title: Emphysema in an adult with galactosialidosis linked to a defect in primary elastic fiber assembly.
abstract: Galactosialidosis is a lysosomal storage disorder caused by loss of function of protective protein cathepsin A, which leads to secondary deficiencies of β-galactosidase and neuraminidase-1. Emphysema has not been previously reported as a possible complication of this disorder, but we now describe this condition in a 41-year-old, non-smoking male. Our patient did not display deficiency in α-1-antitrypsin, the most common cause of emphysema in non-smokers, which brings about disseminated elastolysis. We therefore hypothesized that loss of cathepsin A activity was responsible because of previously published evidence showing it is prerequisite for normal elastogenesis. We now present experimental evidence to support this theory by demonstrating impaired primary elastogenesis in cultures of dermal fibroblasts from our patient. The obtained data further endorse our previous finding that functional integrity of the cell surface-targeted molecular complex of cathepsin A, neuraminidase-1 and the elastin-binding protein (spliced variant of β-galactosidase) is prerequisite for the normal assembly of elastic fibers. Importantly, we also found that elastic fiber production was increased after exposure either to losartan, spironolactone, or dexamethasone. Of immediate clinical relevance, our data suggest that surviving patients with galactosialidosis should have periodic assessment of their pulmonary function. We also encourage further experimental exploration of therapeutic potential of the afore-mentioned elastogenesis-stimulating drugs for the alleviation of pathological processes in galactosialidosis that could be mechanistically linked to impaired deposition of elastic fibers.
authors.affiliation: Department of Medical Genetics and the Child and Family Research Institute, University of British Columbia, Vancouver, Canada. alehman@cw.bc.ca
authors.forename: Anna
authors.initials: A
authors.lastname: Lehman
authors.forename: Andre
authors.initials: A
authors.lastname: Mattman
authors.forename: Don
authors.initials: D
authors.lastname: Sin
authors.forename: Peter
authors.initials: P
authors.lastname: Pare
authors.forename: Zheyuan
authors.initials: Z
authors.lastname: Zong
authors.forename: Alessandra
authors.initials: A
authors.lastname: d'Azzo
authors.forename: Yvan
authors.initials: Y
authors.lastname: Campos
authors.forename: Sandra
authors.initials: S
authors.lastname: Sirrs
authors.forename: Aleksander
authors.initials: A
authors.lastname: Hinek
mesh_terms: D000328:Adult; D043402:Cathepsin A / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004547:Elastic Tissue / Q000201:enzymology / Q000254:growth & development / Q000648:ultrastructure; D004549:Elastin / Q000235:genetics / Q000378:metabolism; D004646:Emphysema / Q000209:etiology / Q000473:pathology; D000071837:Fibrillins; D005347:Fibroblasts; D015870:Gene Expression / Q000235:genetics; D006801:Humans; D016464:Lysosomal Storage Diseases / Q000150:complications / Q000473:pathology; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D009439:Neuraminidase / Q000235:genetics / Q000378:metabolism; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
chemical_list: D000071837:Fibrillins; D008840:Microfilament Proteins; D004549:Elastin; D009439:Neuraminidase; D001616:beta-Galactosidase; D043402:Cathepsin A