Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.2.1.20 (alpha-glucosidase)
 4,237 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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.
 ...
PMID:Nosology of lysosomal glycogen storage diseases without in vitro acid maltase deficiency. Delineation of a neonatal form. 938 33

Acid alpha-glucosidase (GAA) deficiency causes Pompe disease, a lethal lysosomal glycogen storage disease for which no effective treatment currently exists. We investigated the endocytic process in deficient cells of human recombinant GAA produced in Chinese hamster ovary cells, and the potential of GAA-deficient Japanese acid maltase-deficient quail as a model for evaluating the enzyme replacement therapy for Pompe disease. After 24-h incubation with a single dose of recombinant enzyme, intracellular GAA and glycogen levels in deficient human fibroblasts were normalized, and this correction lasted for 7 d. The 110-kD precursor recombinant enzyme was processed to the 76-kD mature form within 24 h after uptake. Intracellular GAA levels in deficient quail fibroblasts and myoblasts were similarly corrected to their average normal levels within 24 h. Differences existed in the efficiency of endocytosis among subfractions of the enzyme, and among different cell types. Fractions with a larger proportion of precursor GAA were endocytosed more efficiently. Quail fibroblasts required a higher dose, 4200 nmol.h-1.mL-1 to normalize intracellular GAA levels than human fibroblasts, 1290 nmol.h-1.mL-1, whereas primary quail myoblasts required 2800 nmol.h-1.mL-1. In all three cell lines, the endocytosed enzyme localized to the lysosomes on immunofluorescence staining, and the endocytosis was inhibited by mannose 6-phosphate (Man-6-P) added to the culture medium. Despite structural differences in Man-6-P receptors between birds and mammals, these studies illustrate that Man-6-P receptor mediated endocytosis is present in quail muscle cells, and demonstrate the potential of acid maltase-deficient quail to test receptor mediated enzyme replacement therapy for Pompe disease.
 ...
PMID:Recombinant human acid alpha-glucosidase corrects acid alpha-glucosidase-deficient human fibroblasts, quail fibroblasts, and quail myoblasts. 950 77

Glycogen storage disease type II (GSD II, Pompe's disease), an autosomal recessive inherited disease, is caused by the deficiency of acid alpha-D-glucosidase, which results in the impaired glycogen degradation in lysosome and causes excess glycogen accumulation in lysosome. In Taiwan, the infantile form of GSD II is the most common type of glycogen storage diseases. The frequency of C1935A mutant allele is 0.8 in these Chinese patients. In this study, we analyzed four single point polymorphic markers (324, 1203, 2065, 2338) by ACRS-based RFLP We observed that the alleles possessing the C1935A mutation in 19 of 25 Chinese patients who were heterozygous or homozygous have conserved polymorphic markers, and all of C1935A mutant alleles in these patients are linked to a specific haplotype. The allele frequency of this specific haplotype in 19 Chinese patients and in 42 normal individuals is 0.95 and 0.17, respectively (P<0.005, chi2 = 66.018). This result suggests that the C1935A mutation in Chinese patients with infantile form of GSD II is due to the founder effect.
 ...
PMID:Frequent mutation in Chinese patients with infantile type of GSD II in Taiwan: evidence for a founder effect. 955 47

Acid alpha-glucosidase (GAA) cleaves the alpha1-4 and alpha1-6 glycosidic linkages of glycogen and related alpha-glucosyl substrates within lysosomes. Its deficiency results in glycogen storage disease type II (GSDII) variants including Pompe disease. To gain insight into the tissue patterns of involvement by glycogen storage in GSDII, GAA mRNA expression in mouse tissues was evaluated by Northern blot and in situ hybridization analyses. Extensive temporal and spatial variation of GAA mRNA was observed. During preterm maturation, GAA mRNA levels of whole mice progressively increased as assessed by Northern analysis. By in situ hybridization with GAA antisense mRNA, low signals were detected in most tissues throughout gestation. However, increased expression in specific cell types of different tissues was observed beginning at 16 days post coitum in developing brain neurons, primitive inner ear cells, and seminiferous tubular epithelium. In adult mice, whole-organ GAA mRNA levels were highest in brain, moderate in heart, liver, and skeletal muscle, and lowest in the series kidney > lung > testis > spleen. By in situ hybridization, the highest-intensity signals were in neurons of the central and peripheral nervous systems whereas neuroglial cells had only low-level signal. Signals of moderate intensity were in cardiomyocytes whereas low signals were in hepatocytes and skeletal muscle myocytes and very low in cells of the lungs, thymus, pancreas, spleen, and adrenal glands. However, testicular Sertoli cells and kidney tubular epithelial cells had significant signals even though surrounding cells had very low signals. The discrete temporal and spatial variations of GAA mRNA during development indicate different physiological roles for this enzyme in various cell types and developmental stages.
 ...
PMID:Murine acid alpha-glucosidase: cell-specific mRNA differential expression during development and maturation. 1023 47

We report here cDNA and genomic sequence of the bovine acidic alpha-glucosidase gene, from the initiation codon to the most 3' polyadenylation signal. The 2814-bp coding sequence predicts a 937-amino acid protein, which is highly conserved compared with the human alpha-glucosidase gene (86% and 83% identity respectively). The intron/exon boundaries are also conserved between the two species. Two mutations have been identified in Brahmans, and one in Shorthorns, that lead to generalized glycogenosis. All three mutations result in premature termination of translation. Evidence is also presented for a missense mutation segregating with the Brahman population, which is responsible for a 70-80% reduction in alpha-glucosidase activity.
 ...
PMID:The bovine alpha-glucosidase gene: coding region, genomic structure, and mutations that cause bovine generalized glycogenosis. 1072 25

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.
 ...
PMID:Modulation of disease severity in mice with targeted disruption of the acid alpha-glucosidase gene. 1083 56

Mitochondrial oxidative metabolism was examined in two infants with Pompe's disease. The clinical diagnosis was confirmed by the demonstration of intralysosomal glycogen accumulation and a deficiency of acid alpha-D-glucosidase in muscle biopsies. Light and electron microscopy studies demonstrated a normal number of mitochondria with normal ultrastructure. Spectrophotometric measurements revealed that the specific activities of citrate synthase and the partial reactions of electron transport were markedly elevated in the skeletal muscle homogenates prepared from both infants with Pompe's disease when calculated as micromoles per minute per gram wet weight of tissue. However, when respiratory chain enzyme activities were expressed relative to citrate synthase as a marker mitochondrial enzyme, a different pattern emerged, in which all Pompe muscle respiratory enzymes, except complex IV, were decreased relative to control subjects. These observations demonstrate that caution should be exercised when analyzing and interpreting data obtained from tissue homogenates in general and, in particular, in those prepared from tissues in which the wet weight of tissue may be altered, for example, by pathologic accumulation of carbohydrate or lipid.
 ...
PMID:Mitochondrial activity in Pompe's disease. 1096 71

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.
 ...
PMID:Recombinant human alpha-glucosidase from rabbit milk in Pompe patients. 1097 74

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.
 ...
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

Pompe disease is a metabolic myopathy caused by deficiency of lysosomal acid alpha-glucosidase. In this report we review the first 36 weeks of a clinical study on the safety and efficacy of enzyme therapy aimed at correcting the deficiency. Four patients with infantile Pompe disease were enrolled. They received recombinant human alpha-glucosidase from transgenic rabbit milk. The product is generally well tolerated and reaches the primary target tissues. Normalization of alpha-glucosidase activity in skeletal muscle was obtained and degradation of PAS-positive material was seen in tissue sections. The clinical condition of all patients improved. The effect on heart was most significant, with an impressive reduction of the left ventricular mass index (LVMI). Motor function improved. The positive preliminary results stimulate continuation and extension of efforts towards the realization of enzyme therapy for Pompe disease.
 ...
PMID:Enzyme therapy for pompe disease with recombinant human alpha-glucosidase from rabbit milk. 1140 45


<< Previous 1 2 3 4 5 6 7 8 9 10