Thesis (Ph.D.)--University of Melbourne, Dept. of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences, 2010. / Typescript. Includes bibliographical references (p. 101-111)

Thesis (Ph. D.)--University of Missouri--Columbia, 2002. / "December 2002." Typescript. Vita. Includes bibliographical references (leaves 143-155). Also available on the Internet.

Orientador: Gabriel Hessel / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-09T01:55:34Z (GMT). No. of bitstreams: 1 Banin_MarciaRegina_M.pdf: 2211563 bytes, checksum: e16e20135efbf828907adc92ed40ba6b (MD5) Previous issue date: 2007 / Resumo: Racional - As doenças de depósito de glicogênio compreendem um grupo de doenças geneticamente determinadas e classificadas em 11 tipos, de acordo com as deficiências enzimáticas identificadas. Há pouca informação sobre a evolução dessas doenças. Objetivos - Descrever as características clínicas e laboratoriais, na admissão e evolução, de pacientes com doença de depósito de glicogênio. Pacientes e métodos ¿ Participaram do estudo 22 pacientes com diagnóstico de glicogenose hepática, sendo 11 (50%) do sexo feminino. O estudo foi descritivo e longitudinal. A ficha de coleta de dados constituiu-se de informações iniciais de: quadro clínico, peso, estatura, índice de massa corporal (IMC) e resultados dos exames laboratoriais (hemograma, enzimas hepáticas, colesterol total e frações, triglicérides, glicemia, ácido úrico, uréia e creatinina). Selecionou-se os momentos 1 (admissão), 3 (12 meses de evolução) e 7 (36 meses de evolução) para coleta dos seguintes dados: peso, estatura, IMC, ácido úrico, glicemia, colesterol e triglicérides. Também, foram comparados os resultados de antropometria e exames bioquímicos dos pacientes em dois momentos: admissão e última consulta. Para as variáveis peso e estatura, calculou-se o Z escore sendo considerado déficit quando o valor se situava abaixo do segundo desvio padrão. A velocidade de crescimento foi calculada a partir da 2ª e 1ª consulta (V1) e a partir da última e penúltima consulta (V2). A taxa de aderência foi determinada pela porcentagem de absenteísmo das consultas da seguinte forma: boa: se absenteísmo menor que 20%; regular: se absenteísmo entre 20% e 40% e ruim: se absenteísmo maior que 40%. Utilizou-se como teste estatístico a análise de variância e os testes de Kruskal-Wallis, Mann-Whintney e Wilcoxon, sendo o nível de significância adotado de 5%. Resultados - A média da idade de início dos sintomas foi de 10,7 meses e do diagnóstico de 28,18 meses. O tempo médio de seguimento foi de 105 meses. As manifestações clínicas iniciais mais freqüentes foram: hepatomegalia em 21 (95%), abdômen protuberante em 19 (86%), face de boneca em 14 (64%), diarréia em 10 (45%) e história de hipoglicemia em 8(36%). Nos exames laboratoriais, observou-se, na maioria dos casos, aumento das enzimas hepáticas, hipercolesterolemia, hipertrigliceridemia e hipoglicemia. Na admissão, o déficit de peso/idade foi de 26% (5/19) e de estatura/idade foi de 35% (7/20). Não houve diferença estatística na comparação do Z escore de peso/idade, estatura/idade, índice de massa corporal e exames laboratoriais na admissão, com 12 e 36 meses. Entre a admissão e a última consulta, observou-se diferença significativa no índice de massa corporal, enzimas hepáticas, glicemia e triglicérides, o que não aconteceu com Z escore de peso/idade, estatura/idade e os exames de ácido úrico e colesterol. A taxa de aderência foi considerada boa em 64% dos pacientes. Na comparação da velocidade de crescimento, observou-se tendência de aumento comparando V1 com V2. Conclusões ¿ Houve demora no encaminhamento ao centro de referência para o diagnóstico das glicogenoses. As manifestações clínicas mais freqüentes foram abdômen protuberante e hepatomegalia e as alterações laboratoriais mais significativas foram a elevação dos triglicérides, colesterol e diminuição da glicemia. Na evolução, não houve diferença nos parâmetros antropométricos, mas uma tendência de melhora de velocidade de crescimento. O tratamento melhorou o desarranjo metabólico / Abstract: Background ¿ Glycogen storage diseases comprise a group of genetic diseases determined and classified into 11 types, according to the identified enzymatic deficiency. There is little information regarding the disease evolution. Aim ¿ Describe clinical and laboratorial characteristics in the admission and evolution of patients with glycogen storage disease. Patients and methods ¿ Twenty-two patients with hepatic glycogen diagnosis participated in the study, 11 (50%) of which were female. The study was descriptive and longitudinal. The collected data file consisted of admission information: clinical features, weight, height, body mass index (BMI) and laboratorial exam results: hemogram, hepatic enzymes, total cholesterol and fractions, triglycerides, glycemia, uric acid, urea and creatin. Afterwards, the following phases were selected: 1 (admission), 3 (12 months of evolution) and 7 (36 months of evolution) for the weight, height, BMI and laboratorial tests: uric acid, glycemia, total cholesterol and triglycerides. The antropometric data, hepatic enzymes and mentioned tests were compared during 2 moments: admission and last appointment of each patient. The score Z was utilized to evaluate the weight and height of patients, considered if the standard deviation was under 2. The growth velocity was calculated among the second and first consult and the last and the penultimate consult. The adherence percentage was determined by the appointment absence percentage: Good: absenteeism minor 20%; regular: absenteeism major 20% and minor 40%; bad: absenteeism major 40%. The statistical tests applied were ANOVA, Kruskal-Wallis, Mann-Whintney, and Wilcoxon. The significance level was 5%. Results - The mean time during the first symptoms was 10,73 months and the mean time up to diagnosis was 28,18 months. The mean time of follow-up was 105 months. The most frequent initial clinical manifestations were: hepatomegaly in 21 (95%), protuberant abdomen in 19 (86%), doll face in 14 (64%), diarrhea in 10 (45%) and history hypoglycemia in 8 (36%). In the admission the deficit of the weight to age was 26% (5/19) and height to age was 35% (7/20), In the initial biochemical tests showed elevation of hepatic enzymes, hypercholesterolemia, hypertriglyceridemia, hypoglycemia. There was no statistical difference among the score Z weight to age, score Z height to age, body mass index and laboratorial tests of admission within 12 and 36 months. Significant differences were observed in BMI, hepatic enzymes, glycemia and triglycerides between the first and the last appointments, opposing to the score Z weight to age, score Z height to age, uric acid and cholesterol exam results. In the comparison of the growth velocity there was elevation tendency between the V1 and V2. There was difference significative of the growth velocity among the first and second versus the penultimate and the last consult. The adherence percentage was considered good in 64%. Conclusions - The patients delayed in seeking the reference center for glycogenosis early diagnosis. The most frequent clinical manifestations were protuberant abdomen, hepatomegaly, elevation of triglycerides and cholesterol, and glycemia reduction. In the evolution, there wasn¿t difference statistic in the antropometric parameters, but there was improvement tendency on the growth velocity. The treatment has improved the metabolic derangement / Mestrado / Saude da Criança e do Adolescente / Mestre em Saude da Criança e do Adolescente

G6Pase-alpha and G6Pase-beta share kinetic properties and active site structures, which lie on the luminal side of the endoplasmic reticulum (ER). For hydrolysis of G6P to glucose, G6Pase-alpha or G6Pase-beta must couple with an ubiquitously expressed ER-transmembrane protein, the G6P transporter (G6PT) that translocates G6P from the cytoplasm into the lumen of the ER. The primary role of the G6Pase/G6PT complex is therefore to provide endogenous glucose to the ER lumen. The essential role of the G6Pase-alpha/G6PT complex in glucose homeostasis has been well established, and the deficiencies in G6Pase-alpha and G6PT cause glycogen storage disease type Ia (GSD-Ia) and GSD-Ib, respectively. Both patients manifest the same metabolic phenotype of disturbed glucose homeostasis. While the metabolic abnormalities of GSD-Ia and GSD-Ib are almost identical, GSD-Ib patients exhibit neutropenia and myeloid dysfunctions which are not observed in GSD-Ia patients. Since G6Pase-beta and G6PT share an ubiquitous expression pattern, we hypothesized that the G6Pase-beta/G6PT complex might be functional in neutrophils and that the myeloid defects in GSD-Ib are due to the loss of activity of that complex. To test this hypothesis, we generated G6Pase-beta-deficient (G6pc3 --/--) mouse strains and showed that G6pc3--/-- mice manifest neutropenia; defects in neutrophil respiratory burst, chemotaxis, and calcium flux; and increased susceptibility to bacterial infection mimicking GSD-Ib patients. Consistent with this, G6pc3--/-- neutrophils exhibit enhanced ER stress and apoptosis. Taken together, the results demonstrate that endogenous glucose production in the ER via G6P translocation and metabolism are critical for normal neutrophil functions and that an ER stress-mediated neutrophil apoptosis is one mechanism underlying myeloid dysfunctions in the G6pc3--/-- mice. / Macrophages are the abundant leukocytes in the decidua throughout pregnancy and were thought to play a vital role in decidual homeostasis, placental development, and maintenance of a successful pregnancy. We hypothesized that endogenous glucose production in the ER might also be critical for normal macrophage function and G6pc3--/-- females manifesting neutropenia, neutrophil and macrophage dysfunctions might suffer from pregnancy-associated complications. Here we show that G6pc3--/-- macrophages exhibited impaired respiratory burst activity and repressed trafficking in vivo during an inflammatory response. The litter size and pregnancy frequency were markedly reduced in female G6pc3--/-- matings as compared to female G6pc3+/--/G6pc3+/+ matings, indicative of reduced fertility. The pregnancy-associated mortality risk was greatly increased in G6pc3--/--. Pathological analyses revealed that the sick or dying G6pc3--/-- mothers were emaciated and suffered from dental dysplasia and otitis media. Consistent with this, parental male and female G6pc3--/-- mice were more neutropenic than their age-matched virgin G6pc3 --/-- mice. Taken together, our results show that macrophage dysfunction, defective macrophage trafficking, neutrophil dysfunction, and enhanced neutropenia underlie the reduced fertility and increased mortality of G6pc3--/-- mothers. / Cheung, Yuk Yin. / Advisers: Janice Chou; Kam Bo Wong. / Source: Dissertation Abstracts International, Volume: 73-03, Section: B, page: . / Thesis (Ph.D.)--Chinese University of Hong Kong, 2009. / Includes bibliographical references (leaves 92-107). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [201-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Abstract also in Chinese.

Thesis (Ph. D.)--University of Missouri--Columbia, 2002. / Typescript. Vita. Includes bibliographical references (leaves 143-155). Also available on the Internet.

Lam Ching-wan. / "May 2000." / Thesis (Ph.D.)--Chinese University of Hong Kong, 2000. / Includes bibliographical references (p. 91-101). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. Ann Arbor, MI : ProQuest Information and Learning Company, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

Indiana University-Purdue University Indianapolis (IUPUI) / Pompe disease (PD) is a rare metabolic myopathy characterized by loss of acid alpha-glucosidase (GAA), the enzyme responsible for breaking down glycogen to glucose within the lysosomes. PD cells accumulate massive quantities of glycogen within their lysosomes, and as such, PD is classified as a “lysosomal storage disease” (LSD). GAA-deficient cells also exhibit accumulation of autophagic debris. Symptoms of severe infantile PD include extreme muscle weakness, hypotonia, and hypertrophic cardiomyopathy, resulting in death before one year of age. Certain LSDs are currently being successfully treated with enzyme replacement therapy (ERT), which involves intravenous infusion of a recombinant enzyme to counteract the endogenous deficiency. ERT has been less successful in PD, however, due to ineffective delivery of the recombinant enzyme. Alternatively, specific genes deletion may reduce lysosomal glycogen load, and could thus be targeted in PD therapy development. Absence of malin (EPM2B) or laforin (EPM2A) has been proposed to impair autophagy, which could reduce lysosomal glycogen levels. Additionally, deficiency of Stbd1 has been postulated to disable lysosomal glycogen import. Furthermore, Ptg deficiency was previously reported to abrogate Lafora body formation and correct neurological abnormalities in Lafora disease mouse models and could have similar effects on PD pathologies. The goal of this study was to characterize the effects of homozygous disruption of Epm2a, Epm2b, Stbd1, and Ptg loci on total glycogen levels in PD mouse model heart tissue, as in severe infantile PD, it is accumulation of glycogen in the heart that results in fatal hypertrophic cardiomyopathy. Gaa-/- mice were intercrossed with Epm2a-/-, Epm2b-/-, Stbd1-/-, and Ptg-/- mice to generate wildtype (WT), single knockout, and double knockout mice. The results indicated that Gaa-/- hearts accumulated up to 100-fold more glycogen than the WT. These mice also displayed cardiac hypertrophy. However, deficiency of Epm2a, Epm2b, Stbd1, or PTG in the Gaa-/- background did not reveal changes of statistical significance in either heart glycogen or cardiac hypertrophy. Nevertheless, since total glycogen was measured, these deficiencies should not be discarded in future discussions of PD therapy, as increasing sample sizes and/or distinguishing cytosolic from lysosomal glycogen content may yet reveal differences of greater significance.

Abstract Present Situation: Research investigation deals with nursing care of the child with glycogen storage disease type I., as well as its diagnosis, nutritional management and complications. Glycogen storage disease (GSD) belongs among rare hereditary metabolic disorders. There are several types of GSD, divided into hepatic, myopathic and generalized forms. Early diagnosis is essential for effective treatment of the disease, the signs and symptoms of which first appear in babies soon after birth. The aim of this thesis was to describe the nursing care of the child with glycogen storage disease type I and identify the problems parents of affected children have to face. Methodology: Quantitative research method was used for empirical part of the thesis. The data collection was carried out through In-depth interviews with paediatric-ward nurses and a mother of the child with GSD type I. All interviews were audio recorded, transcribed and coded using paper-and-pencil method and finally categorized. The research sample consisted of nine paediatric-ward nurses and the mother taking care of the child with glycogen storage disease type I, also known as Gierke's disease. Selection of the sample was purposive and its size was determined by theoretical saturation of data. Results: Nursing care of children with glycogenosis type I requires regular feedings of a special diet enriched with corn starch substances to maintain the level of glycemia in the physiological range and to avoid dangerous hypoglycaemia. Problems for nursing staff mainly involve the unstable health condition of a child, fluctuating glycemia levels and limited knowledge of the disease. Parents not only worry about potential health complications of their child but they are also concerned about technical problems with feeding aids, poor recognition of hypoglycaemia and the child's mental welfare. The disease presents increased physical and emotional demands on the patient and their family. Conclusions and recommendations for practice: The thesis presents an outlook on the issue of paediatric-ward nursing care of the child with glycogen storage disease type I and indicates the common problems of the family with a child affected by the disease. The effort was to thoroughly understand the nature of the disease and to identify basic nursing care procedures which can benefit nurses in other facilities dealing with the same diagnosis. The results of the research will be presented in the magazine "Pediatrie pro praxi" in the nursing section.

Orientadores: Carlos Eduardo Steiner, Carmen Silvia Bertuzzo / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-17T18:18:42Z (GMT). No. of bitstreams: 1 Carlin_MarceloPaschoalete_M.pdf: 1614647 bytes, checksum: 62e5b428719069b2b173ab2baf51970f (MD5) Previous issue date: 2011 / Resumo: A transformação de glicogênio em glicose acontece através de reações químicas realizadas por enzimas específicas e uma deficiência em uma delas leva ao acúmulo de glicogênio, resultando em distúrbios hereditários conhecidos como doenças de depósito de glicogênio (GSD, da sigla em inglês), ou glicogenoses. A glicogenose tipo I (GSDI), responsável por mais de 90% dos casos, é causada pela deficiência de G6Pase, enzima chave na homeostase da glicose sanguínea. Seu complexo enzimático é constituído por duas subunidades (catalítica e translocase) que determinam os subtipos Ia e Ib. A GSDIa, também conhecida como doença de von Gierke, é a mais comum das GSDI com 80 a 90% dos casos e corresponde a uma deficiência na sub-unidade catalítica da G6Pase. A GSDIb é a segunda forma mais prevalente e mais grave. É resultante da deficiência da glicose-6-fosfato translocase que transporta a glicose-6-fosfato para o lúmen do retículo endoplasmático, onde a unidade catalítica da G6Pase está situada. Em ambas, a deficiência enzimática é o resultado de mutações genéticas nos genes que codificam estas enzimas, conhecidos respectivamente como G6PC e G6PT1. O diagnóstico bioquímico é recomendável caso se queira desvendar e recomendar modalidades de tratamento, porém não fornece informação suficiente para a determinação do subtipo envolvido. Para essa diferenciação é necessário análise enzimática da G6Pase. Como essa enzima não é expressa em tecidos como fibroblastos ou linfócitos, sua aferição só é possível por procedimento cirúrgico, através de biópsia hepática. Nesse contexto, a clonagem do cDNA do G6PC e G6PT1 possibilitou o rastreamento de mutações responsáveis pelos subtipos Ia e Ib, o que permite a alternativa de um diagnóstico menos invasivo baseado em técnicas de biologia molecular através de amostras de sangue. No presente estudo, treze pacientes com sintomas clínicos sugestivos de GSDIa e Ib foram investigados através do sequenciamento genético. Foram detectadas para o gene G6PC cinco alterações, incluindo, três mutações de ponto (G68R, R83C e Q347X) e dois polimorfismos (c.511G>A e c.1176T>C), todos previamente descritos. Já para o gene G6PT1 foram encontradas quatro alterações: uma mutação de ponto conhecida (G149E), uma inserção do tipo frameshift inédita na literatura especializada (c.1338_1339insT) e dois polimorfismos (c.1287G>A e c.1076-28C>T). A frequência das mutações em nosso meio é semelhante à observada na literatura, na qual a mutação R83C também é a mais frequente. Além disso, o presente estudo acrescentou a descrição de uma nova mutação. A pesquisa de ambos os genes deve ser considerado na investigação dessa condição para definir os subtipos envolvidos, pois no caso de ausência de alterações no gene 6PC, sugere-se o rastreamento no gene G6PT1. O estudo molecular dessa condição abre a possibilidade do diagnóstico precoce que é importante para estabelecer um tratamento correto aos pacientes, evitando o surgimento de complicações tardias e melhorando a qualidade de vida. Além disso, contribui para o aconselhamento genético adequado do casal podendo confirmar a estimativa do isco entre os próximos filhos e, eventualmente, permitir diagnóstico pré-natal por nálise de mutação / Abstract: Glucose transformation into glycogen is mediated by specific enzymes and a deficiency in one of them may cause glycogen accumulation, resulting in hereditary disorders known as glycogen storage diseases (GSD), or glycogenosis. Glycogenosis type I (GSDI), responsible for more than 90% of cases, is caused by deficiency of the glucose-6-phosphatase (G6Pase), the key enzyme in blood glucose homeostasis. Its enzyme complex consists of two subunits (catalytic and transporter) that determine subtypes Ia and Ib. GSDla, also known as von Gierke disease, is the most common GSDI responsible for 80 to 90% of cases and corresponds to a deficiency in the catalytic subunit of G6Pase. GSDIb is the second most prevalent but also the most severe, resulting from deficiency of lucose-6- phosphate translocase that transports glucose-6-phosphate into the lumen of the endoplasmic reticulum, where the catalytic unit of G6Pase is located. In both types, enzymatic deficiency results from genetic mutations in the genes that codify these enzymes, known as G6PC and G6PT1. Biochemical essay for GSDI is useful to confirm the diagnosis and to recommend treatment, however it does not allow the determination of the disease subtype. For this differentiation, enzymatic analysis of G6Pase is necessary. Since this enzyme is not expressed in tissues such as fibroblasts or lymphocytes, activity determination is only possible by liver biopsy. In this context, the cDNA cloning of G6PC and G6PT1 allowed the screening of mutations responsible for subtypes Ia and Ib, which gives the alternative of a less invasive diagnosis based on molecular biology techniques, using blood samples. In this study, thirteen patients with clinical symptoms suggestive of GSDIa and Ib were investigated through genetic sequencing. Five changes were detected in G6PC, including three known point mutations (G68R, R83C and Q347X) and two polymorphisms (c.511G> A and c.1176T>C). Concerning the G6PT1 gene, four changes were found: a known point mutation (G149E), a novel frameshift insertion (c.1338_1339insT) and two polymorphisms (c.1287G>A and c.1076-28C>T). The frequency of mutations in this population is similar to that observed in the literature, in which R83C is also the most frequent. Additionally, this study added a description of a new mutation. As result of this study, molecular analysis of both genes should be considered in he investigation of individuals with this GSDI in order to define the subtypes involved. Molecular analysis of G6PC and G6PT1 genes enable the achievement of positive diagnosis of GSDIa and Ib, securely without the need for liver biopsy. It also allows the differentiation of types and subtypes, which is not possible by the biochemical diagnosis. Finally, the identification of the mutation provides an additional tool for the genetic counseling (and eventually prenatal diagnosis) of the parents and other family members / Mestrado / Ciencias Biomedicas / Mestre em Ciências Médicas

Indiana University-Purdue University Indianapolis (IUPUI) / Glycogen, a branched polymer of glucose, acts as an intracellular carbon and energy reserve in many tissues and cell types. The breakdown of glycogen by hormonally regulated degradation involving the coordinated action of glycogen phosphorylase and debranching enzyme has been well studied. However, the importance of lysosomal disposal of glycogen has been underscored by a glycogen storage disorder, Pompe disease. This disease destroys tissues by over-accumulating glycogen in lysosomes due to a genetic defect in the lysosomal acid α-glucosidase. Details of the intracellular trafficking of glycogen are not well understood. Starch-binding domain-containing protein 1 (Stbd1) is a protein of previously unknown function with predicted hydrophobic N-terminus and C-terminal CBM20 carbohydrate binding domain. The protein is highly expressed in the liver and muscle, the major repositories of glycogen. Stbd1 binds to glycogen in vitro and in vivo with a preference for less branched and more phosphorylated polysaccharides. In animal models, the protein level of Stbd1 correlates with the genetic depletion of glycogen. Endogenous Stbd1 is found in perinuclear compartments in cultured mouse and rat cells. When over-expressed in cells, Stbd1 accumulates and coincides with glycogen and GABARAPL1, the autophagy protein. They form enlarged perinuclear structures which are abolished by removing the hydrophobic N-terminus of Stbd1. Stbd1, with point mutations in the CBM20 domain, retains the perinuclear localization but without concentration of glycogen in this compartment. In cells that are stably over-expressing glycogen synthase, glycogen exists as large perinuclear deposits, where Stbd1 can also be present. Removing glucose from the culture leads to a breakdown of the massive glycogen accumulation into numerous smaller and scattered deposits which are still positive for Stbd1. Furthermore, the autophagy protein GABARAPL1 co-immunoprecipates and co-localizes with Stbd1 when co-expressed in cells. Point mutation or deletion of the autophagy protein interacting region on Stbd1 eliminates the interaction and co-localization with GABARAPL1 but not the characteristic perinuclear distribution of Stbd1. We propose that Stbd1 is involved in glycogen metabolism. In particular, it participates in the vesicular transfer of glycogen to the lysosome with the recruitment of autophagy related proteins GABARAPL1 and/or GABARAP, as these vesicles mature prior to lysosomal fusion.