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Relato do primeiro paciente brasileiro com a forma infantil da doença de Pompe tratado com alfa-glicosidase recombinante humana; Report of the first Brazilian infantile Pompe disease patient to be treated with recombinant human acid alpha-glucosidase

PEREIRA, Sandra J.; BERDITCHEVISKY, Célia R.; MARIE, Suely K. N.
Fonte: Sociedade Brasileira de Pediatria Publicador: Sociedade Brasileira de Pediatria
Tipo: Artigo de Revista Científica
POR
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Objetivo: Relatar o primeiro caso de forma infantil da doença de Pompe tratado no Brasil. Descrição: Trata-se de doença de depósito lisossomal que se caracteriza por defeitos da enzima alfa-glicosidase ácida, com acúmulo intracelular de glicogênio, principalmente nos músculos. São descritas a forma infantil e tardia. Desde 2006, está disponível tratamento com enzima recombinante humana. Descreve-se o primeiro caso de forma infantil da doença tratado no Brasil. Trata-se de menina com 2,5 meses de idade e progressão rápida da doença, com perda dos movimentos dos membros, miocardiopatia hipertrófica e insuficiência respiratória aos 7 meses de idade. Após 10 meses de tratamento, apresentou boa resposta clínica, com remissão da insuficiência respiratória, recuperação parcial dos movimentos dos membros e melhora importante do quadro cardiológico. Comentários: Apesar de pouco freqüente, a forma infantil da doença de Pompe é letal. A disponibilidade de tratamento eficaz aumenta a necessidade de conhecimento e diagnóstico precoce da doença.; Objective: To describe the first case of infantile Pompe disease to be treated in Brazil. Description: Pompe disease is a glycogen storage disease related to defects in the acid alpha-glucosidase enzyme...

Pompe disease in a Brazilian series: clinical and molecular analyses with identification of nine new mutations

OBA-SHINJO, Sueli M.; SILVA, Roseli da; ANDRADE, Fernanda G.; PALMER, Rachel E.; POMPONIO, Robert J.; CIOCIOLA, Kristina M.; CARVALHO, Mary S.; GUTIERREZ, Paulo S.; PORTA, Gilda; MARRONE, Carlo D.; MUNOZ, Veronica; GRZESIUK, Anderson K.; LLERENA JR., Juan
Fonte: DR DIETRICH STEINKOPFF VERLAG Publicador: DR DIETRICH STEINKOPFF VERLAG
Tipo: Artigo de Revista Científica
ENG
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Pompe disease (glycogen storage disease type II or acid maltase deficiency) is an inherited autosomal recessive deficiency of acid alpha-glucosidase (GAA), with predominant manifestations of skeletal muscle weakness. A broad range of studies have been published focusing on Pompe patients from different countries, but none from Brazil. We investigated 41 patients with either infantile-onset (21 cases) or late-onset (20 cases) disease by muscle pathology, enzyme activity and GAA gene mutation screening. Molecular analyses identified 71 mutant alleles from the probands, nine of which are novel (five missense mutations c.136T > G, c.650C > T, c.1456G > C, c.1834C > T, and c.1905C > A, a splice-site mutation c.1195-2A > G, two deletions c.18_25del and c.2185delC, and one nonsense mutation c.643G > T). Interestingly, the c.1905C > A variant was detected in four unrelated patients and may represent a common Brazilian Pompe mutation. The c.2560C > T severe mutation was frequent in our population suggesting a high prevalence in Brazil. Also, eight out of the 21 infantile-onset patients have two truncating mutations predicted to abrogate protein expression. Of the ten late-onset patients who do not carry the common late-onset intronic mutation c.-32-13T > G...

Distribuição do tipo de fibras musculares e sua correlação genotípica na doença de Pompe; Muscle fiber type distribution and genotype correlation in the Pompe disease

Matsunaga, Erika Midoli
Fonte: Biblioteca Digitais de Teses e Dissertações da USP Publicador: Biblioteca Digitais de Teses e Dissertações da USP
Tipo: Dissertação de Mestrado Formato: application/pdf
Publicado em 27/02/2009 PT
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A doença de Pompe (GSDII), autossômica recessiva, é causada pela deficiência da enzima lisossomal que degrada o glicogênio, -glucosidase ácida (GAA). O quadro clínico varia de acordo com a idade de início da doença, grau de progressão e envolvimento dos tecidos: predominantemente cardíaco e muscular esquelético na forma de início-precoce (FIP) e mais restrito no músculo esquelético na forma de início-tardio (FIT). A sobrevida média na FIP é de 9-12 meses. Com avanço dos métodos histológicos, histoquímicos e imunoistoquímicos intensificou-se a análise estrutural e funcional dos tipos de fibras musculares. O estudo da vascularização também é de importância pelo aporte nutricional e funcional das fibras. O objetivo do presente trabalho é analisar a correlação da distribuição do tipo de fibras com a forma de apresentação clínica da doença de Pompe, seu genótipo correspondente e a quantidade residual da enzima GAA. Analisou-se 10 biópsias musculares de pacientes FIP e 09 de FIT comparados com o grupo controle, pareados por idade e gênero. Os pacientes foram selecionados segundo dados clínicos e laboratoriais, sendo feito o seqüenciamento de toda parte codificante do gene e Western Blotting (WB) com anticorpo monoclonal 15362-157...

Muscle biopsy in Pompe disease

Werneck,Lineu Cesar; Lorenzoni,Paulo José; Kay,Cláudia Suemi Kamoi; Scola,Rosana Herminia
Fonte: Academia Brasileira de Neurologia - ABNEURO Publicador: Academia Brasileira de Neurologia - ABNEURO
Tipo: Artigo de Revista Científica Formato: text/html
Publicado em 01/05/2013 EN
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Pompe disease (PD) can be diagnosed by measuring alpha-glucosidase levels or by identifying mutations in the gene enzyme. Muscle biopsies can aid diagnosis in doubtful cases. Methods: A review of muscle biopsy from 19 cases of PD (infantile, 6 cases; childhood, 4 cases; and juvenile/adult, 9 cases). Results: Vacuoles with or without glycogen storage were found in 18 cases. All cases had increased acid phosphatase activity. The vacuole frequency varied (almost all fibers in the infantile form to only a few in the juvenile/adult form). Atrophy of type 1 and 2 fibers was frequent in all forms. Atrophic angular fibers in the NADH-tetrazolium reductase and nonspecific esterase activity were observed in 4/9 of the juvenile/adult cases. Conclusion: Increased acid phosphatase activity and vacuoles were the primary findings. Most vacuoles were filled with glycogen, and the adult form of the disease had fewer fibers with vacuoles than the infantile or childhood forms.

Systemic correction of the muscle disorder glycogen storage disease type II after hepatic targeting of a modified adenovirus vector encoding human acid-α-glucosidase

Amalfitano, A.; McVie-Wylie, A. J.; Hu, H.; Dawson, T. L.; Raben, N.; Plotz, P.; Chen, Y. T.
Fonte: The National Academy of Sciences Publicador: The National Academy of Sciences
Tipo: Artigo de Revista Científica
Publicado em 03/08/1999 EN
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This report demonstrates that a single intravenous administration of a gene therapy vector can potentially result in the correction of all affected muscles in a mouse model of a human genetic muscle disease. These results were achieved by capitalizing both on the positive attributes of modified adenovirus-based vectoring systems and receptor-mediated lysosomal targeting of enzymes. The muscle disease treated, glycogen storage disease type II, is a lysosomal storage disorder that manifests as a progressive myopathy, secondary to massive glycogen accumulations in the skeletal and/or cardiac muscles of affected individuals. We demonstrated that a single intravenous administration of a modified Ad vector encoding human acid α-glucosidase (GAA) resulted in efficient hepatic transduction and secretion of high levels of the precursor GAA proenzyme into the plasma of treated animals. Subsequently, systemic distribution and uptake of the proenzyme into the skeletal and cardiac muscles of the GAA-knockout mouse was confirmed. As a result, systemic decreases (and correction) of the glycogen accumulations in a variety of muscle tissues was demonstrated. This model can potentially be expanded to include the treatment of other lysosomal enzyme disorders. Lessons learned from systemic genetic therapy of muscle disorders also should have implications for other muscle diseases...

Homozygosity for Multiple Contiguous Single-Nucleotide Polymorphisms as an Indicator of Large Heterozygous Deletions: Identification of a Novel Heterozygous 8-kb Intragenic Deletion (IVS7–19 to IVS15–17) in a Patient with Glycogen Storage Disease Type II

Huie, Maryann L.; Anyane-Yeboa, Kwame; Guzman, Edwin; Hirschhorn, Rochelle
Fonte: The American Society of Human Genetics Publicador: The American Society of Human Genetics
Tipo: Artigo de Revista Científica
EN
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Current methods for detection of mutations by polymerase chain reaction (PCR) and sequence analysis frequently are not able to detect heterozygous large deletions. We report the successful use of a novel approach to identify such deletions, based on detection of apparent homozygosity of contiguous single-nucleotide polymorphisms (SNPs). The sequence analysis of genomic DNA PCR products containing all coding exons and flanking introns identified only a single heterozygous mutation (IVS18+2t→a) in a patient with classic infantile-onset autosomal recessive glycogen storage disease type II (GSDII). Apparent homozygosity for multiple contiguous SNPs detected by this sequencing suggested presence of a large deletion as the second mutation; primers flanking the region of homozygous SNPs permitted identification and characterization by PCR of a large genomic deletion (8.26 kb) extending from IVS7 to IVS15. The data clearly demonstrate the utility of SNPs as markers for large deletions in autosomal recessive diseases when only a single mutation is found, thus complementing currently standard DNA PCR sequence methods for identifying the molecular basis of disease.

The conservative substitution Asp-645-->Glu in lysosomal alpha-glucosidase affects transport and phosphorylation of the enzyme in an adult patient with glycogen-storage disease type II.

Hermans, M M; de Graaff, E; Kroos, M A; Wisselaar, H A; Willemsen, R; Oostra, B A; Reuser, A J
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 01/02/1993 EN
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Glycogen-storage disease type II (GSDII) is caused by the deficiency of lysosomal alpha-glucosidase (acid maltase). This paper reports on the analysis of the mutant alleles in an American black patient with an adult form of GSDII (GM1935). The lysosomal alpha-glucosidase precursor of this patient has abnormal molecular features: (i) the molecular mass is decreased, (ii) the phosphorylation is deficient and (iii) the proteolytic processing is impaired. Sequence analysis revealed four mutations leading to amino acid alterations: Asp-645-->Glu, Val-816-->Ile, Arg-854-->Stop and Thr-927-->Ile. By using allele-specific oligonucleotide hybridization on PCR-amplified cDNA we have demonstrated that the Arg-854-->Stop mutation is located in one allele that is not expressed, and that the other allele contains the remaining three mutations. Each of the mutations was introduced in wild-type cDNA and expressed in COS cells to analyse the effect on biosynthesis, transport and phosphorylation of lysosomal alpha-glucosidase. The Val-816-->Ile substitution appeared to have no significant effect in contrast with results [Martiniuk, Mehler, Bodkin, Tzall, Hirshhorn, Zhong and Hirschhorn (1991) DNA Cell Biol. 10, 681-687] and was therefore defined as a polymorphism. The Thr-927-->Ile substitution deleting one of the seven glycosylation sites was found to be responsible for the decrease in molecular-mass...

Glucose 6-phosphate transport in fibroblast microsomes from glycogen storage disease type 1b patients: evidence for multiple glucose 6-phosphate transport systems.

Leuzzi, R; Fulceri, R; Marcolongo, P; Bánhegyi, G; Zammarchi, E; Stafford, K; Burchell, A; Benedetti, A
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em 15/07/2001 EN
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In liver endoplasmic reticulum the intralumenal glucose-6-phosphatase activity requires the operation of a glucose 6-phosphate transporter (G6PT1). Mutations in the gene encoding G6PT1 cause glycogen storage disease type 1b, which is characterized by a loss of glucose-6-phosphatase activity and impaired glucose homoeostasis. We describe a novel glucose 6-phosphate (G6P) transport activity in microsomes from human fibroblasts and HeLa cells. This transport activity is unrelated to G6PT1 since: (i) it was similar in microsomes of skin fibroblasts from glycogen storage disease type 1b patients homozygous for mutations of the G6PT1 gene, and in microsomes from human control subjects; (ii) it was insensitive to the G6PT1 inhibitor chlorogenic acid; and (iii) it was equally active towards G6P and glucose 1-phosphate, whereas G6PT1 is highly selective for G6P. Taken together, our results provide evidence for the presence of multiple transporters for G6P (and other hexose phosphoesters) in the endoplasmic reticulum.

Enhanced Efficacy of an AAV Vector Encoding Chimeric, Highly-Secreted Acid α-glucosidase in Glycogen Storage Disease Type II

Sun, Baodong; Zhang, Haoyue; Benjamin, Daniel K.; Brown, Talmage; Bird, Andrew; Young, Sarah P.; McVie-Wylie, Alison; Chen, Y-T; Koeberl, Dwight D.
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
EN
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Glycogen storage disease type II (GSD-II; Pompe disease; MIM 232300) is an inherited muscular dystrophy caused by deficiency in the activity of the lysosomal enzyme acid α-glucosidase (GAA). We hypothesized that chimeric GAA containing an alternative signal peptide could increase the secretion of GAA from transduced cells and enhance the receptor-mediated uptake of GAA in striated muscle. The relative secretion of chimeric GAA from transfected 293 cells increased up to 26-fold. Receptor-mediated uptake of secreted, chimeric GAA corrected cultured GSD-II patient cells. High-level hGAA was sustained in the plasma of GSD-II mice for 24 weeks following administration of an AAV2/8 vector encoding chimeric GAA; furthermore, GAA activity was increased and glycogen content was significantly reduced in striated muscle and in the brain. Administration of only 1×1010 vector particles increased GAA activity in the heart and diaphragm for >18 weeks, whereas 3×1010 vector particles increased GAA activity and reduced glycogen content in the heart, diaphragm, and quadriceps. Furthermore, an AAV2/2 vector encoding chimeric GAA produced secreted hGAA for >12 weeks in the majority of treated GSD-II mice. Thus, chimeric, highly secreted GAA enhanced the efficacy of AAV vector-mediated gene therapy in GSD-II mice.

Therapeutic approaches in Glycogen Storage Disease type II (GSDII)/Pompe disease

Schoser, Benedikt; Hill, Victoria; Raben, Nina
Fonte: PubMed Publicador: PubMed
Tipo: Artigo de Revista Científica
Publicado em /10/2008 EN
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Glycogen storage disease type II (GSDII)/Pompe disease is an autosomal recessive multi-system disorder due to a deficiency of the glycogen-degrading lysosomal enzyme, acid alpha-glucosidase (GAA). Without adequate levels of GAA, there is a progressive accumulation of glycogen inside the lysosome, resulting in lysosomal expansion in many tissues, although the major clinical manifestations are seen in cardiac and skeletal muscle. Pompe disease presents as a continuum of clinical phenotypes. In the most severe cases, disease onset is in infancy and death results from cardiac and respiratory failure within the first one or two years of life. In the milder late-onset forms, cardiac muscle is spared and muscle weakness is the primary symptom. Weakness of respiratory muscles is the major cause of mortality in these cases. Enzyme replacement therapy (ERT) with alglucosidase alfa (Myozyme@, Genzyme Corporation, Framingham, MA) is now available for all forms of GSDII. ERT has shown remarkable success in reversing pathology in cardiac muscle and extending life expectancy in infantile patients. However, skeletal muscle has proven to be a more challenging target for ERT. Although ERT is less effective in skeletal muscle than was hoped for, the lessons learned from both clinical and pre-clinical ERT studies have greatly expanded our understanding of the pathogenesis of the disease. A combination of fundamental studies and clinical follow-up...

Glycogen storage disease type II: clinical overview

Di Rocco, M; Buzzi, D; Tarò, M
Fonte: Pacini Editore SpA Publicador: Pacini Editore SpA
Tipo: Artigo de Revista Científica
Publicado em /07/2007 EN
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Glycogen storage disease type II has a broad continuous clinical spectrum in terms of onset, involvement of organs and life expectancy.

Progress in Enzyme Replacement Therapy in Glycogen Storage Disease Type II

Angelini, Corrado; Semplicini, Claudio; Tonin, Paola; Filosto, Massimiliano; Pegoraro, Elena; Sorarù, Gianni; Fanin, Marina
Fonte: SAGE Publications Publicador: SAGE Publications
Tipo: Artigo de Revista Científica
Publicado em /05/2009 EN
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Glycogen storage disease type II (GSDII) is an autosomal recessive lysosomal disorder caused by mutations in the gene encoding alpha-glucosidase (GAA). The disease can be clinically classified into three types: a severe infantile form, a juvenile and an adultonset form. Cases with juvenile or adult onset GSDII mimic limb-girdle muscular dystrophy or polymyositis and are often characterized by respiratory involvement. GSDII patients are diagnosed by biochemical assay and by molecular characterization of the GAA gene. Ascertaining a natural history of patients with heterogeneous late-onset GSDII is useful for evaluating their progressive functional disability. A significant decline is observed over the years in skeletal and respiratory muscle function. Enzyme replacement therapy (ERT) has provided encouraging results in the infantile form. It is not yet known if ERT is effective in late-onset GSDII. We examined a series of 11 patients before and after ERT evaluating muscle strength by MRC, timed and graded functional tests, 6-minute walk test (6MWT), respiratory function by spirometric parameters and quality of life. We observed a partial improvement during a prolonged follow-up from 3 to 18 months. The use of different clinical parameters in the proposed protocol seems crucial to determine the efficacy of ERT...

The role of autophagy in the pathogenesis of glycogen storage disease type II (GSDII)

Nascimbeni, A C; Fanin, M; Masiero, E; Angelini, C; Sandri, M
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
EN
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Regulated removal of proteins and organelles by autophagy–lysosome system is critical for muscle homeostasis. Excessive activation of autophagy-dependent degradation contributes to muscle atrophy and cachexia. Conversely, inhibition of autophagy causes accumulation of protein aggregates and abnormal organelles, leading to myofiber degeneration and myopathy. Defects in lysosomal function result in severe muscle disorders such as Pompe (glycogen storage disease type II (GSDII)) disease, characterized by an accumulation of autophagosomes. However, whether autophagy is detrimental or not in muscle function of Pompe patients is unclear. We studied infantile and late-onset GSDII patients and correlated impairment of autophagy with muscle wasting. We also monitored autophagy in patients who received recombinant α-glucosidase. Our data show that infantile and late-onset patients have different levels of autophagic flux, accumulation of p62-positive protein aggregates and expression of atrophy-related genes. Although the infantile patients show impaired autophagic function, the late-onset patients display an interesting correlation among autophagy impairment, atrophy and disease progression. Moreover, reactivation of autophagy in vitro contributes to acid α-glucosidase maturation in both healthy and diseased myotubes. Together...

Impaired autophagy contributes to muscle atrophy in glycogen storage disease type II patients

Nascimbeni, Anna Chiara; Fanin, Marina; Masiero, Eva; Angelini, Corrado; Sandri, Marco
Fonte: Landes Bioscience Publicador: Landes Bioscience
Tipo: Artigo de Revista Científica
Publicado em 01/11/2012 EN
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The autophagy-lysosome system is essential for muscle cell homeostasis and its dysfunction has been linked to muscle disorders that are typically distinguished by massive autophagic buildup. Among them, glycogen storage disease type II (GSDII) is characterized by the presence of large glycogen-filled lysosomes in the skeletal muscle, due to a defect in the lysosomal enzyme acid α-glucosidase (GAA). The accumulation of autophagosomes is believed to be detrimental for myofiber function. However, the role of autophagy in the pathogenesis of GSDII is still unclear. To address this issue we monitored autophagy in muscle biopsies and myotubes of early and late-onset GSDII patients at different time points of disease progression. Moreover we also analyzed muscles from patients treated with enzyme replacement therapy (ERT). Our data suggest that autophagy is a protective mechanism that is required for myofiber survival in late-onset forms of GSDII. Importantly, our findings suggest that a normal autophagy flux is important for a correct maturation of GAA and for the uptake of recombinant human GAA. In conclusion, autophagy failure plays an important role in GSDII disease progression, and the development of new drugs to restore the autophagic flux should be considered to improve ERT efficacy.

Exercise testing in late-onset glycogen storage disease type II patients undergoing enzyme replacement therapy

Marzorati, Mauro; Porcelli, Simone; Bellistri, Giuseppe; Morandi, Lucia; Grassi, Bruno
Fonte: Pergamon Press Publicador: Pergamon Press
Tipo: Artigo de Revista Científica
Publicado em 01/12/2012 EN
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Enzyme replacement therapy (ERT) has recently became available for patients with glycogen storage disease type II. Previous studies have demonstrated clinical efficacy of enzyme replacement therapy, however, data on physiological variables related to exercise tolerance are scarce. Four glycogen storage disease type II late-onset patients (45 ± 6 years) performed an incremental exercise on a cycle ergometer, up to voluntary exhaustion, before (BEFORE) and after 12 months of ERT (AFTER). Peak workload, oxygen uptake, heart rate, cardiac output (by impedance cardiography) and vastus lateralis oxygenation indices (by continuous-wave near-infrared spectroscopy, NIRS) were determined. Peak workload and oxygen uptake values significantly increased during ERT (54 ± 30 vs. 63 ± 31 watt, and 17.2 ± 4.4 vs. 19.7 ± 3.5 ml/kg/min, respectively, in BEFORE vs. AFTER). On the other hand, for both peak cardiac output (12.3 ± 5.3 vs. 14.8 ± 4.5 L/min) and the NIRS-determined peak skeletal muscle fractional O2 extraction, expressed as a percentage of the maximal values during a transient limb ischemia (30 ± 39% vs. 38 ± 28%), the observed increases were not statistically significant. Our findings suggest that in glycogen storage disease type II patients enzyme replacement therapy is associated with a mild improvement of exercise tolerance. The findings need to be validated during a longer follow-up on a larger group of patients.

Muscle-directed gene and enzyme replacement therapies for glycogen storage disorder type II, Pompe disease

Fraites, Thomas Joseph, 1974-
Fonte: Universidade da Flórida Publicador: Universidade da Flórida
Tipo: Artigo de Revista Científica Formato: xiv, 124 leaves : ill. (if no del a in ILLUS in FF) ; 29 cm.
Publicado em //2003 ENGLISH
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(Thesis) Thesis (Ph.D)--University of Florida, 2003.; (Bibliography) Bibliography: leaves 107-123.; (Additional Physical Form) Also available online.; Typescript.; Vita.; (Statement of Responsibility) by Thomas Joseph Fraites.

Induction of tolerance to a recombinant human enzyme, acid alpha-glucosidase, in enzyme deficient knockout mice

Raben, N.; Nagaraju, K.; Lee, A.; Lu, N.; Rivera, Y.; Jatkar, T.; Hopwood, J.; Plotz, P.
Fonte: Kluwer Academic Publ Publicador: Kluwer Academic Publ
Tipo: Artigo de Revista Científica
Publicado em //2003 EN
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When knockout mice are used to test the efficacy of recombinant human proteins, the animals often develop antibodies to the enzyme, precluding long-term pre-clinical studies. This has been a problem with a number of models, for example, the evaluation of gene or enzyme replacement therapies in a knockout model of glycogen storage disease type II (GSDII; Pompe syndrome). In this disease, the lack of acid alpha-glucosidase (GAA) results in lysosomal accumulation of glycogen, particularly in skeletal and cardiac muscle. Here, we report that in a GAA-deficient mouse model of GSDII, low levels of transgene-encoded human GAA expressed in skeletal muscle or liver dramatically blunt or abolish the immune response to human recombinant protein. Of two low expression transgenic lines, only the liver-expressing line exhibited a profound GAA deficiency in skeletal muscle and heart indistinguishable from that in the original knockouts. The study suggests that the induction of tolerance in animal models of protein deficiencies could be achieved by restricting the expression of a gene of interest to a particular, carefully chosen tissue.; Nina Raben, Kanneboyina Nagaraju, Alicia Lee, Nina Lu, Yesenia Rivera, Tejas Jatkar, John J. Hopwood, Paul H. Plotz

Common antigenicity for two glycosidases

Kakavanos, R.; Lehn, P.; Callebaut, I.; Meikle, P.; Parkinson-Lawrence, E.; Hopwood, J.; Brooks, D.
Fonte: Elsevier Science BV Publicador: Elsevier Science BV
Tipo: Artigo de Revista Científica
Publicado em //2006 EN
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Enzyme replacement therapy (ERT) has proven to be an effective therapy for some lysosomal storage disorder (LSD) patients. A potential complication during ERT is the generation of an immune response against the replacement protein. We have investigated the antigenicity of two distantly related glycosidases, alpha-glucosidase (Pompe disease or glycogen storage disease type II, GSD II), and alpha-L-iduronidase (Hurler syndrome, mucopolysaccharidosis type I, MPS I). The linear sequence epitope reactivity of affinity purified polyclonal antibodies to recombinant human alpha-glucosidase and alpha-L-iduronidase was defined, to both glycosidases. The polyclonal antibodies exhibited some cross-reactive epitopes on the two proteins. Moreover, a monoclonal antibody to the active site of alpha-glucosidase showed cross-reactivity with a catalytic structural element of alpha-L-iduronidase. In a previous study, in MPS I patients who developed an immune response to ERT, this same site on alpha-L-iduronidase was highly antigenic and the last to tolerise following repeated enzyme infusions. We conclude that glycosidases can exhibit cross-reactive epitopes, and infer that this may relate to common structural elements associated with their active sites.; http://www.elsevier.com/wps/find/journaldescription.cws_home/506085/description#description; Revecca Kakavanos...

Late-Onset Glycogen Storage Disease Type II (Pompe's Disease) with a Novel Mutation: A Malaysian Experience

Fu Liong, Hiew; Abdul Wahab, Siti Aishah; Yakob, Yusnita; Lock Hock, Ngu; Thong, Wong Kum; Viswanathan, Shanthi
Fonte: Hindawi Publishing Corporation Publicador: Hindawi Publishing Corporation
Tipo: Artigo de Revista Científica
EN
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Pompe's disease (acid maltase deficiency, glycogen storage disease type II) is an autosomal recessive disorder caused by a deficiency of lysosomal acid α-1,4-glucosidase, resulting in excessive accumulation of glycogen in the lysosomes and cytoplasm of all tissues, most notably in skeletal muscles. We present a case of adult-onset Pompe's disease with progressive proximal muscles weakness over 5 years and respiratory failure on admission, requiring prolonged mechanical ventilation. Electromyography showed evidence of myopathic process with small amplitudes, polyphasic motor unit action potentials, and presence of pseudomyotonic discharges. Muscle biopsy showed glycogen-containing vacuoles in the muscle fibers consistent with glycogen storage disease. Genetic analysis revealed two compound heterozygous mutations at c.444C>G (p.Tyr148∗) in exon 2 and c.2238G>C (p.Trp746Cys) in exon 16, with the former being a novel mutation. This mutation has not been reported before, to our knowledge. The patient was treated with high protein diet during the admission and subsequently showed good clinical response to enzyme replacement therapy with survival now to the eighth year. Conclusion. In patients with late-onset adult Pompe's disease, careful evaluation and early identification of the disease and its treatment with high protein diet and enzyme replacement therapy improve muscle function and have beneficial impact on long term survival.

Splicing mutations in glycogen-storage disease type II: evaluation of the full spectrum of mutations and their relation to patients' phenotypes

Zampieri, Stefania; Buratti, Emanuele; Dominissini, Silvia; Montalvo, Anna Lisa; Pittis, Maria Gabriela; Bembi, Bruno; Dardis, Andrea
Fonte: Nature Publishing Group Publicador: Nature Publishing Group
Tipo: Artigo de Revista Científica
EN
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Glycogen-storage disease type II is an autosomal recessive-inherited disorder due to the deficiency of acid α-glucosidase. A large number of mutations in the acid α-glucosidase gene have been described to date. Among them, ∼15% are variations that may affect mRNA splicing process. In this study, we have for the first time comprehensively reviewed the available information on splicing mutations of the acid α-glucosidase gene and we have evaluated their possible impact on the splicing process using different in silico approaches. Out of the 39 different GAA-sequence variations described, an in silico analysis using seven different programs showed that 97% of them are predicted to have an impact on the splicing process. Moreover, this analysis showed a quite good correlation between the impact of the mutation on the splicing process and the clinical phenotype. In addition, we have performed the functional characterization of three novel sequence variants found in Italian patients and still uncharacterized. Using a minigene system, we have confirmed their pathogenic nature. In conclusion, this study has shown that in silico analysis represents a useful tool to select mutations that affect the splicing process of the acid α-glucosidase gene and provides an updated picture of all this kind of mutations reported till now.