title: Differences in the predominance of lysosomal and autophagic pathologies between infants and adults with Pompe disease: implications for therapy.
abstract: Pompe disease is a lysosomal storage disorder caused by the deficiency of acid alpha-glucosidase, the enzyme that degrades glycogen in the lysosomes. The disease manifests as a fatal cardiomyopathy and skeletal muscle myopathy in infants; in milder late-onset forms skeletal muscle is the major tissue affected. We have previously demonstrated that autophagic inclusions in muscle are prominent in adult patients and the mouse model. In this study we have evaluated the contribution of the autophagic pathology in infants before and 6 months after enzyme replacement therapy. Single muscle fibers, isolated from muscle biopsies, were stained for autophagosomal and lysosomal markers and analyzed by confocal microscopy. In addition, unstained bundles of fixed muscles were analyzed by second harmonic imaging. Unexpectedly, the autophagic component which is so prominent in juvenile and adult patients was negligible in infants; instead, the overwhelming characteristic was the presence of hugely expanded lysosomes. After 6 months on therapy, however, the autophagic buildup becomes visible as if unmasked by the clearance of glycogen. In most fibers, the two pathologies did not seem to coexist. These data point to the possibility of differences in the pathogenesis of Pompe disease in infants and adults.
authors.affiliation: Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892-1820, USA. rabenn@mail.nih.gov
authors.forename: Nina
authors.initials: N
authors.lastname: Raben
authors.forename: Evelyn
authors.initials: E
authors.lastname: Ralston
authors.forename: Yin-Hsiu
authors.initials: YH
authors.lastname: Chien
authors.forename: Rebecca
authors.initials: R
authors.lastname: Baum
authors.forename: Cynthia
authors.initials: C
authors.lastname: Schreiner
authors.forename: Wuh-Liang
authors.initials: WL
authors.lastname: Hwu
authors.forename: Kristien J M
authors.initials: KJ
authors.lastname: Zaal
authors.forename: Paul H
authors.initials: PH
authors.lastname: Plotz
mesh_terms: D000328:Adult; D001343:Autophagy / Q000502:physiology*; D002648:Child; D002675:Child, Preschool; D056947:Enzyme Replacement Therapy; D006009:Glycogen Storage Disease Type II / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008247:Lysosomes / Q000201:enzymology / Q000473:pathology*; D018485:Muscle Fibers, Skeletal / Q000473:pathology; D000520:alpha-Glucosidases / Q000172:deficiency / Q000378:metabolism / Q000627:therapeutic use
chemical_list: C509951:GAA protein, human; D000520:alpha-Glucosidases
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