Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.2.1.20 (alpha-glucosidase)
4,237 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The present study examines the role of cardiac lysosomal enzymes in the pathogenesis of the cardiomyopathy that develops in genetically diabetic C57BL/KsJ db+/db+ mice. Db+/db+ mice and littermate controls were sacrificed as age-matched pairs between 5-26 weeks of age. C57BL/6J ob/ob mice and littermates served as other controls. The hearts were excised, homogenized, and the following enzymatic activities measured: N-Acetyl-beta-glucosaminidase, N-acetyl-beta-galactosaminidase, beta-glucosaminidase, aryl sulphatase, alpha-mannosidase, alpha-glucosidase, beta-galactosidase, beta glucosidase, total p-nitrophenyl phosphatase, acid phosphatase and 5'-phosphodiesterase type IV. There is a progressive decrease in cardiac lysosomal enzyme activities of db+/db+ mice for the period 5-21 weeks of age. All enzyme activity is depressed significantly during the 9-21 week interval with beta-glucuronidase, aryl sulphatase and beta-glucosidase decreased about 40-50%. The decrease in lysosomal enzyme activity can explain the accumulation of large residual bodies and interstitial material in the myocardium of the db+/db+ animals
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PMID:Lysosomal enzymes in experimental diabetic cardiomyopathy. 678 Feb 37

The purpose of the present study was to determine the role of cardiac lysosomal enzymes in the pathogenesis of the cardiomyopathy that develops in the genetically diabetic C57BL/KsJ db+/db+ mice. Db+/db+ mice and littermate controls were sacrificed as age-matched pairs between 5 and 26 weeks of age. C57BL/6J ob/ob mice and littermates served as other controls. Following anesthesia, the hearts were excised, homogenized, and the following enzymatic activities measured: N-acetyl-beta-glucosaminidase, N-acetyl-beta-galactosaminidase, beta-glucosaminidase, aryl sulfatase, alpha-mannosidase, alpha-glucosidase, beta-galactosidase, beta-glucosidase, total rho-nitrophenyl phosphatase, acid phosphatase. and 5'-phosphodiesterase type IV. There is a progressive decrease in cardiac lysosomal enzyme activities of db+/db+ mice for the period 5 to 21 weeks of age. All enzyme activity is depressed significantly during the 9- to 21-week interval: alpha-glucosidase, beta-glucosidase, alpha-mannosidase, beta-galactosidase, acid phosphatase, N-acetyl-beta-galactosaminidase, 5'-phosphodiesterase type IV, and total rho-nitrophenyl phosphatase are reduced approximately 10 to 20 per cent, whereas beta-glucosaminidase, aryl sulfatase, and N-acetyl-beta-glucosaminidase are decreased almost 40 to 50 per cent. In contrast, cardiac lysosomal enzymic activity in the ob/ob mice does not differ significantly from controls aside from aryl sulfatase (20 per cent decrease) and beta-glucosidase (10 per cent decrease). This decrease in lysosomal enzyme activity can explain the accumulation of large residual bodies and interstitial material that occurs in the myocardium of the db+/db+ animals as part of the cardiomyopathy.
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PMID:Lysosomal enzymes in the heart of the genetically diabetic mouse. 742 Nov 26

We describe a boy with an early lethal hypertrophic vacuolar cardiomyopathy of neonatal onset. Abnormal intra- and extralysosomal glycogen storage disease was demonstrated in heart and skeletal muscles. Glycogen content was twice the normal in muscles and over 3-fold the normal in the heart. In this organ, over 50% of the intracellular space was occupied by glycogen and possibly oligosaccharides, as demonstrated by the quantitative morphometric analysis of electron micrographs. The activity of acid alpha-glucosidase was increased in the heart, skeletal muscles, and liver, but was normal in leukocytes. A review of the 11 previously published pedigrees of lysosomal glycogen storage disease with normal in vitro alpha-glucosidase activity allows the delineation of three clinical entities: juvenile and neonatal pseudo-Pompe diseases and partial Pompe disease. Partial Pompe disease, due to the tissue-specific absence of acid alpha-glucosidase, was observed in a single patient. The most common form is the late-onset pseudo-Pompe disease, which is characterized by severe cardiomyopathy and mild myopathy appearing in the second or third decade, prominent arrhythmia with Wolf-Parkinson-White syndrome, and sometimes mental retardation. Patients reported as suffering from Antopol disease probably belong to this group. Dominant inheritance (autosomal or X linked) is likely in most families. The present report appears to be the first one to describe a rapidly fatal neonatal form of lysosomal glycogenosis without acid maltase deficiency. The mode of inheritance of this form is not known. Differential diagosis includes Pompe disease (similar histology) and cardiac phosphorylase b kinase deficiency (similar clinical course). The delineation of neonatal pseudo-Pompe disease makes enzymatic confirmation mandatory in each case suspected of Pompe disease.
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PMID:Nosology of lysosomal glycogen storage diseases without in vitro acid maltase deficiency. Delineation of a neonatal form. 938 33

Glycogen storage disease type II (GSDII) is a recessively inherited disorder caused by defects in lysosomal acid alpha-glucosidase. In an attempt to reproduce the range of clinical manifestations of the human illness we have created null alleles at the acid alpha-glucosidase locus (GAA) with several gene targeting strategies. In each knockout strain, enzyme activity was completely abolished and glycogen accumulated at indistinguishable rates. The phenotypes, however, differed strikingly. Acid alpha-glucosidase deficiency on a 129xC57BL/6 background resulted in a severe phenotype with progressive cardiomyopathy and profound muscle wasting similar to that in patients with glycogen storage disease type II. On a 129/C57BL/6xFVB background, homozygous mutants developed a milder phenotype with a later age of onset. Females were more affected than males irrespective of genetic background. As in humans with glycogen storage disease type II, therefore, other genetic loci affect the phenotypic expression of a single gene mutation.
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PMID:Modulation of disease severity in mice with targeted disruption of the acid alpha-glucosidase gene. 1083 56

Pompe's disease is a fatal muscular disorder caused by lysosomal alpha-glucosidase deficiency. In an open-label study, four babies with characteristic cardiomyopathy were treated with recombinant human alpha-glucosidase (rhGAA) from rabbit milk at starting doses of 15 mg/kg or 20 mg/kg, and later 40 mg/kg. The enzyme was generally well tolerated. Activity of alpha-glucosidase normalised in muscle. Tissue morphology and motor and cardiac function improved. The left-ventricular-mass index decreased significantly. We recommend early treatment. Long-term effects are being studied.
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PMID:Recombinant human alpha-glucosidase from rabbit milk in Pompe patients. 1097 74

Acid alpha-glucosidase, the product of a housekeeping gene, is a lysosomal enzyme that degrades glycogen. A deficiency of this enzyme is responsible for a recessively inherited myopathy and cardiomyopathy, glycogenesis type II. We have previously demonstrated that the human acid alpha-glucosidase gene expression is regulated by a silencer within intron 1, which is located in the 5'-untranslated region. In this study, we have used deletion analysis, electrophoretic mobility shift assay, and footprint analysis to further localize the silencer to a 25-base pair element. The repressive effect on the TK promoter was about 50% in both orientations in expression plasmid, and two transcriptional factors were identified with antibodies binding specifically to the element. Mutagenesis and functional analyses of the element demonstrated that the mammalian homologue 1 of Drosophila hairy and Enhancer of split (Hes-1) binding to an E box (CACGCG) and global transcription factor-YY1 binding to its core site function as a transcriptional repressor. Furthermore, the overexpression of Hes-1 significantly enhanced the repressive effect of the silencer element. The data should be helpful in understanding the expression and regulation of the human acid alpha-glucosidase gene as well as other lysosomal enzyme genes.
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PMID:Transcriptional regulation of the human acid alpha-glucosidase gene. Identification of a repressor element and its transcription factors Hes-1 and YY1. 1103 50

Glycogen storage disease type II (GSD-II) is a lethal, autosomal recessive metabolic myopathy caused by a lack of acid-alpha-glucosidase (GAA) activity in the cardiac and skeletal muscles. Absence of adequate intralysosomal GAA activity results in massive amounts of glycogen accumulation in multiple muscle groups, resulting in morbidity and mortality secondary to respiratory embarrassment and/or cardiomyopathy. In a mouse model of GSD-II, we demonstrate that infection of the murine liver with a modified adenovirus (Ad) vector encoding human GAA (hGAA) resulted in long-term persistence of the vector in liver tissues for at least 6 months. Despite both a rapid shutdown of hGAA mRNA expression from the vector, as well as the elicitation of anti-hGAA antibody responses (hGAA is a foreign antigen in this model), the hGAA secreted by the liver was taken up by all muscle groups analyzed and, remarkably, persisted in them for at least 6 months. The persistence of the protein also correlated with long-term correction of pathologic intramuscular glycogen accumulations in all muscle groups tested, but most notably the cardiac tissues, which demonstrated a significantly decreased glycogen content for at least 190 days after a single vector injection. The results suggest that gene therapy strategies may have the potential to significantly improve the clinical course for GSD-II patients.
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PMID:Long-term efficacy after [E1-, polymerase-] adenovirus-mediated transfer of human acid-alpha-glucosidase gene into glycogen storage disease type II knockout mice. 1138 60

Acid alpha-glucosidase (GAA) is a lysosomal enzyme that degrades glycogen. A deficiency of GAA is responsible for a recessively inherited myopathy and cardiomyopathy, glycogenosis type II. Previously, we identified an intronic repressor element in the GAA gene and demonstrated that Hes-1, a basic helix-loop-helix factor, binds to a C class E box within the element and functions as a transcriptional repressor in HepG2 cells. Hes-1 is a well studied downstream target gene in the Notch signaling pathway. In this study, over-expression and depletion of Notch-1 intracellular domain (NICD) strategies were used to investigate whether expression of the GAA gene is under the control of Notch-1/Hes-1 signaling. In co-transfection experiments, Hes-1, up-regulated by over-expressed NICD, enhanced the repressive effect of the DNA element with wild type Hes-1 binding sites but not with mutant Hes-1 binding sites. Conversely, depletion of Notch-1 with phosphorothioated antisense oligonucleotides, corresponding to the fourth ankyrin repeat within NICD, led to reduced Hes-1. Constitutively over-expressed Hes-1 and Notch-1 repressed GAA gene expression. Therefore, our data establish that the human GAA gene, encoding a lysosomal enzyme, is a downstream target of the Notch-1/Hes-1 signaling pathway.
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PMID:The human acid alpha-glucosidase gene is a novel target of the Notch-1/Hes-1 signaling pathway. 1206 98

The development and recent approval of recombinant acid alpha-glucosidase for enzyme replacement therapy have been major milestones in Pompe disease research. Acid alpha-glucosidase is the enzyme responsible for degradation of glycogen polymers to glucose in the acidic milieu of the lysosomes. Cardiac and skeletal muscles are the two major tissues affected by the accumulation of glycogen within the lysosomes. Both cardiomyopathy and skeletal muscle myopathy are observed in patients with complete enzyme deficiency; this form of the disease is fatal within the first year of life. Skeletal muscle myopathy eventually leading to respiratory insufficiency is the predominant manifestation of partial enzyme deficiency. The recombinant enzyme alglucosidase alfa is the first drug ever approved for this devastating disorder. This review discusses the benefits and the shortcomings of the new therapy.
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PMID:Acid alpha-glucosidase deficiency (Pompe disease). 1721 57

Pompe disease is a rare autosomal recessive myopathy due to the deficiency of lysosomal acid alpha-glucosidase. Clinical phenotypes range from the severe classic infantile form (hypotonia and hypertrophic cardiomyopathy), to milder late onset forms (skeletal myopathy and absence of significant heart involvement). Enzyme replacement therapy with recombinant human alpha-glucosidase derived from either rabbit milk or Chinese hamster ovary cells has been introduced and is undergoing clinical trials. Reported is a long-term follow-up of 3 Pompe patients presenting without cardiomyopathy, treated with recombinant human alpha-glucosidase derived from Chinese hamster ovary cells. This study suggests that enzyme replacement therapy can lead to significant motor and respiratory improvement in the subgroup of patients who start the therapy before extensive muscle damage has occurred. The recombinant enzyme derived from Chinese hamster ovary cells, administered at doses significantly higher than previously reported, appears to have the same safety as the drug derived from rabbit milk.
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PMID:Long-term enzyme replacement therapy for pompe disease with recombinant human alpha-glucosidase derived from chinese hamster ovary cells. 1769 63


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