage disorder caused by deficiency in the activity of the enzyme iduronate-2-sulphatase. This enzyme is responsible for the catabolism of two different glycosaminoglycans (GAGs), dermatan sulfate and heparan sulfate. Lysosomal accumulation of these glycosaminoglycan molecules results in cell, tissue and organ dysfunction. The musculoskeletal system involvement is due to essential accumulated glycosaminoglycans in joints and connective tissue. MPS-II has many clinical features and includes two recognized clinical entities, mild and severe, that represent two ends of a wide spectrum of clinical severity. The aim of this study was to describe the musculoskeletal system in a sample of subjects with MPS-II relating the biomechanics and functional consequences. Biomechanical alterations were found, essentially in superior limbs joints that interfered in some functional activities of the subjects in the study. Deficit in movement amplitude in many joints, especially shoulders and elbows, was observed through the goniometry. The subjects showed force loss in several muscular groups, especially the flexors and extensors of the fingers as well as pronators and supinators. Dysostosis multiplex was seen in all individuals and typical postural changes were noted. These alterations contributed with the deficits in daily activities. PEDI and FIM scales was applied and the results demonstrated larger deficits in tasks with the functions of superior members, such as: to comb the hair, to dress a shirt and to tie the shoes
Mestrado
Saude da Criança e do Adolescente
Mestre em Saude da Criança e do Adolescente

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Diel, Dirnete. "Microencapsulação celular por extrusão eletrostática : aplicação na expressão de α-L-iduronidase para o tratamento da Mucopolissacaridose tipo I". reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2017. http://hdl.handle.net/10183/164444.

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A mucopolissacaridose tipo I (MPS I) é uma doença autossômica recessiva causada pela deficiência da enzima α-L-iduronidade (IDUA). Essa deficiência resulta no acúmulo de glicosaminoglicanos levando a diversas manifestações clínicas. A microencapsulação de células recombinantes que superexpressam IDUA tem sido considerada uma estratégia promissora para o tratamento de MPS I. Neste contexto, o presente estudo teve por objetivo a otimização da encapsulação de células BHK (Baby Hamster Kidney) superexpressando IDUA em microcápsulas de alginato revestidas com poli-L-lisina (PLL) utilizando-se um extrusor eletrostático. Em uma primeira etapa, um estudo de otimização das microcápsulas de alginato (MC-A) foi realizado por meio de um desenho experimental do tipo Box-Behnken (software Mini-Tab®) que permitiu avaliar simultaneamente a influência da voltagem (kV), fluxo alginato/células (mL/h) e concentração de alginato (%) sobre o tamanho das microcápsulas e a atividade de IDUA. Após, as microcápsulas foram revestidas sequencialmente com PLL e alginato (MC-APA) com o objetivo de aumentar a sua estabilidade. Nas condições experimentais empregadas, MC-A e MC-APA apresentaram-se monodispersas (span < 1,22) com um diâmetro médio inferior a 350 μm, determinado por difração a laser. O revestimento alterou a morfologia das microcápsulas (microscopia eletrônica de varredura) e a sua resistência mecânica (analisador de textura), sendo observado um aumento de cerca de 6 vezes na força necessária para compressão das mesmas. O revestimento final pelo alginato (MC-APA) parece ter sido parcial de acordo com as análises de infravermelho por transformada de Fourier com refletância atenuada. Em uma última etapa, a atividade enzimática foi avaliada em modelo murino MPS I após implante subcutâneo de MC-APA. Foi observado um aumento significativo da atividade de IDUA na pele, após 30 dias de tratamento. Nas análises histológicas foi observado um infiltrado inflamatório no local da aplicação que não impediu a liberação da enzima nas condições avaliadas. No seu conjunto, esse estudo demonstra a potencialidade das MC-APA para a liberação local de IDUA.
Mucopolysaccharidosis type I (MPS I) is an autosomal recessive disorder caused by the deficiency of α-L-iduronidase (IDUA). This deficiency results in the accumulation of glycosaminoglycans leading to various clinical manifestations. The microencapsulation of recombinant cells overexpressing IDUA has been considered as a promising strategy for the treatment of MPS I. In this context, the present study aimed to optimize the encapsulation of BHK cells overexpressing IDUA in poly-L-lysine (PLL) coated alginate microcapsules using an electrostatic extruder. In a first step, a Box-Behnken experimental design (Mini-Tab® software) was carried out for the optimization of the alginate microcapsules (MC-A), which allowed to evaluate simultaneously the influence of voltage (kV), alginate/cell flow (mL/h) and alginate concentration (%) on the size of the microcapsules and IDUA activity. Thereafter, the microcapsules were sequentially coated with PLL and alginate (MC-APA) in order to increase their stability. In the experimental conditions used, MC-A and MC-APA were monodisperse (span <1.22) with an average diameter of less than 350 μm, determined by laser diffraction. The coating modified microcapsules morphology (scanning electron microscopy) and their mechanical resistance (texture analyzer), being observed a six-fold increase in the required force for their compression. The final alginate coating (MC-APA) appears to have only partially coated the microcapsules, according to the attenuated total reflectance Fourier transform infrared spectroscopy analyses. In a final step, the enzymatic activity was evaluated in a MPS I murine model after subcutaneous implantation of MC-APA. A significant increase in IDUA activity was observed in the skin at 30 days after treatment. Histological analszes revealed an inflammatory infiltrate at the application site, which did not prevent the release of the enzyme under the evaluated conditions. Overall, this study demonstrates the potentiality of MC-APA for the local release of IDUA.

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Ogez, Brittney Dawn. "Efficacy of AAV2 and AAV8 to cross the blood brain barrier in the MPS IIIA mouse model". Oklahoma City : [s.n.], 2009.

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33

Schuh, Roselena Silvestri. "Desenvolvimento de vetores nanotecnológicos lipídicos do sistema CRISPR/Cas9 visando à terapia gênica para Mucopolissacaridose tipo I". reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2017. http://hdl.handle.net/10183/175139.

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Abstract (sommario):

A mucopolissacaridose tipo I (MPS I) é causada pela deficiência de alfa-L-iduronidase (IDUA), responsável pelo catabolismo de glicosaminoglicanos (GAGs), levando ao acúmulo multissistêmico de sulfato de heparano e dermatano. Este estudo tem por objetivo avaliar o potencial de sistemas lipídicos nanoestruturados como carreadores do plasmídeo do sistema CRISPR/Cas9 e um vetor doador da sequência do gene IDUA/Idua para edição gênica em fibroblastos de pacientes e em modelo murino de MPS I. Foram produzidos lipossomas (DOTAP, DOPE e DSPE-PEG) e nanoemulsões (e TCM) por homogeneização à alta pressão e microfluidização. O DNA foi associado às formulações por adsorção, ou por encapsulamento dos complexos pré-formados DNA/DOTAP no núcleo oleoso da nanoemulsão. A eficiência de transfecção dos complexos foi avaliada em fibroblastos de pacientes MPS I e ocorreu um aumento significativo da atividade de IDUA em 2, 15 e 30 dias após os tratamentos, que promoveu uma redução na quantidade de lisossomos nos fibroblastos tratados. A caracterização físico-química de formulações produzidas por microfluidização complexadas a somente um plasmídeo ou juntamente com um oligonucleotídeo foi verificada e pode-se afirmar que a capacidade de complexação e transfecção depende diretamente do tipo celular e da relação de cargas, e não há implicações quanto ao tamanho das sequências de ácidos nucleicos. Camundongos MPS I receberam os complexos lipossomais por injeção hidrodinâmica e sua biodistribuição foi detectada principalmente no pulmão, coração e fígado. A atividade sérica de IDUA normal aumentou em cerca de 6% e foi mantida por seis meses. A atividade aumentada no pulmão, coração, fígado e rim após eutanásia promoveu redução dos GAGs na urina e nos mesmos tecidos, corroborando com as análises histológicas. Em um estudo em andamento, foi realizada uma investigação mais aprofundada do efeito do tratamento lipossomal na morfologia óssea, sistemas cardiovascular e respiratório, e funções cerebrais dos animais tratados. A análise ecocardiográfica demonstrou uma melhora na hipertrofia e contratilidade do coração, porém não houve melhora na espessura das válvulas. O diâmetro da aorta foi similar ao de animais normais, porém as quebras de elastina ficaram entre o grupo normal e o não tratado. A morfologia facial dos animais tratados foi intermediária, assim como a espessura do osso zigomático. Entretanto, o osso femoral demonstrou espessura comparável ao normal. Já a resistência pulmonar apresentou uma tendência de redução nos animais tratados em relação aos animais MPS I. O conjunto de resultados demonstra o potencial das nanoestruturas lipídicas co-complexadas com o plasmídeo CRISPR/Cas9 e um vetor doador da sequência IDUA/Idua para terapia gênica da MPS I.
Mucopolysaccharidosis type I (MPS I) is caused by the deficiency of alpha-L-iduronidase (IDUA), responsible for the catabolism of glycosaminoglycans (GAGs), leading to multisystemic accumulation of heparan and dermatan sulfate. This study aims to evaluate the potential of lipid-based nanostructures as carriers of the CRISPR/Cas9 plasmid and a vector donor of the IDUA/Idua sequence for gene editing in patients’ fibroblasts and in a murine model of MPS I. Liposomes (DOTAP, DOPE, and DSPE-PEG) and nanoemulsions (also MCT) were produced through high-pressure homogenization or microfluidization. DNA was associated with liposomes and nanoemulsions by adsorption or by encapsulation of DNA/DOTAP preformed complexes in the oil core of nanoemulsions. The transfection efficiency of complexes was evaluated in fibroblasts from MPS I patients and a significant increase in IDUA activity was demonstrated at 2, 15, and 30 days after treatments. It was also possible to observe a significant reduction in lysosomal amount in treated fibroblasts. The physicochemical characterization of liposomes and nanoemulsions produced through microfluidization complexed with a single plasmid or along with an oligonucleotide has been verified and it can be stated that the complexing and transfection capacity of the complexes depends directly on the cell type and the charge ratio, and there are no implications of the size of the nucleic acid sequences. MPS I mice received the liposomal complexes by hydrodynamic injection and their immediate biodistribution was detected mainly in the lung, heart, and liver. An increase of about 6% in normal serum IDUA activity was maintained for six months, in addition to increased lung, heart, liver, and kidney activity after euthanasia. The enhanced enzymatic activity promoted a significant GAGs reduction in urine and in the same tissues, corroborating with histological analysis. In an ongoing study, a deeper investigation was carried out on the effect of liposomal treatment on bone morphology, cardiovascular and respiratory systems, and brain function. The echocardiographic analysis showed an improvement in the parameters of hypertrophy and contractility of the heart, but there was no improvement in heart valves. Aorta diameter was similar to that of normal animals, but elastin breaks were between the normal and untreated groups. Facial morphology of treated animals was intermediate, as well as the analysis of zygomatic bone thickness. However, femoral bone showed thickness comparable to normal animals. Lung resistance, on the other hand, showed a tendency to reduction in treated animals when compared to MPS I. The set of results demonstrates the potential of the co-complexed lipid nanostructures with the CRISPR/Cas9 plasmid and a donor vector of the IDUA/Idua sequence for MPS I gene therapy.

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Silva, Lilian Corrêa da. "Caracterização da doença articular e óssea em camundongos com mucopolissacaridose II (Síndrome de Hunter)". reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2017. http://hdl.handle.net/10183/172153.

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Abstract (sommario):

Base teórica: A Mucopolissacaridose II (MPS II) é uma doença genética recessiva ligada ao X causada por mutações no gene IDS. Como consequência, há acúmulo dos glicosaminoglicanos (GAGs) no lisossomo, fato que é responsável pelo fenótipo de MPS II. Anormalidades articulares e ósseas são conhecidas nos pacientes com MPS II e os tratamentos existentes não são eficientes para sanar tais anormalidades, portanto, realizamos este estudo de caracterização da doença articular e óssea, buscando evidenciar possíveis mecanismos responsáveis pela progressão da doença. Objetivo: Avaliar a progressão das alterações osteoarticulares em animais com MPS II dos dois aos oito meses de idade. Métodos: Foram utilizados camundongos nocaute B6N.Cg-Idstm1Muen/J, adquiridos do Jackson’s Lab. Os machos foram genotipados para compor o grupo controle (normal) ou o grupo de animais com MPS II. Ambos foram avaliados aos 2, 4, 6 e 8 meses de idade. Foi realizada análise histológica da articulação tíbio-femural, avaliando presença de infiltrado inflamatório, reabsorção óssea, reabsorção cartilaginosa e proliferação fibrocartilaginosa. Também foi realizada a mensuração do tamanho total da placa de crescimento e suas zonas e avaliação de anormalidades ósseas mediante exame de imagem por Raio-X dos ossos fêmur e zigomático. Resultados: Nos animais MPS II foi observado que o focinho era menos afilado (mais arredondado) e, em comparação com os animais controle, os animais MPS II apresentaram peso significativamente maior a partir dos 4 meses de idade. O escore histológico teve como principal característica a presença de reabsorção cartilaginosa, presente em 80% (4/5 animais) dos animais aos 8 meses, outras anormalidades encontradas neste tempo foram presença de infiltrado inflamatório (2/5 animais aos 8 meses) e proliferação fibrocartilaginosa (1/5 animais) Não houve diferença significativa entre animais normais e MPS II no tamanho das zonas de cartilagem da placa de crescimento ósseo. As medidas em diâmetro do osso zigomático apresentaram-se significativamente superiores nos animais MPS II aos 4, 6 e 8 meses. Quanto ao comprimento do fêmur não houve diferença significativa entre os grupos. Já, na medida da espessura do fêmur, os animais MPS II do grupo de 6 meses de idade mostraram diferença significativa. Conclusões: Anormalidades na articulação tíbio-femural foram detectadas nos animais aos 8 meses de idade. Não foram encontradas anormalidades óbvias na estrutura da placa de crescimento. Foi observado aumento na espessura do fêmur e do zigomático nos animais MPS II, sem alterações do tamanho do fêmur.
Background: Mucopolysaccharidosis II (MPS II) is a recessive X-linked genetic disease caused by mutations in the IDS gene. Consequently, there is an accumulation of glycosaminoglycans (GAGs) in the lysosome, fact that is responsible by the MPS II phenotype. Joints and bone abnormalities are known in MPS II patients and existing treatments are not efficient in correcting these abnormalities. Therefore, this study was performed to evidence bone and joint disease description in the animal model, searching for mechanisms responsible for disease progression. Objective: To evaluate the progression of osteoarticular changes in animals with MPS II from two to eight months of age. Methods: Male animals from the MPS II colony (B6N.Cg-Idstm1Muen/J) were genotyped to form the control (normal) group or MPS II group. Both groups were evaluated at the 2, 4, 6 or 8 months. Histological analysis of knee joint (presence of inflammatory infiltrate, bone resorption, cartilaginous reabsorption and fibrocartilaginous proliferation), measurement of total growth plate size and its zones, and evaluation of bone abnormalities by X-ray imaging of the femur and zygomatic bones were performed. Results: MPS II mice presented progressive abnormal features, such as a more rounded snout and a significative increased weight from 4 months of age. The main histological alteration was the presence of cartilage reabsorption, present in 80% (4/5 animals) of the eighth-month old animals. Other abnormalities found at this period were the presence of inflammatory infiltrate (2/5 animals at the eighth months old) and fibrocartilaginous proliferation (1/5 animals). There was no significant difference in the growth plate between normal and MPS II animals. The zygomatic bone diameter was increased in MPS II at fourth, sixth and eighth months There were no significant differences in femur length between groups. Thickness of the femur was increased in MPS II at six months. Conclusions: Abnormalities in the joint were detected in the animals at 8 months of age. No obvious abnormalities were found in the growth plate structure. An increase in femur and zygomatic thickness was observed in MPS II animals, with no changes in femur size.

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Pérez, Castro Jennifer Ana. "Estrategia de terapia génica para el tratamiento de las alteraciones auditivas y visuales de la mucopolisacaridosis tipo IIIB". Doctoral thesis, Universitat Autònoma de Barcelona, 2021. http://hdl.handle.net/10803/671992.

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Abstract (sommario):

La Mucopolisacaridosi tipus IIIB (MPSIIIB) és una malaltia minoritària d’acumulació lisosòmica, d’herència autosòmica recessiva, causada per la deficiència de l’enzim lisosòmic α-N-acetilglucosaminidasa (NAGLU), la qual cosa provoca l’acumulació de formes parcialment degradades del glicosaminoglicà (GAG) heparan sulfat (HS) a l’interior dels lisosomes. Aquesta acumulació sostinguda en el temps genera disfunció cel·lular i la posterior mort de les cèl·lules. La MPSIIIB presenta una profunda afectació progressiva del Sistema Nerviós Central (SNC) caracteritzada per neurodegeneració i neuroinflamació, acompanyades d’alteracions perifèriques moderades. A més, amb l’edat, els pacients presenten també afectacions altament invalidants de les funcions auditiva i visual, que provoquen una severa hipoacúsia i una progressiva pèrdua de la visió. Actualment, no existeix cap teràpia efectiva aprovada pel tractament de la MPSIIIB. Les teràpies disponibles se centren en pal·liar la simptomatologia i millorar la qualitat de vida dels pacients i de les seves famílies. Per tant, és fa necessària la cerca d’una teràpia eficaç que permeti revertir les alteracions derivades de la MPSIIIB. La teràpia gènica in vivo basada en l’administració de vectors virals adenoasociados (AAV) representa una alternativa atractiva, ja que una única administració del vector permetria una eficàcia terapèutica a llarg termini. Prèviament, en el nostre laboratori, es va desenvolupar una aproximació de teràpia gènica basada en una única administració al Líquid Cefalorraquidi (LCR) de vectors AAV9 codificants per a l’enzim NAGLU murí (AAV9-Naglu) a la dosi de 3.0x1010 genomes virals (vg)/ratolí a ratolins model de la malaltia. Aquest estudi va donar lloc a la correcció de les alteracions del SNC i perifèriques de la malaltia, així com també a la reversió de les alteracions conductuals i a un augment de l’esperança de vida del model murí de la MPSIIIB. Per a la translació a la clínica de la qualsevol aproximació de teràpia gènica amb vectors AAV és necessari realitzar estudis per tal de minimitzar la dosi de vector administrada, preservant la màxima eficàcia terapèutica. Per aquesta raó, es va realitzar un estudi basat en l’administració IC del vector AAV9-Naglu a ratolins MPSIIIB, a 4 dosis diferents equidistants entre sí, amb l’objectiu de determinar la dosi "mínima terapèutica". Finalment, es va poder assignar la dosi de 9.3x109 vg/ratolí com la mínima terapèutica, ja que donava lloc a la correcció de les principals alteracions del SNC i perifèriques, així com també conductuals del model murí de la MPSIIIB. Aquesta dosi va ser aproximadament 3 vegades menor que la utilitzada al treball anterior del nostre laboratori. A continuació, es va avaluar l’eficàcia del tractament IC amb el vector AAV9-Naglu a la dosi de 9.3x109 vg/ratolí sobre les alteracions auditives del ratolí model de la MPSIIIB. Es va demostrar la capacitat d’aquest tractament per recuperar els nivells d’activitat NAGLU i de normalitzar el contingut de GAGs a la còclea, preservant la citoarquitectura coclear i l’audició després de 4 mesos de tractament. També es va poder observar que aquest tractament donava lloc a l’augment de l’activitat NAGLU de l’ull i a la correcció de la distensió lisosòmica de la retina, la qual cosa es va traduir en la prevenció de la degeneració de la retina i a la conservació de l’agudesa visual, després de 10 mesos de tractament a llarg termini. En conjunt, aquests resultats demostren l’eficàcia terapèutica d’una única administració al LCR del vector AAV9-Naglu en ratolins MPSIIIB joves sobre la preservació de les afectacions auditives i visuals.
La Mucopolisacaridosis tipo IIIB (MPSIIIB) es una enfermedad rara de acúmulo lisosomal autosómica recesiva causada por la deficiencia en la enzima lisosomal α-N-acetilglucosaminidasa (NAGLU). La deficiencia de esta enzima provoca la acumulación de formas parcialmente degradadas del glucosaminoglicano (GAG) heparán sulfato (HS) en el interior de los lisosomas. Esta acumulación anómala sostenida en el tiempo genera la disfuncionalidad celular y la posterior muerte de las células. La MPSIIIB presenta una profunda afectación del Sistema Nervioso Central (SNC) caracterizada por la neurodegenración y la neuroinflamación. Alteraciones periféricas moderadas también están presentes en esta enfermedad. Además, con la edad, los pacientes presentan afectaciones altamente invalidantes de las funciones auditiva y visual, que provocan una severa hipoacusia y una progresiva pérdida de la visión. Actualmente, no existe ninguna terapia efectiva aprobada para tratar la MPSIIIB. Los tratamientos disponibles se centran en paliar la sintomatología y mejorar la calidad de vida de los pacientes y sus familias. Por tanto, es necesaria la búsqueda de una terapia eficaz que permita revertir las alteraciones derivadas de la MPSIIIB. La terapia génica in vivo basada en la administración de vectores virales adenoasociados (AAV: Adeno-Associated Virus) representa una alternativa prometedora, ya que una única administración del tratamiento permitiría una eficacia terapéutica a largo plazo. Previamente, en nuestro laboratorio, se desarrolló una aproximación de terapia génica basada en una única administración al Líquido Cefalorraquídeo (LCR) de ratones modelo de la enfermedad de vectores AAV9 codificantes para la NAGLU murina (AAV9-Naglu) a la dosis de 3.0x1010 genomas virales (vg)/ratón. Este estudió demostró la eficacia del tratamiento en la corrección de las alteraciones periféricas y del SNC de la enfermedad, así como una reversión de las alteraciones conductuales y un aumento en la esperanza de vida del modelo murino de la MPSIIIB. Para la traslacionalidad clínica de la cualquier aproximación de terapia génica con vectores AAV es crucial minimizar la dosis de vector administrada preservando la máxima eficacia terapéutica. Por ello, se realizó un estudio con el objetivo de establecer una dosis del vector AAV9-Nalgu más baja que se pudiera designar como la "mínima terapéutica". En este trabajo se observó que, tras la evaluación de 4 dosis diferentes equidistantes entre sí, se pudo designar la de 9.3x109 vg/ratón como la mínima terapéutica, pues era 3 veces menor q la empleada en el estudio anterior y además corregía tanto las alteraciones del SNC y periféricas, como las alteraciones del comportamiento. Además, se evaluó la eficacia del tratamiento a esta dosis sobre las alteraciones auditivas del ratón modelo de la MPSIIIB y se demostró su capacidad de recuperar los niveles de actividad NAGLU en la cóclea y de normalizar el contenido de GAGs en este tejido, preservando la citoarquitectura coclear y de la audición tras 4 meses de tratamiento. Además, también se observó que este tratamiento repercutía en la normalización de la actividad NAGLU en el ojo y la corrección de la distensión lisosomal en la retina. Ello contribuyó a la prevención de la degeneración retiniana, conllevando a la conservación de la agudeza visual a largo plazo. En conjunto, estos resultados demuestran la eficacia terapéutica de una única administración al LCR del vector AAV9-Naglu en ratones MPSIIIB jóvenes sobre la preservación de las afectaciones auditivas y visuales.
Mucopolysaccharidosis type IIIB (MPSIIIB) is a rare autosomal recessive lysosomal storage disease caused by the deficiency of a lysosomal enzyme called α-N-acetylglucosaminidase (NAGLU). This deficiency causes the accumulation of partially degraded forms of the glycosaminoglycan (GAG) heparan sulfate (HS) within the lysosomes. This abnormal accumulation sustained over time generates cellular dysfunction and subsequent cell death. MPSIIIB presents a profound involvement of the central nervous system (CNS) characterized by neurodegeneration and neuroinflammation. Moderate peripheral alterations are also present in this disease. In addition, with age, patients present highly disabling impairments of the auditory and visual functions, which cause severe hearing loss and progressive loss of vision. Currently, there is no effective treatment approved for MPSIIIB. The available treatments are focused on alleviating the symptoms and improving the quality of life of patients and their families. Therefore, it is necessary to develop an effective therapy that allows the correction of the alterations derived from MPSIIIB. In vivo gene therapy based on the administration of adeno-associated viral vectors (AAV) represents a promising alternative, since a single administration of the treatment would allow long-term therapeutic efficacy. Previously, in our laboratory, a gene therapy approach was developed based on a single administration to the cerebrospinal fluid (CSF) of AAV9 vectors encoding murine NAGLU (AAV9-Naglu) at the dose of 3 x 1010 viral genomes (vg)/mouse on the MPSIIIB mouse model. This study demonstrated the efficacy of the treatment in correcting the peripheral and CNS pathology, as well as a reversing the behavioural alterations and increasing the life expectancy of the MPSIIIB mouse model. For the clinical translation of any AAV-mediated gene therapy approach, it is crucial to minimize the vector dose administered while preserving maximum therapeutic efficacy. Therefore, a study was conducted with the aim of establishing a lower dose of the AAV9-Naglu vector that could be designated as the “minimum therapeutic dose”. Among 4 different equidistant doses, it was possible to designate 9.3 x 109 vg/mouse as the minimum therapeutical dose. Even though it was 3 times lower than the one used in the previous study, it was able to correct the behaviour and the CNS and peripheral alterations. In addition, the therapeutic efficacy of this dose in the hearing alterations of the MPSIIIB mice model was evaluated, resulting in the recovery of NAGLU activity and normalization of GAG accumulation in the cochlea. Cochlear cytoarchitecture and hearing function were preserved in MPSIIIB mice 4 months after treatment. Furthermore, we also observed that this treatment was able to normalize the NAGLU activity in the eye, thus correcting the lysosomal pathology in the retina. This contributed to the prevention of retinal degeneration, leading to long-term preservation of visual acuity. Overall, these results demonstrate the therapeutic efficacy of a single CSF administration of the AAV9-Naglu vector in young MPSIIIB mice on the preservation of auditory and visual impairments.
Universitat Autònoma de Barcelona. Programa de Doctorat en Bioquímica, Biologia Molecular i Biomedicina

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Langford-Smith, Kia Jane. "Non-myeloablative bone marrow transplantation for Mucopolysaccharide diseases". Thesis, University of Manchester, 2012. https://www.research.manchester.ac.uk/portal/en/theses/nonmyeloablative-bone-marrow-transplantation-for-mucopolysaccharide-diseases(5d3fd9c5-01f2-42aa-81ed-a2ce6ef140fe).html.

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Abstract (sommario):

The Mucopolysaccharide (MPS) diseases are a group of lysosomal storage disorders, caused by a lack of the enzymes required for catabolism of glycosaminoglycans (GAGs), leading to severe neurological decline, skeletal deformities, organomegaly, cardiac and respiratory compromise, and premature death. The severe form of MPS I, Hurler syndrome, can be successfully treated using haematopoietic stem cell transplantation (HSCT), but the risks associated with myeloablation and immune suppression limit the broader application of HSCT to attenuated diseases. Successful engraftment in MPS I has been difficult to achieve, and requires fully myeloablative conditioning, whilst reduced intensity conditioning is a risk factor for graft rejection. Non-myeloablative conditioning generating reliable graft acceptance and high donor chimerism could increase safety and applicability of HSCT in genetic disease, therefore the aim of this research was to identify such a regimen in a clinically relevant mouse model of HSCT.Conditioning regimens developed in existing mouse models of HSCT have had limited clinical success, and often require clinically unachievable high cell doses or less stringent strain combinations to overcome allogeneic transplant rejection. To improve clinical relevance we used CBA donors and C57BL/6 recipients, which require full myeloablation with busulfan and immune suppression using non-depleting anti-CD4 and anti-CD8 monoclonal antibodies for engraftment of low cell doses across a major histocompatibility complex barrier. In syngeneic transplant donor chimerism was improved by generating a greater ratio of donor:recipient haematopoietic cells in the bone marrow initially, therefore we tested granulocyte colony stimulating factor (G-CSF), high cell dose and stem cell niche disruption and compared this to anti-CD40L costimulatory blockade in allogeneic transplant performed with a reduced dose of busulfan that was insufficient for graft acceptance. Despite improvements in initial engraftment with some of these treatments, only combined signal 1 and 2 T cell blockade were effective in reducing the dose of busulfan required for long-term graft acceptance. Early detection of MPS is important in treatment success; good disease biomarkers are vital, and biomarkers suitable for monitoring treatment outcome in MPS are lacking. We evaluated serum heparin cofactor II-thrombin (HCII-T) complex for MPS. We determined optimal sample collection and storage conditions, assay limitations and developed measurement in dried blood spots. Dermatan sulphate has a greater effect on in vivo HCII-T complex formation than heparan sulphate, thus in the MPS mouse models HCII-T is a reliable biomarker for MPS I, but not MPS IIIA or IIIB. HCII-T is greatly elevated in MPS I, II and VI patients, who all store dermatan sulphate, but it is also elevated by a small but significant amount in MPS III patients, who store heparan sulphate. HCII-T was also measured longitudinally in MPS I, II and VI patients, compared to an existing clinical biomarker, and validated against clinical outcomes to show that it is a good biomarker of short-term treatment outcomes and responds rapidly to perturbations in treatment. Finally, we determined whether an engraftment defect was observed in the MPS I mouse model, and show that this is present following both syngeneic and allogeneic HSCT. The effect of enzyme replacement therapy (ERT) and anti-inflammatory treatment prior to allogeneic HSCT was investigated, and initial results suggest that ERT, but not ibuprofen, may improve HSCT outcome. Overall, a clinically relevant mouse model of allogeneic HSCT has been developed and used to determine a non-myeloablative conditioning regimen that generates high levels of donor chimerism with a minimal dose of busulfan and blockade of both signal 1 and 2 of T cell activation. The conditions required to observe an engraftment defect in MPS I mice have also been defined, and preliminary studies have suggested that ERT, but not anti-inflammatory treatment, may overcome the engraftment defect in MPS I. Alongside this work, the HCII-T biomarker has been evaluated in MPS mouse models and patients, determining that it correlates well with short-term treatment outcomes. The techniques and models developed here will provide an excellent basis for further work in developing non-myeloablative conditioning for bone marrow transplant in MPS I.

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Bruyere, Julie. "Cascades physiopathologiques dans la maladie de Sanfilippo B". Thesis, Paris 5, 2012. http://www.theses.fr/2012PA05T020/document.

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Abstract (sommario):

La mucopolysaccharidose de type IIIB (MPSIIIB), ou maladie de Sanfilippo B, est une maladie de surcharge lysosomale caractérisée par des atteintes neurologiques. Cette maladie génétique rare est causée par la déficience en a-N-acétylglucosaminidase (NAGLU), une enzyme nécessaire pour la dégradation des héparanes sulfates (HS). La dégradation incomplète des HS cause l’accumulation de saccharides d’HS dans les lysosomes et à la surface des cellules. Mais la cascade physiopathologique induite par ces saccharides n’est pour l’instant pas connue. D’une part, ces recherches fournissent des preuves que la communication avec l’environnement des cellules neurales déficientes en NAGLU est altérée. En effet, l’intégrine ß1 et ses effecteurs sont suractivés et recrutés au niveau des plaques d’adhérence dans des astrocytes déficients. Les comportements cellulaires dépendants des intégrines, tels que la polarisation et la migration, sont également altérés. Ces phénotypes sont restaurés par l’apport de l’enzyme déficiente. Cette restauration indique que l’accumulation de saccharides d’HS provoque l’activation de la signalisation des intégrines, et perturbe la polarisation et la migration des cellules neurales. L’ajout de saccharides d’HS purifiés sur des cellules neurales normales confirme que les saccharides d’HS extracellulaires activent des composants des plaques d’adhérence. D’autre part, l’étude d’un modèle cellulaire humain, dont l’expression de NAGLU a été inhibée par shRNA, a montré que l’accumulation de vésicules de stockage caractéristiques de la maladie est causée, entre autre, par une déformation de l’appareil de Golgi et la surexpression de GM130. Ces phénotypes sont également observés dans les neurones atteints. Ils s’accompagnent d’une augmentation de la stabilité et de la nucléation des microtubules, au niveau de l’appareil de Golgi. Les défauts de communication entre la cellule malade et son environnement semblent donc modifier la dynamique et la structure cellulaire. Nous présumons que les mécanismes physiopathologiques déchiffrés en culture sont reliés à la neuropathologie de la MPSIIIB. En perturbant la perception de l’environnement cellulaire, la polarité, la migration, et la pousse neuritique, les saccharides d’HS accumulés dans les tissus cérébraux malades, affectent probablement divers mécanismes clefs de la maturation corticale
Mucopolysaccharidosis type IIIB (Sanfilippo B disease) is a lysosomal storage disease characterized by severe neurological manifestations in children. This rare monogenic disease is caused by a-Nacetylglucosaminidase (NAGLU) deficiency, a lysosomal hydrolase necessary for heparan sulfate (HS) degradation. This deficiency leads to the accumulation of HS saccharides. Mechanisms mediating HS saccharides deleterious effects on brain cells are not well understood. This research provides evidences that neural cell sensing of environment is altered in MPSIIIB cells. Integrins and focal adhesion components are over-recruited and over-activated in deficient mouse astrocytes. Consistently, integrin-dependant cell behavior such as cell polarization and directed migration were defective in affected astrocytes and neural stem cells. HS saccharide clearance, by NAGLU gene transfer, rescues a normal phenotype suggesting that HS saccharides induce focal adhesion formation. Addition of purified HS saccharides on normal astrocytes confirms that extracellular HS saccharides can activate the recruitment of focal adhesion components and provides an in vitro assay to decipher the saccharide code of HS. Otherwise, investigations performed on HeLa cell model, in which NAGLU expression was inhibited by shRNA, showed that accumulation of intracellular storage vesicles, a hallmark of the disease, is due over expression of a cis-Golgi protein. This affects the Golgi morphology and microtubule nucleation and stability. It seems that alterations of environment cell sensing and downstream signaling also modify the dynamic and the structure of cells. We assume that mechanisms deciphered in cell cultures are related to MPSIIIB neuropathology. By affecting cell perception of environmental cues, cell polarity, cell migration and neurite outgrowth, HS saccharides, which accumulate in brain tissues defective for a HS degradation enzyme, likely affect various processes important for accurate cortical maturation

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Munõz, Rojas Maria Verônica. "Tratamento inovador da compressão medular com reposição enzimática intratecal nas mucopolissacaridoses tipos I e VI : relato de uma série de casos". reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2010. http://hdl.handle.net/10183/29034.

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As mucopolissacaridoses apresentam uma história natural progressiva, causada por defeitos no metabolismo dos glicosaminoglicanos. Frequentemente graves, as mucopolissacaridoses encurtam de forma considerável a expectativa de vida do paciente. Apesar de que em muitos casos a função intelectual é normal, morbidade neurológica considerável pode ser causada por compressão medular secundária ao acúmulo de glicosaminoglicanos nas meninges. O tratamento deste problema pode requerer a descompressão medular através de laminectomia cervical. A terapia de reposição enzimática endovenosa, para o tratamento de mucopolissacaridose, reduz o acúmulo lisossômico e alivia muitos dos sintomas da doença, porém não oferece benefício direto para o sistema nervoso central uma vez que não atravessa a barreira hemato-encefálica. Esta limitação da reposição enzimática endovenosa levou alguns pesquisadores a trabalhar com uma nova opção de via de liberação medicamentosa de alcance direto no sistema nervoso central, aproveitando o extenso contato que existe entre o líquido cefaloraquidiano e as meninges e com as granulações aracnoideas, para o tratamento de algumas doenças de depósito lisossomal. Estudos em modelos animais têm sido conduzidos e com resultados promissores. Este trabalho se propõe a estudar uma nova via de administração da enzima recombinante, diretamente no espaço liquórico que foi utilizada em dois pacientes com MPS I e em um paciente com MPS VI, com acesso a esta terapêutica através de uso compassivo individual aprovado pelo Comitê de Ética, no Hospital de Clínicas de Porto Alegre. Até então, apenas estudos animais haviam sido realizados abordando esta via de acesso em doenças de depósito lisossomal e estes pacientes foram os primeiros indivíduos com MPS no mundo a receber terapia de reposição intratecal para o tratamento de compressão medular sintomática por depósito de glicosaminoglicanos. Em 2005 um paciente adulto com MPS I apresentando compressão medular foi incluído em um protocolo de terapia de reposição enzimática intratecal por uso compassivo no Hospital de Clínicas de Porto Alegre. Em 2006 uma menina com MPS I apresentando compressão cervical medular sintomática também recebeu terapia de reposição enzimática intratecal por uso compassivo no Hospital de Clínicas de Porto Alegre. Em 2007 um menino com MPS VI e com compressão medular cervical também foi tratado através de reposição enzimática intratecal por uso compassivo neste mesmo hospital.
The mucopolysaccharidoses present a progressive natural course caused by defects on glycosaminoglycan degradation pathways. Usually severe, the mucopolysaccharidoses considerably shorten patient lifespan. Although in many cases the cognitive function is preserved, considerable neurological morbidity can be present due to spinal cord compression which is secondary to glycosaminoglycan storage in the meninges. Treatment for this complication usually requires surgical intervention with cervical laminectomy for thickened meninges removal. Enzyme replacement therapy used for the treatment of mucopolysaccharidoses reduces lysosomal storage and ameliorates many somatic symptoms but does not provide any direct benefit to central nervous system as the enzyme does not cross the blood-brain-barrier. Due to this limitation of intravenous enzyme replacement therapy some researchers have been working with an alternative option of enzyme delivery with direct action on central nervous system through the extensive close contact provided by cefalo-spinal fluid and meniniges and arachnoid villosities, to the treatment of some lysosomal disorders. Animal model studies have been conducted and some promising results have been achieved. This study intends to present an alternative route for the administration of a recombinant enzyme, directly in the cefalo-spinal fluid, which was used in two patients with mucopolysaccharidosis I and one patient with mucopolysaccharidois VI. These patients gained access to this therapy by individual compassionate use enrollment approved by local Ethics Board at Hospital de Clínicas de Porto Alegre. So far, only animal model trials had been conducted with the use of this administration route in lysosomal storage diseases, and these were the first three patients with mucopolysaccharidoses and cord compression to receive intrathecal enzyme replacement therapy in the world. In 2005, an adult mucopolysaccharidosis I patient presenting cervical cord compression was enrolled in a compassionate use trial of intrathecal enzyme replacement therapy, at the Hospital de Clínicas de Porto Alegre. In 2006, a girl with mucopolysaccharidosis I presenting spinal cord compression was also enrolled in a compassionate use trial of intrathecal enzyme replacement therapy, at the Hospital de Clínicas de Porto Alegre. In 2007, a boy with mucopolysaccharidosis VI and cord compression was enrolled in compassionate use trial of intrathecal enzyme replacement therapy in the same hospital.

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John, Angela Beatriz. "Avaliação do sono em pacientes com mucopolissacaridose tipo VI". reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2008. http://hdl.handle.net/10183/19019.

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Realizamos um estudo transversal prospectivo com o objetivo de determinar a prevalência de apnéia obstrutiva do sono em um grupo de pacientes sul-americanos com mucopolissacaridose tipo VI sem tratamento prévio ou atual com terapia de reposição enzimática ou transplante de medula óssea. Os critérios de inclusão foram: ter 4 anos ou mais de idade e confirmação bioquímica da doença (níveis reduzidos da atividade da arilsulfatase B, aumento de glicosaminoglicanos (GAGs) urinários e atividade normal de outra sulfatase). Foram avaliados 28 pacientes através de anamnese, exame físico, ecocardiograma Doppler transtorácico e polissonografia realizada em noite inteira. A amostra estudada tinha 14 (50%) meninos. No momento da avaliação, a média de idade foi de 98,5 meses e a média de idade do diagnóstico de MPS VI foi de 48,4 meses. Em 88% da amostra os sintomas iniciaram com menos de 36 meses e em 27% das famílias houve relato de consangüinidade entre os pais. As manifestações clínicas mais freqüentes durante o sono foram roncos e apnéias observadas. Ao exame físico, 78,6% apresentavam macroglossia e 82,1% deformidade torácica tipo pectus carinatum. Três (10,71%) pacientes já tinham realizado adenotonsilectomia e 6 (21,42%) adenoidectomia isoladamente. Os dados polissonográficos evidenciaram apnéia obstrutiva do sono em 23 (85,1%) pacientes, sendo 4 com transtorno leve, 5 moderado e 14 grave. A média do índice de apnéia hipopnéia (IAH) foi de 19,84 ± 26,25 eventos/hora, da saturação periférica da oxihemoglobina (SpO2) 93,25 ± 5,06%, do nadir da SpO2 80,29 ± 10,01% e do pico do dióxido de carbono final exalado (EtCO2) 44,1 ± 6,01 mmHg. A ocorrência de apnéias centrais foi rara. Quatorze indivíduos da amostra (50%) tiveram evidência de hipertensão pulmonar (HP) documentada através de ecocardiograma. Foi observada associação positiva entre a média e o nadir da SpO2 mais baixos e a presença de HP. No grupo com HP, a média e o nadir da SpO2 foram de 91,2 ± 6,4% e 75,4 ± 10,9% respectivamente, enquanto que nos pacientes sem HP os valores de média e nadir da SpO2 foram 95,3 ± 1,8% e 85,2 ± 6,1% respectivamente (p=0,037 para média; p=0,007 para nadir). A presença de apnéias observadas durante o sono foi a variável mais importante em predizer HP nessa amostra (p=0,016; OR 9,9; IC 1,5 a 63,7). As manifestações clínicas sugestivas de alterações respiratórias durante o sono não apresentaram correlação significativa com o IAH, a média e o nadir de SpO2 e o pico de EtCO2. Também não houve correlação significativa entre a excreção urinária de GAGS e a atividade enzimática com resultado da polissonografia e do ecocardiograma. Concluímos que a prevalência de apnéia obstrutiva do sono nos pacientes com mucopolissacaridose tipo VI é elevada e o nível de dessaturação apresenta correlação positiva com a presença de hipertensão pulmonar. Os sintomas durante o sono não apresentaram associação com o resultado da polissonografia. A presença de apnéias observadas durante o sono foi a variável mais importante para predizer HP.
This prospective cross-sectional study was conducted to determine the prevalence of obstructive sleep apnea in a group of South American patients with mucopolysaccharidosis type VI who had no previous or current treatment with enzyme replacement or bone marrow transplant. Inclusion criteria were: age 4 years or older; and biochemical confirmation of the disease – reduced arylsulfatase B activity, increased glycosaminoglycans (GAGs) in urine, and normal activity of at least one other sulfatase. Twenty-eight patients were examined and data were collected from clinical history, physical examination, transthoracic Doppler echocardiogram and overnight polysomnography. Of the 28 participants, 14 (50%) were boys; mean age at evaluation was 98.5 months, and mean age at MPS diagnosis, 48.4 months. Symptoms started before 38 months of age in 88% of the sample; 27% reported parental consanguinity. The most frequent clinical symptoms during sleep were snoring and witnessed apnea. Physical examination revealed that 78.6% had macroglossia, and 82.1%, pectus carinatum. The most frequent clinical symptoms during sleep were snoring and witnessed apnea. Physical examination revealed that 78.6% had macroglossia, and 82.1%, pectus carinatum. Three (10.71%) patients had already undergone adenotonsillectomy, and 6 (21.42%), isolated adenoidectomy. Polysomnography results showed that 23 (85.1%) patients had obstructive sleep apnea: 4 mild, 5 moderate, and 14 severe. Mean apnea-hypopnea index (AHI) was 19.84 ± 26.25 events/hour, oxygen saturation (SpO2), 93.25 ± 5.06%, SpO2 nadir, 80.29 ± 10.01%, and peak end-tidal carbon dioxide (EtCO2), 44.1 ± 6.01 mmHg. Central apneas were rare. Pulmonary hypertension (PH) was detected by echocardiography in 14 (50%) patients. Lower SpO2 mean and nadir were positively associated with PH. In the group of patients with PH, SpO2 mean and nadir were 91.2 ± 6.4% and 75.4 ± 10.9%, and in the group without PH, 95.3 ± 1.8% and 85.2 ± 6.1% (p=0.037 for mean; p=0.007 for nadir). Witnessed apneas during sleep were the most important variable to predict PH in this sample (p=0.016; OR 9.9; CI, 1.5 to 63.7). Clinical signs suggestive of respiratory abnormalities during sleep were not significantly correlated with AHI, SpO2 mean and nadir, or peak EtCO2. There was no significant correlation between GAGs in urine or enzyme activity and polysomnography or echocardiogram results. The prevalence of obstructive sleep apnea in patients with mucopolysaccharidosis type VI was high, and the level of desaturation was positively correlated with the presence of pulmonary hypertension. Symptoms observed during sleep were not associated with polysomnography results. Witnessed apneas during the sleep were the most important variable to predict PH.

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AragÃo, Lia Barroso BrandÃo. "AvaliaÃÃo da situaÃÃo periodontal de pacientes diagnosticados com mucopolissacaridose no Estado do CearÃ em 2007". Universidade Federal do CearÃ, 2008. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=2230.

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CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior
As Mucopolissacaridoses (MPS) constituem um grupo de doenÃas raras, caracterizadas por deficiÃncias enzimÃticas que resultam em bloqueio na degradaÃÃo dos glicosaminoglicanos. O objetivo deste estudo foi avaliar a situaÃÃo periodontal de todos os pacientes com Mucopolissacaridose, atendidos no Hospital Infantil Albert Sabin e no Hospital Geral CÃsar Cals, FortalezaâCE. Foram avaliados 18 pacientes, por um cirurgiÃo-dentista previamente calibrado, que registrou os Ãndice de Pernus, Ãndice de Placa Bacteriana VisÃvel, Ãndice de Sangramento Gengival, PSR e Ãndice CPO-D/ceo-d. Em relaÃÃo ao volume gengival, observou-se que 72,2% dos pacientes apresentaram Ãndice de Pernus nos escores 1, 2 ou 3, que corresponde Ã presenÃa de hiperplasia gengival. Quando se avaliaram os cuidados com relaÃÃo Ã higiene oral dos pacientes, observou-se que quanto ao Ãndice de Sangramento Gengival 77,8% dos pacientes apresentaram Ãndice maior que 10%, 66,6% dos pacientes apresentaram Ãndice de Placa Bacteriana VisÃvel maior que 40%. Com relaÃÃo ao PSR 94,4% dos pacientes apresentou escore 1, correspondendo a sangramento, e 5,6% escore 2, correspondendo Ã presenÃa de cÃlculo alÃm de sangramento, e quanto ao CPO-D/ceo-d 61,1% apresentou Ãndice maior que 5. De uma maneira geral, observou-se que a situaÃÃo periodontal dos pacientes portadores de mucopolissacaridose Ã uma situaÃÃo que inspira maior cuidado, mostrando caracterÃsticas prevalentes como o aumento gengival, alÃm de altos Ãndices de Sangramento Gengival, Placa Bacteriana VisÃvel e CPO-D/ceo-d.
The Mucopolysaccharidosis (MPS) are a group of rare diseases characterized by enzyme deficiency that results in nondegradation of the glicosaminoglicans (GAGs). The aim of this study was to evaluate the periodontal status of all the patiente with MPS that are treated at the Hospital Infantil Albert Sabin and at the Hospital Geral CÃsar Cals, in Fortaleza, CearÃ, Brazil. A number of 18 patients were evaluated by a dentist that was previously calibrated, which registered the Pernus Index (IP), Visible Bacterium Plaque Index (IPB-V), Gingival Bleeding Index (ISG), PSR and Index that shows number of teeth that showed cavities, tooth loss or restoration (CPO-D/ceo-d). In relation to the gingival volume it was observed that 72,2% of the patients showed that the gingival was not in itÂs regular size. On the evaluation of dental hygiene, it was observed that 77,8% of the patients showed ISG greater than 10% and 66,6% of the patients showed IPB-V greater than 40%. In relation to PSR, 94,4% of the patients showed scored 1 which means gingival bleeding and 5,6% showed score 2 which means calculus besides gingival bleeding. And in relation to CPO-D/ceo-d 61,1% of the patients showed score greater than 5. In a general way it was observed that the periodontal status of the patients is a situation that requires more care, showing characteristics like gingival hyperplasias besides high scores of ISG, IPB-V and CPO-D/ceo-d.

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Guarany, Nicole Ruas. "Avaliação do efeito da terapia de reposição enzimática na capacidade funcional de pacientes com mucopolissacaridose". reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2011. http://hdl.handle.net/10183/31815.

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Introdução: As mucopolissacaridoses (MPS) são doenças genéticas raras causadas pela atividade deficiente de enzimas lisossômicas que afetam o catabolismo de glicosaminoglicanos, o que leva ao seu acúmulo no organismo e a um quadro clínico multisistêmico. As manifestações clínicas geram limitações nas tarefas cotidianas. Objetivos: Avaliar a capacidade funcional e a amplitude de movimento articular (ADM), e o efeito da Terapia de Reposição Enzimática (TRE) em ambas as variáveis, em um grupo de pacientes com MPS acompanhados por um centro de referência em doenças lisossômicas do Hospital de Clínicas de Porto Alegre, Brasil. Métodos: Estudo prospectivo, longitudinal, com amostragem por conveniência. Utilizou-se o Pediatric Evaluation of Disability Inventory (PEDI) e a Medida de Independência Funcional (MIF) para avaliar funcionalidade, e a goniometria para avaliar ADM. Foram realizadas três avaliações em 0, 6 e 12 meses após inclusão no estudo (Momento 1, Momento 2 e Momento 3). Para fins de análise, os pacientes foram divididos em rês grupos: Grupo 1: pacientes sem TRE; Grupo 2: pacientes em TRE antes e após inclusão no estudo; Grupo 3: pacientes em TRE após inclusão no estudo. Resultados: 21 pacientes foram incluídos: Grupo 1=7 (MPS II, MPS III-B, MPS IV-A); Grupo 2=6 (MPS I; MPS IV) e Grupo 3=8 (MPS I, MPS II, VI), mediana de idade de 10,5 anos, 18,5 anos e 2 anos; e intervalo interquartil de 9-14,5 anos, 11,5-21,75 anos e 1,5-5 anos, respectivamente. Não houve diferença estatisticamente significativa entre os grupos para ADM. Encontrou-se diferença para a área de autocuidado do PEDI para o Grupo 3 (p=0,05), a melhora clínica na ADM foi observada somente para este grupo. No teste MIF o Grupo 2 apresentou melhores escores em todos os domínios avaliados. Houve correlação positiva entre a área de autocuidado do PEDI e flexão de punho (r=,718). Discussão/Conclusão: A TRE parece promover a manutenção da ADM e funcionalidade. No entanto, é difícil avaliar se isso decorre da TRE, da melhora clínica geral proporcionada pelo tratamento, ou da combinação destes fatores. A preservação da funcionalidade é um desafio no tratamento clínico destes pacientes e a manutenção do desempenho ocupacional deve ser definida como objetivo a ser alcançado.
Introduction: The mucopolysaccharidoses (MPS) are rare genetic disorders caused by a deficiency in lysosomal enzymes that affect the catabolism of glycosaminoglycans and cause their accumulation, resulting in a multisystemic clinical picture. Their clinical manifestations result in limitations to perform daily life tasks. Objectives: To evaluate functional capacity, joint range of motion (ROM), and the effect of enzyme replacement therapy (ERT) in both variables in patients with MPS followed at the reference center for lysosomal disorders at Hospital de Clínicas de Porto Alegre, Brazil. Methods: The present was a prospective, longitudinal study with convenience samples. The Pediatric Evaluation of Disability Inventory (PEDI) and the Functional Independence Measure (FIM) were used to evaluate functionality, and goniometry was used to evaluate ROM, at three moments (study allocation, and 6 and 12 months after study inclusion). For the analysis, three groups were formed, as follows: Group 1 (patients without ERT); Group 2 (patients on ERT before and after study inclusion), and Group 3 (patients that initiated ERT after study inclusion). Results: 21 patients were included: 7 in Group 1 (MPS II: 3, MPS III-B: 2, MPS IV-A: 2); 6 in Group 2 (MPS I: 3; MPS VI: 3), and 8 in Group 3 (MPS I: 3, MPS II: 4, MPS VI: 1). A statistically significant difference was found in the area of self-care of the PEDI for Group 3 (p=0,05), and clinical improvement in ROM was seen only in Group 3. Group 2 showed higher scores in all domains evaluated by the FIM. No statistically significant difference was found between the groups for ROM in the three moments evaluated. There was a positive correlation between the area of self-care of the PEDI and wrist flexion (r=0.718). Discussion/Conclusion: ERT seems to promote maintenance of ROM and functionality. However, it is difficult to evaluate whether or not this is due to ERT, to the general clinical improvement resulting from the treatment, or the combination of both. The preservation of functionality is an increasing challenge in the treatment of these patients, and maintenance of occupational performance should be defined as an objective to be reached by therapies used.

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Pereira, Denise Rotta Ruttkay. "Correlação entre os achados da fibronasolaringoscopia e da polissonografia em pacientes com mucopolissacaridose Tipo VI". reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2015. http://hdl.handle.net/10183/129695.

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INTRODUÇÃO: As mucopolissacaridoses (MPSs) formam um grupo raro de doenças congênitas lisossômicas de depósito, relacionadas a desordens do metabolismo dos glicosaminoglicanos (GAG). Os GAG, parcialmente degradados, acumulam-se nos diversos tecidos do organismo, principalmente das vias aéreas superiores, levando a apneia obstrutiva do sono nesses pacientes. OBJETIVO: Descrever os achados em vias aéreas de pacientes com mucopolissacaridose tipo VI, identificados pela fibronasolaringoscopia (FNL), e compará-los com as alterações na polissonografia (PSG). DELINEAMENTO: Estudo transversal. MÉTODOS: Incluíram-se todos os pacientes com MPS tipo VI, com idade entre 14 e 24 anos, que fazem acompanhamento no Serviço de Genética do Hospital de Clínicas de Porto Alegre. Coletaram-se informações clinico-epidemiológicas dos pais ou responsáveis por meio de entrevista. Realizou-se PSG de noite inteira, classificada em normal, leve, moderada ou gravemente alterada. FNL foi efetuada em consultório, sem sedação, entre 7 dias antes e 7 dias após a PSG. As fibronasolaringoscopias foram gravadas em DVD e analisadas com cegamento para os achados na PSG. A FNL foi classificada em 1- sem obstrução, 2- obstrução leve, 3 - obstrução moderada ou 4 - obstrução grave de vias aéreas, de acordo com o maior escore obtido nas diferentes regiões. RESULTADOS: Avaliaram-se 11 pacientes com MPS tipo VI, sendo 7 (63,6%) do sexo masculino. Na FNL, oito (72,7%) apresentaram obstrução grave, dois (18,2%) obstrução moderada e um (9,1%), obstrução leve de vias aéreas. Na PSG, nove pacientes (81,8%) apresentaram síndrome da apneia obstrutiva do sono (SAOS). Destes, cinco (45,5%) apresentaram SAOS leve, três (27,2%) SAOS moderada e um (9,1%) SAOS grave. Encontrou-se hipertrofia moderada a grave das conchas nasais em 81,8% dos sujeitos e 64% apresentaram obstrução grave em região supraglótica. Não houve associação entre os achados da FNL e da PSG (p=0,454; kappa = - 0,09; IC 95%: - 0,34 a 0,17), demonstrando que não há concordância entre os métodos de avaliação. CONCLUSÃO: A apneia apresenta alta prevalência na amostra e não se correlaciona com o grau de obstrução da via aérea superior.
INTRODUCTION: Mucopolysaccharidosis (MPS) is a lysosomal storage disease that affects an enzyme responsible for the degradation of glycosaminoglycans (GAGs). Partially degraded GAGs accumulate in several tissues, such as the upper airways, which leads to the development of obstructive sleep apnea (OSA) in these patients. OBJECTIVE: To describe airway findings in mucopolysaccharidosis type VI patients, identified with flexible fiberoptic laryngoscopy (FFL), and compare it with polysomnography (PSG) abnormalities. STUDY DESIGN: Cross-sectional study. METHODS: All MPS VI diagnosed patients, age ranging from 14 to 24 years, followed at the Genetic Division of Hospital de Clinicas de Porto Alegre were included. Clinical and epidemiological data were obtained by an interview with parents. Overnight PSG was performed, and results were classified as normal or mildly, moderately or severely abnormal. FFL was performed at the outpatient clinics, without sedation, between 7 days prior and seven days after PSG. Flexible fiberoptic laryngoscopies were recorded in DVD and analyzed by a blind researcher. FFL was classified as 1 - no obstruction, 2 - mild obstruction, 3 - moderate obstruction or 4 - severe obstruction of the airways, using the highest score obtained in all the regions. RESULTS: Eleven patients with MPS VI were included, and seven (63.6%) were males. Eight (72.7%) had severe obstruction of the airways, two (18.2%) had moderate obstruction, and one (9.1%) had mild obstruction at FFL. At PSG, nine (81.8%) patients had obstructive sleep apnea syndrome (OSAS). Of these, five (45.5%) were mild, three (27.2%) moderate, and one (9.1%) severe OSAS. Moderate to severe hypertrophy of the nasal turbinates was found in 81.8% of the patients, and 64% had severe infiltration of the supraglotic area. There was no association between FFL and PSG findings (p=0.454; kappa= -0.09; CI= -0.34 to 0.17), demonstrating no agreement between the two methods. CONCLUSIONS: In the present study, all patients with MPS showed some degree of airway obstruction. As there was no correlation between FFL and PSG findings, we suggest performing PSG in all subjects with MPS in order to determine disease severity.

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Camelier, Marli Teresinha Viapiana. "Diagnóstico de mucopolissacaridose tipo IVA em amostras de sangue impregnado em papel filtro". reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2011. http://hdl.handle.net/10183/30961.

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INTRODUÇÃO: As mucopolissacaridoses (MPS) são doenças de depósito lisossômico, caracterizadas pela deficiência de enzimas lisossômicas envolvidas na degradação dos glicosaminoglicanos (GAGs). O acúmulo anormal dessas macromoléculas no interior dos lisossomos provoca alterações estruturais e funcionais, de caráter multissistêmico e progressivo. Os GAGs acumulados também são excretados na urina, onde podem ser identificados através de diversos métodos bioquímicos. Estas doenças estão presentes em todos os grupos étnicos e a incidência conjunta das MPS, é estimada entre 1:10.000 a 1:25.000 nascidos vivos. (Baehner, 2005). A causa das MPS é a deficiência de uma enzima específica na rota de degradação dos GAGs. As MPS são classificadas segundo o tipo de substrato (GAGs) acumulado e a enzima específica deficiente. Na síndrome de Morquio A, ou mucopolissacaridose tipo IVA (MPS IVA), o substrato acumulado é o queratan sulfato e a enzima deficiente é a N-acetilgalactosamina-6-sulfatase. (GALNS). Os pacientes afetados por MPS IVA apresentam baixa estatura, disostose múltipla, opacidade de córnea, entre outros sinais e sintomas. O desenvolvimento psicomotor e mental é normal. O método de detecção inicial das MPS baseia-se na identificação dos GAGs, que são excretados em excesso na urina destes pacientes. A presença de queratan sulfato na eletroforese ou a detecção de níveis aumentados na dosagem quantitativa, direciona a investigação laboratorial para a MPS IV. O diagnóstico definitivo se estabelece através da medida da atividade enzimática em leucócitos ou fibroblastos, onde se constata a deficiência enzimática. OBJETIVOS: Este estudo teve como objetivo principal, tornar disponível um novo método, mais simples, rápido e acessível, para o diagnóstico bioquímico de mucopolissacaridose tipo IVA, utilizando amostras de sangue impregnadas em papel filtro (SIPF). MATERIAIS E MÉTODOS: Amostras de SIPF e leucócitos de 35 pacientes de ambos os sexos, com idade entre 3 e 47 anos, com diagnóstico previamente estabelecido de MPS IVA, pelo método convencional, em leucócitos e /ou fibroblastos, foram analisadas. Para o estabelecimento dos valores de referência, foram estudadas amostras de leucócitos e de SIPF de 54 indivíduos saudáveis (18-50 anos), de ambos os sexos. Após assinatura do termo de consentimento, amostras de sangue periférico de pacientes e controles, foram coletadas, para a obtenção de leucócitos e sangue impregnado em papel filtro.(SIPF). Os ensaios enzimáticos foram realizados nas amostras de leucócitos e SIPF, simultaneamente, para comparar os resultados. RESULTADOS: Os resultados obtidos nos ensaios enzimáticos de todos os pacientes apresentando MPS IVA, confirmaram a deficiência da atividade enzimática em ambos materiais (leucócitos e SIPF) com uma diferença estatisticamente significativa em relação ao grupo controle. (Mann-Witney U test, p< 0,001). Neste estudo, a medida de GALNS em amostras de SIPF permitiu a identificação dos pacientes com MPS IVA, com sensibilidade de 100 %. Os testes de estabilidade realizados nas amostras de SIPF indicaram que amostras coletadas para a medida da atividade de GALNS devem ser mantidas a 4ºC sempre que possível, sendo estáveis nesta temperatura por mais de 30 dias. CONCLUSÕES: Nas condições utilizadas, amostras de SIPF se mostraram adequadas para a identificação segura de pacientes com MPS tipo IVA. O método que utiliza amostras de SIPF é mais acessível e rápido, simplificando a etapa de coleta e transporte, podendo ser utilizado para detectar pacientes afetados, especialmente em áreas de difícil acesso para a coleta e transporte de amostras líquidas.
INTRODUCTION: Mucopolysaccharidosis (MPS) are lysosomal deposit diseases characterized by lysosomal enzymes deficiency involved in the degradation of glycosaminoglycans (GAGs). The abnormal accumulation of these macromolecules inside the lysosomes provokes structural and functional alterations multi-systemically and progressively. The accumulated GAGs are also excreted in the urine, where they may be identified through many different biochemical methods. These diseases occur among all ethnical groups and the combined incidence of MPS is estimated at 1:10.000 to 1:25.000 live births. (Baehner, 2005). The MPS’ cause is the deficiency of a specific enzyme in the GAGs degradation route. The MPS are classified according to a type of substrate accumulated (GAGs) and the deficiency of a specific enzyme. In Morquio syndrome A or Mucopolysaccharidosis type IVA (MPS IVA), the accumulated substrate is the keratan sulfate and the deficient enzyme is the N-acetylgalactosamine-6-sulfatase (GALNS). The patients affected by MPS IVA present short stature, dysostosis multiplex, corneal opacity, among others signs and symptoms. The cognitive and mental developments are normal. The MPS initial detection method is based on the identification of the GAGs which are excreted in the patients’ urine. The presence of the keratan sulphate in the electrophoresis or the detection of the increased levels in the quantitative dosage directs the laboratory investigation to MPS IV. The definitive diagnosis is established through measuring the enzymatic activity in leukocytes or fibroblasts, in which the enzymatic deficiency is proved. OBJECTIVE: This study’s main purpose is to offer an original, simpler, faster and more accessible method for biochemical diagnosis of Mucopolysaccharidosis type IVA using dried blood samples (DBS). MATERIALS AND METHODS: DBS and leukocytes from 35 patients from both sexes between 3 and 47 years of age with previously established diagnosis of MPS IVA through the conventional method in leukocytes and/or fibroblasts were analyzed. In order to establish reference values DBS and leukocytes samples from 54 healthy people (18-50 years of age) from both sexes were studied. After signing a paper consent form, peripheral blood samples from patients and controls were collected for obtaining leukocytes and dried blood samples (DBS). To validate the method, we made a simultaneous GALNS assay in leukocytes and DBS. RESULTS: The results obtained in the enzymatic assays from all patients presenting MPS IVA confirmed the deficiency of enzymatic activity in both materials (leukocytes and DBS) with a significant statistical difference in relation to the control group. (Mann-Witney U tes, p< 0,001). In this study, the quantity of GALNS in DBS allowed the identification of patients with MPS IVA with sensibility of 100%. The stability tests indicate that DBS samples collected for measuring the activity of GALNS must be kept at 4ºC whenever possible, being stable in this temperature for more than 30 days. CONCLUSION: In the used conditions, DBS were adequate for a safe identification of patients with MPS type IVA. The method which utilizes DBS is cheaper and faster, what simplifies the collection and transportation stage and can be used to detect affected patients especially in difficult access areas for the collection and transportation of liquid samples.

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Federhen, Andressa. "Mucopolissacaridose tipo I: avaliação de um novo instrumento para classificação fenotípica". reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2012. http://hdl.handle.net/10183/52961.

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Introdução: A mucopolissacaridose tipo I é comumente classificada em três síndromes clínicas (Hurler, Hurler-Scheie e Scheie), de acordo com a gravidade do fenótipo. Devido à alta heterogeneidade da doença e à sobreposição de sintomas em pacientes, alguns autores consideram esta forma de classificação ultrapassada e defendem que a doença apresenta um espectro fenotípico mais amplo. Para tanto, seria muito útil o desenvolvimento de novas ferramentas que possam contribuir para uma melhor classificação dos pacientes. Objetivo: Avaliar um novo instrumento para a classificação fenotípica da MPS I e verificar a correlação dos resultados obtidos com o mesmo com as características bioquímicas e moleculares dos pacientes avaliados. Materiais e Método: Um instrumento elaborado por um grupo de especialistas foi por nós adaptado para avaliar a gravidade do fenótipo ao diagnóstico de 43 pacientes brasileiros com MPS I. Uma nota de zero a 14 foi obtida com a aplicação deste instrumento pela avaliação da presença ou ausência dos seguintes sinais e sintomas ao diagnóstico: atraso no desenvolvimento neuropsicomotor e/ou declínio cognitivo, rigidez articular/artropatia/contraturas articulares, cifose, disostose multiplex, macrocefalia e bossa frontal. Os pacientes incluídos foram também avaliados em relação aos mesmos parâmetros do instrumento e quanto ao seu fenótipo por três geneticistas com reconhecida experiência com essa doença. Dados bioquímicos e moleculares também foram utilizados para comparação com os resultados da aplicação do instrumento. Resultados: Os pontos de corte com melhor balanço de sensibilidade e especificidade encontrados a partir da aplicação do instrumento e a partir da avaliação dos geneticistas foram, respectivamente 7 e 9. Os parâmetros do instrumento para os quais foi observada diferença estatisticamente significativa foram atraso do desenvolvimento neuropsicomotor/declínio cognitivo (entre o fenótipo Hurler e os fenótipos Hurler-Scheie e Scheie) e disostose múltipla (entre os fenótipos Hurler e Scheie). Não foi observada correlação entre a nota obtida no instrumento e os valores de GAGs urinários, nos diferentes fenótipos. A maior parte dos pacientes com mutações sem sentido foi classificada como grave, tanto a partir do instrumento quanto pela avaliação dos geneticistas. Conclusões: Os pontos de corte encontrados podem ser úteis para a classificação dos pacientes em dois grupos distintos – grave e atenuado. O atraso no dsenvolvimento neuropsicomotor/declínio cognitivo e a disostose múltipla são achados importantes para predizer a gravidade da doença. Mutações sem sentido parecem determinar o fenótipo mais grave da síndrome. Não foi possível distinguir os diferentes fenótipos a partir dos valores de GAGs na urina. A ferramenta desenvolvida parece ser útil para auxiliar na classificação da gravidade da MPS I, mas é recomendável sua aplicação em um número maior de pacientes para melhor dimensionar sua potencial aplicação.
Introduction: Mucopolysaccharidosis type I is usually classified into three clinical syndromes (Hurler, Hurler-Scheie and Scheie) according to the severity of the phenotypic expression. Some authors believe this classification is not accurate because of disease variation and overlapping findings in some patients, and suggest that its phenotypic spectrum is wider. With this view, it would be useful the development of new tools which could contribute to a better classification of patients. Objective: To evaluate a new tool the phenotypic classification of MPS I and investigate whether the results obtained are correlated with biochemical and molecular characteristics of the patients. Material and methods: A tool developed by a group of specialists was adapted by us for the evaluation of the phenotypic severity at diagnosis in 43 Brazilian patients with MPS I. A score of zero to 14 was obtained using this tool, which evaluated presence or absence of the following signs and symptoms: delay in neurological and psychomotor development and cognitive decline; joint stiffness, arthropathy and joint contractures; kyphosis; dysostosis multiplex; macrocephaly; and frontal bossing. The same patients had the same parameters evaluated by three MDs with expertise in MPS who also provided their impression about the phenotype. Biochemical and molecular findings were also compared with the results obtained in the proposed tool. Results: The cut-off points with better balance of sensitivity and specificity found with the use of the tool and according to the experts' evaluations were 7 and 9, respectively. The tool parameters with statistically significant differences were neurological and psychomotor development delay and cognitive decline (when the Hurler phenotype was compared with the Hurler-Scheie and Scheie phenotypes), and dysostosis multiplex (for the comparison between the Hurler and Scheie phenotypes). There was no correlation between the scores obtained when using the tool and the urinary GAG values across the different phenotypes. Most patients with nonsense mutations were classified as severe according to the tool scores and to the experts’ evaluations. Conclusions: The cut-off points found in this study may be useful for the classification of patients into two distinct groups - severe and attenuated. Neurological and psychomotor developmental delay and cognitive decline, as well as dysostosis multiplex, are important findings to predict disease severity. Nonsense mutations seem to determine the most severe syndrome phenotype. The urinary GAG values do not allow differentiating the different phenotypes. The tool developed seems to be useful to help in the classification of the severity of MPS I, but it would be advisable its application in a larger number of patients to better evaluate its potential application.

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PARIS, ERIC. "Circonstances inhabituelles du diagnostic des mucopolysaccharidoses". Rennes 1, 1993. http://www.theses.fr/1993REN1M058.

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Kubaski, Francyne. "Padronização de um protocolo para identificação de mutações no gene da GALNS em pacientes com MPS IVA através das técnicas de PCR-ARMS (Amplification Refractory Mutation System) e sequenciamento". reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2012. http://hdl.handle.net/10183/67647.

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Introdução: Mucopolissacaridose IVA ou Síndrome de Morquio A é uma doença autossômica recessiva causada pela deficiência da enzima lisossomal Nacetilgalactosamina- 6-sulfatase (GALNS), que resulta no acúmulo lisossomal dos glicosaminoglicanos: Queratan sulfato e Condroitin-6-sulfato nos tecidos causando as manifestações clínicas. Os fenótipos variam da forma clássica à forma atenuada, ambas sem comprometimento cognitivo. A prevalência de MPS IVA varia de 1/76.000 a 1/640.000 nascidos vivos. Objetivos: Analisar e caracterizar o genótipo de pacientes brasileiros com MPS IVA através de estudos de mutações no gene da GALNS, possibilitando a estimativa de frequência de mutações recorrentes e o estabelecimento um protocolo de rotina para triagem dessas mutações. Métodos: Análise molecular do gene da GALNS foi realizada em 26 pacientes brasileiros inicialmente através de PCR-ARMS para detecção de seis mutações recorrentes (p.G116S/ p.G139S/ p.L307P/ p.N164T/ p.R386C e p.S341R) seguidas pela amplificação de regiões codificantes por PCR e sequenciamento. Resultados: Essas mutações foram encontradas em 61,5% da nossa amostra, com uma frequência alélica de 55,8%. Destas, a mutação mais frequente foi p.S341R (26,9%), seguida de p.R386C (21,1%) e p.G116S (7,7%). As mutações p.N164T, p.G139S, p.L307P não foram encontradas em nossa amostra. Além destas, foi encontrada por sequenciamento do éxon 5 uma mutação nova p.C165Y. Conclusão: O protocolo usado para detecção de mutações comuns mostrou-se adequado como um screening inicial de mutações no gene da GALNS, identificando mutações em 61,5% dos pacientes e permitiu a caracterização de 55,8% dos alelos. A mutação p.S341R foi encontrada apenas em pacientes do Nordeste. A identificação de indivíduos heterozigotos nessas famílias será importante para aconselhamento genético e para estimar a prevalência da doença nessa região. Estudos adicionais para identificação da origem dessa mutação, incluindo análises de segregação e haplótipo estão em andamento, e serão avaliadas em conjunto com dados epidemiológicos.
Background: Mucopolysaccharidosis IVA or Morquio A syndrome, is an autosomal recessive disorder caused by deficiency of lysosomal enzyme Nacetylgalactosamine- 6-sulfatase (GALNS), which results in lysosomal storage of glycosaminoglycans: Keratan sulfate and Chondroitin-6-sulfate in tissues causing clinical manifestations. The phenotypes vary from the classical to attenuated form, both without cognitive impairment. The prevalence of MPS IVA ranges from 1/76.000 to 1/640.000 live births. Objective: To analyze and characterize the genotype of Brazilian patients with MPS IVA, through molecular study of mutations in the GALNS gene, enabling the estimative of frequency of recurrent mutations and the establishment of a protocol for routine screening of these mutations. Methods: Molecular analysis of GALNS gene was performed in 26 Brazilian patients initially by ARMS-PCR to detect six recurrent mutations (p.G116S/ p.G139S/ p.L307P/ p.N164T/ p.R386C and p.S341R) followed by amplification of coding regions by PCR and sequencing. Results: These mutations were found in 61.5% of our sample, which were present in 55.8% of the alleles. The most frequent mutation was p.RS341R (26.9%), followed by p.R386C (21.1%) and p.G116S (7.7%). Mutations p.N164T, p.G139S, p.L307P were not found in our sample. A novel mutation p.C165Y was found after sequencing of exon 5. Conclusion: The protocol used for detection of common mutations was shown to be adequate for a first screening of mutations at the GALNS gene, once it identified the genotype in 61.5% of patients and allowed the characterization of 55.8% of alleles. The p.S341R was found only in patients from the Northeast. The identification of heterozygous individuals within these families will be important for genetic counseling and for estimating the disease prevalence in this region. Further studies to identify the origin of this mutation, including haplotype and segregation analyses are in progress, and will be evaluated in conjunction with epidemiological data.

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Ribeiro, Patrícia Carneiro. "O sujeito na mucopolissacaridose : uma análise discursiva". Universidade Católica de Pernambuco, 2013. http://www.unicap.br/tede//tde_busca/arquivo.php?codArquivo=833.

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Na literatura científica brasileira as publicações referentes à Mucopolissacaridose (MPS) abordam a dimensão biológica numa visão organicista sobre o paciente e a doença. Diante disso, uma proposta diferenciada foi pensada. Analisar o discurso dos pais e profissionais de saúde que estão em contato com os sujeitos com Mucopolissacaridose é o objetivo desta pesquisa. Para chegar a tal objetivo foram entrevistados os responsáveis e os profissionais da equipe de saúde. Os dados coletados a partir da gravação das entrevistas foram transcritos e alguns recortes foram selecionados para serem analisados à luz da Análise do Discurso (AD) de linha francesa, tal como proposta por Pêcheux e desenvolvida no Brasil por Eni Orlandi e diversos autores. Os resultados mostraram que os efeitos de sentido produzidos pelos discursos encontram-se em cinco Formações Discursivas/Ideológicas que foram cotejadas entre si e confrontadas com a teoria. O interdiscurso que fala sobre o sujeito se mostra cristalizado nas alterações e limitações secundárias à doença, enquanto que o interdiscurso sobre linguagem limita-se à emissão de sinais linguísticos regidos pela norma padrão da língua. Estes discursos configuram tanto o sujeito quanto a linguagem presos ao componente orgânico e estão determinados pela identificação a Formações Ideológicas que compreendem as condições sócio-históricas de produção do dizer marcando a presença de outras vozes no fio discursivo. Apenas uma Formação Discursiva diferenciou-se marcando a significação do sujeito. Concluiu-se que a imagem sobre o sujeito com MPS está sendo construída a partir de conceitos que enaltecem a fisiologia e a anatomia, capturada pela doença em detrimento a imagem de sujeito constituído na e pela linguagem.
In the scientific literature regarding the Brazilian publications Mucopolysaccharidosis (MPS) approach to a biological dimension in an organicist view of the patient and the disease. Therefore, a differentiated proposal was conceived. Analyze the discourse the fathers and professionals of the healthcare team who are in direct contact with those people with Mucopolysaccharidosis (MPS) that is the objective of this research. To reach this goal were interviewed officials and professionals of the healthcare team. The collected data from the recording of the interviews were transcribed and some clippings were selected to be analyzed in the light of Discourse Analysis of the French line, as proposed by Pêcheux and developed in Brazil by Eni Orlandi and several authors. The results showed that the sense effects produced by the discourses are found on five Discourse Formations / Ideological, which were courted together and confronted with theory. The interdiscourse that talk about the subject shown themselves crystallized in the changes and in the secondary limitations of the disease, while interdiscourse about language is limited to the issue of linguistic signals regulated by the standard language. These discourses configure both the subject and the language attached to the organic component and are determined by identifying the Discursive Formations / Ideological comprising the socio-historical conditions of to say, marking the presence of "other voices" in discursive thread. Only a Discursive Formation made the difference marking the significance of the subject. It was concluded that the image on the subject with MPS is being built from concepts that exalts the physiology and anatomy, captured by the disease, rather than the image of a subject constituted in and through language.

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Franco, José Francisco da Silva. "Avaliação clínico-laboratorial dos pacientes com mucopolissacaridose tipos I,II e VI em terapia de reposição enzimática (TRE)". Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/5/5141/tde-24032016-142203/.

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Introdução: As mucopolissacaridoses (MPSs) são doenças de depósito lisossômico causadas por deficiências enzimáticas envolvidas na degradação dos glicosaminoglicanos (GAGs). As MPSs dos tipos I, II e VI decorrem da deficiência das enzimas alfa-L-iduronidase, iduronato-2-sulfatase e Nacetilgalactosamina 4-sulfatase, respectivamente. As manifestações clínicas são multissistêmicas e progressivas. Objetivo: O objetivo deste estudo foi descrever a evolução clínica e laboratorial de pacientes com Mucopolissacaridose I, II e VI, em terapia de reposição enzimática (TRE). Métodos: Foram avaliados 27 pacientes com MPS (13 MPS I, 8 MPS II e 6 MPS VI), com diagnóstico confirmado pela dosagem enzimática e GAGs urinários, acompanhados em três centros de referência para TRE. Resultados: Cinco pacientes eram casos familiares (3 MPS I e 2 MPS VI). Todos os indivíduos estudados nasceram sem alterações clínicas e as mães relataram o aparecimento dos sintomas (alteração da face, aumento do volume abdominal, rigidez articular e déficit de crescimento) a partir dos 6 meses a 8 anos de idade, MPS I-Hurler (média 7m), MPS I Hurler-Scheie (média 2a), MPS I- Scheie (6a10m), MPS II (média 3a6m) e MPS VI (média 1a). A idade ao diagnóstico foi: MPS I-H (média 1a6m), I-HS (média 4a8m) e I-S (média 13a7m), MPS II e VI (média 5a). Entre os pacientes avaliados, observaram-se cinco casos familiais, sendo uma família com duas irmãs com MPS VI e outra família com dois irmãos e um primo com MPS I-S. Todos os pacientes apresentaram dismorfismos faciais típicos, associados a outros achados frequentes: restrição articular, mãos em garra, macrocefalia, baixa estatura, déficit ponderal. Pacientes com atraso no DNPM e/ou deficiência intelectual foram: Hurler (3/3), Hurler-Scheie (3/5) e MPS II (4/8). A idade do início da TRE foi de 1a2m a 31a9m. O tempo de TRE variou de 40 semanas a 556 semanas (média 259 semanas). Ao diagnóstico, todos os pacientes I, II e VI apresentaram o nível de GAGs urinários aumentado de 2 a 13 vezes o valor de referência para a idade. Aproximadamente 26 semanas após TRE, houve redução de GAGs urinários com a normalização do nível em 12/27 (44%) e o valor ainda um pouco acima do normal em 15/27(56%). Antes da TRE, 24/26 (92%) pacientes apresentaram alterações ecocardiográficas, e a despeito da TRE, houve persistência ou progressão das anormalidades. A polissonografia foi realizada em 10 pacientes antes da TRE sendo constatada a Síndrome da Apnéia Obstrutiva do Sono (SAOS) em nove pacientes (2 Hurler, 3 HurlerScheie, 3 MPS II e 1 MPS VI). Mesmo com o uso da TRE observou-se aumento do índice de apneias. As reações às infusões foram observadas em 55% dos pacientes (15/27), a maioria, presente nas primeiras semanas de infusão. Elas consistiram de: erupção cutânea, HAS, febre e broncoespasmo, revertidas após o uso de anti-histamínicos, antitérmicos e/ou redução da velocidade da infusão. As reações mais graves foram encontradas em dois pacientes. As principais complicações clínicas diagnosticadas, antes da TRE, foram: HAS (25%), perda auditiva (37%) e hidrocefalia (15%). Durante a TRE, houve aumento das frequências das complicações: HAS (37%), perda auditiva (59%) e hidrocefalia (22%). Entre os pacientes submetidos a intervenções cirúrgicas, cinco apresentaram complicações anestésicas e dois faleceram durante o procedimento. Conclusões: Este estudo mostrou heterogeneidade clínica pela variabilidade inter e intrafamilial. A utilização da TRE é capaz de atenuar, mas não de impedir a progressão da doença, cuja mortalidade permanece elevada. O diagnóstico precoce e a instituição da TRE pode modificar substancialmente a história natural da doença e melhorar a qualidade de vida
Introduction: Mucopolysaccharidosis (MPS) are lisosomal storage disorders caused by glycosaminoglycans (GAGs) enzymatic catabolism deficiencies, leading to mucopolysaccharides organ and tissues deposition. MPS types I, II and VI are due to deficiency of respectively, alpha-L-iduronidase, iduronate-2sulfatase and N-acetylgalactosamine-4-sulfatase. Clinical manifestations are progressive and multisystemic. Objective: The aim of this study was to describe the clinical and laboratory data of patients with MPS types I, II and VI receiving Enzyme Replacement Therapy (ERT). Methods: This study involved 27 patients with MPS (13 MPS I; 8 MPS II and 6 MPS VI) diagnosed by enzymatic and urinary GAGs measurement, followed in three reference centers for ERT. Results: Five patients were familial cases (3 MPS I and 2 MPS VI). All patients. All patients were born without clinical complications and their mothers referred the first signs and symptoms (coarse face, enlarged abdomen, stiff joints, short stature) had started at 6mo to 8y: MPS I Hurler (mean 7mo), MPS I Hurler-Scheie (mean 2y), MPS I Scheie (mean 6y10mo), MPS II (mean 3y6mo) and MPS VI (mean 1y). The mean age of diagnosis was: MPS I Hurler (1y6mo), MPS I Hurler-Scheie (4y8mo), MPS I Scheie (13y7mo), MPS II and VI (5y). There were five familial cases, including a MPS VI family (two sisters) and a MPS I Scheie family (two brothers and one cousin). All patients presented progressive typical facial coarsening. Other frequent findings were: stiff joints, clowded hands, macrocrania, failure to thrive. The prevalence of developmental milestones delay and/or mental intellectual disability was: MPS I Hurler (3/3), MPS I Hurler-Scheie (3/5) and MPS II (4/8). The age of onset of ERT ranged from 1y 2mo to 31y 9mo. The follow-up time after ERT initiation ranged from 40w to 556w (mean 259w). The baseline levels of urinary GAGs were increased two to 13 folds compared to reference values according to age. Approximately 26 weeks after ERT, urinary GAGs levels decreased. Normal levels of urinary GAGs in 12/27 (44%) and slightly increased in 15/27(56%) patients were observed. Before ERT, 24/26 (92%) patients presented echocardiographic abnormalities, which persisted or worsened in spite of ERT. Polysomnography was performed in 10 patients before ERT and revealed obstructive sleep apnea in nine patients (2 MPS I Hurler, 3 MPS I Hurler-Scheie, 3 MPS II and 1 MPS VI); the apnea/hypopnea index increased after ERT. Adverse infusion reactions were reported in 55% (15/27) of patients. Most of them was observed during the first weeks of treatment and included: skin rash, arterial hypertension, fever and bronchospasm, and were solved with antihistamines, antipyretics and/or reduction of infusion rate. Severe reactions were noted in two patients. Regarding clinical complications, arterial hypertension (25%), hypoacusia (37%) and hydrocephalus (15%) were diagnosed before ERT. After ERT arterial hypertension (37%), hypoacusia (59%) and hydrocephalus (22%) were reported. Among the patients that undergone surgical procedures, five presented anesthestical complications and two patients deceased during the procedure. Conclusions: This study showed both inter and intrafamilial clinical heterogeneity. ERT is able to ameliorate but not to stop the progression of the disease that remains with high mortality rate. This study emphasizes that the early diagnosis and ERT are critical for a better outcome and for enhancing the quality of life of these patients

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Oliveira, Fabiane Lopes. "Avaliação da qualidade de vida de pacientes com doença de gaucher, doença de fabry e mucopolissacaridoses". reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2010. http://hdl.handle.net/10183/26931.

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Introdução: As doenças de Gaucher (DG), Fabry (DF) e Mucopolissacaridoses (MPS) constituem-se nos tipos mais frequentes de doenças lisossômicas (DL) tratados por terapia de reposição enzimática (TRE). No Brasil, até o presente momento, não há dados de avaliação da qualidade de vida de pacientes com DL, nem instrumento específico validado paratanto. Objetivo: Avaliar a qualidade de vida (QV) de uma amostra de pacientes brasileiros com DG, DF e MPS por meio da aplicação do questionário SF-36. Método: Estudo transversal observacional. O SF-36 é composto por 8 domínios: capacidade funcional, aspecto físico, dor e estado geral de saúde; vitalidade, aspecto social e saúde mental. O questionário foi aplicado, em uma consulta de rotina no ano de 2008, aos pacientes atendidos no ambulatório de DL do Serviço de Genética Médica do Hospital de Clínicas de Porto Alegre, Brasil (SGM/HCPA), com idade igual ou superior a 12 anos e com habilidade cognitiva para preenchimento do mesmo. Resultados: Quarenta e quatro pacientes foram incluídos no estudo (DG= 21, DF=14, MPS= 9; média de idade=27,5±13,7 anos; sexo masculino=27), sendo que 34 (77,2%) estavam em TRE. Considerando a amostra total de pacientes tratados, houve diferença significativa em relação aos domínios capacidade funcional (p=0,036) e estado geral de saúde (p=0,030), sugestiva de melhor QV na DG. Doença de Gaucher: quinze pacientes estavam recebendo TRE com imiglucerase (DG tipo I= 14; DG tipo III= 1; μ tratamento= 8,5±2,5 anos). O domínio com maior pontuação foi saúde mental (μ= 77,3±9,7 para o grupo com TRE, e 72,0±10,8, para o grupo sem TRE); o domínio com menor pontuação foi vitalidade (μ= 67,7±19,9) para o grupo com TRE, e aspectos emocionais (μ= 38,8±44,7) para o grupo sem TRE. A comparação dos pacientes com e sem TRE mostrou que os mesmos diferem somente no domínio “dor” (p= 0,036), cujo escore foi maior entre os pacientes tratados. Doença de Fabry: oito pacientes estavam recebendo TRE com alfagalsidase e 4 com betalgasidase (μ tratamento= 3,5±2,2 anos). Considerando somente os pacientes do sexo masculino (n=10, todos em TRE), o domínio que apresentou maior pontuação foi aspectos emocionais (μ= 66,6±39,4) e o que apresentou menor pontuação foi aspectos físicos (μ= 45,0±40,0. Não foi encontrada diferença estatisticamente significativa entre os grupos recebendo alfagalsidase ou betalgasidase. Para os indivíduos do sexo feminino (n=4, dois em TRE), o domínio que apresentou maior pontuação foi aspectos sociais (μ= 89,8±6,0) e o que apresentou menor pontuação foi estado geral de saúde (μ= 62,2±27,4). Mucopolissacaridoses: nove pacientes foram incluídos (MPS I=3; MPS II=2 MPSIV A= 2, MPS VI=2), sendo que 7 estavam em TRE (MPS I=3; MPS II=2, MPS VI=2; μ tratamento= 4,2 ±2,3 anos). Considerando os pacientes em TRE, a média de pontuação dos domínios variou de 71,4±45,7 (aspectos físicos) a 44,1±21,7 (dor), sendo que em 4 domínios a média foi superior a 60..Entre os pacientes sem TRE, o domínio que apresentou maior pontuação foi aspectos sociais (média= 93,5±6,25) e o que apresentou menor pontuação foi vitalidade (média= 37,5±17,5), sendo que em 5 domínios a média foi superior a 60. Discussão/Conclusão: Embora os nossos achados sejam limitados pelo tamanho amostral, eles sugerem a TRE com imiglucerase tem efeito benéfico na dor apresentada pelos pacientes com DG, e que estes pacientes apresentam melhor QV quando comparados aos pacientes com DF e MPS. Em relação à DF, os escores obtidos foram maiores nas heterozigotas, o que pode ser explicado pela doença ser ligada ao X. Parece existir diferenças tipo-específicas na QV de pacientes com MPS. Estudos adicionais devem ser realizados para confirmar estes achados.
Introduction: Gaucher (GD) and Fabry (FD) disease and mucopolysaccharidosis are the most frequent types of lysosomal storage diseases (LSD) treatable with enzyme replacement therapy (ERT). In Brazil, no data are currently available about the quality of life (QoL) of patients with LSD. Objective: To evaluate QoL in a sample of Brazilian patients with GD, FD and MPS using the SF-36 survey. Method: Observational cross-sectional study. The SF-36 survey was administered to cognitively able patients 12 years or older, who were seen in the Medical Genetics Service of Hospital de Clínicas de Porto Alegre, (SGM/HCPA), Porto Alegre, Brazil. Results: Forty-four patients were included (GD = 21; FD = 14; MPS = 9); mean age was 27.5 ± 13.7 years; and 34 (77.2%) were receiving ERT. The analysis of patients receiving ERT revealed a statistically significant difference in the physical function (p = 0.036) and general health (p = 0.030) domains; results suggests that QoL is better in GD. The comparison of patients with GD on ERT (n= 15) and naïve to ERT (n = 6) revealed differences only in the bodily pain domain (p = 0.036). In the analysis of patients with FD, no significant differences were found in SF-36 scores between male patients receiving agalsidase alpha (n = 7) or agalsidase beta (n = 3); heterozygous women had higher scores than hemizygous individuals. In the group of patients with MPS receiving ERT (MPS I = 3; MPS II = 2; MPS VI = 2), mean domain scores ranged from 71.4 ± 48.7 (role-physical) to 44.1 ± 23.4 (bodily pain), whereas in the group of patients not receiving ERT (MPS IV A = 2), scores ranged from 37.5 ± 24.7 (vitality) to 93.7 ± 8.8 (social functioning). Discussion and Conclusion: Although limited because of the small number of patients included, findings suggest that patients with GD receiving ERT have a better QoL than patients with FD or MPS, and that ERT with imiglucerase has a beneficial effect on pain for patients with GD. In the group of patients with FD, scores were higher in heterozygous women, which may be explained by the fact that FD is an X-linked disorder. There seem to be type-specific QoL differences in the group of patients with MPS. Further studies should be conducted to confirm our findings.

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Erceg, Vicki Heather. "Detection of behavioural and cognitive dysfunction in mucopolysaccharidosis IIIA affected dogs : a thesis presented in partial fulfilment of the requirements for the degree of Master of Veterinary Science at Massey University, Palmerston North, New Zealand". Massey University, 2009. http://hdl.handle.net/10179/1053.

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This study investigated whether behavioural and cognitive dysfunction caused by mucopolysaccharidosis (MPS) IIIA can be detected early in affected dogs’ lives, and to describe the behaviours of these dogs. No other scientific papers have been published on this topic and the population of dogs examined in this study are the only MPS IIIA affected dog colony available worldwide for study. Three main tests were performed on the population of MPS IIIA affected dogs. Physical behavioural assessment tests were performed at six and eight weeks of age and from twenty weeks of age a cognitive function task was taught and then tested to measure the dogs’ performance. A previously validated questionnaire, the canine behavioural assessment and research questionnaire (C-BARQ), was completed at three, six and twelve months of age. The researchers in these studies were blinded to the MPS IIIA status of the dogs examined. The behaviours shown by the MPS IIIA puppies at six and eight weeks of age were not significantly different from the behaviours of the unaffected puppies. This finding supported the research of other MPS IIIA studies and suggests that clinical behavioural changes do not occur at such a young age. The behaviours shown by the MPS IIIA affected puppies appeared to be normal puppy behaviours similar to those described in previous research on puppies. The C-BARQ measured the behaviours shown by the MPS IIIA affected and unaffected dogs. Most of the MPS IIIA affected dogs’ behaviours were not significantly different from the unaffected dogs’ behaviours, but MPS IIIA affected dogs did retrieve significantly more than unaffected dogs at three months of age, and were less distractible at twelve months of age. It would be worth investigating these findings further to decide whether it suggests a subtle alteration in brain functioning. The cognitive function test showed a significant decrease in the success of the MPS IIIA affected dogs in the final maze test. This is the first study on dogs affected with MPS IIIA to find a decline in cognitive function before the occurrence of cerebellar clinical signs and this new knowledge may lead to future developments measuring therapy response and disease progression. The T-shaped maze testing may be valuable in future research on cognitive function in dogs with other diseases such as epilepsy. Thus this thesis provides valuable information on canine MPS IIIA and provides a foundation for future disease investigations.

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