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)

Glycogen storage disease in the alpha-glucosidase knockout(6neo(-)/6neo(-)) (GAA KO) mouse, a model of Pompe disease, results in the pathologic accumulation of glycogen primarily within skeletal myocytes and cardiomyocytes. Intravenous administration of recombinant human alpha-glucosidase (rhGAA, Myozyme, aglucosidase alfa) can result in significant glycogen clearance from both cardiomyocytes and skeletal myocytes, however, the degree of clearance varies from one skeletal muscle type to another. We sought to determine what role muscle fiber type predominance played in this variability. To examine this question in the GAA KO mouse model we delivered intravenous doses of 100 mg/kg rhGAA on Day 1, and Day 14, and harvested a variety of fast and slow twitch muscles on Day 28. We measured glycogen clearance, muscle fiber type content and capillary density by light microscopy with computer morphometry. Recombinant human-GAA administration resulted in differential clearance of glycogen in the various muscles examined. Slow twitch-predominant muscles cleared glycogen significantly more efficiently than fast twitch-predominant muscles. There was a strong correlation between capillary density and glycogen clearance (r=0.55), suggesting that at the high doses used in this study the differential glycogen clearance observed between muscles is largely due to differential bioavailability of rhGAA regulated by blood flow.
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PMID:Differential muscular glycogen clearance after enzyme replacement therapy in a mouse model of Pompe disease. 1757 27

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. Without adequate levels of alpha-glucosidase, 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 occurs in infancy and death results from cardiac and respiratory failure within the first 1 or 2 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 Corp., Framingham, MA) is now available for all forms of glycogen storage disease type II. 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, as well as exploration of other therapies, is necessary to take treatment for glycogen storage disease type II to the next level.
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PMID:Therapeutic approaches in glycogen storage disease type II/Pompe Disease. 1901 8