Cellular and tissue localization of globotriaosylceramide in Fabry disease

The pathogenesis of Fabry disease is poorly understood. We used a variety of immunohistological techniques to localize globotriaosylceramide, the main glycolipid that accumulates in Fabry disease. Globotriaosylceramide immunoreactivity in a heterogenous pattern was present in all organs examined of...

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Bibliographic Details
Published in:Virchows Archiv : an international journal of pathology 2007-10, Vol.451 (4), p.823-834
Main Authors: ASKARI, Hasan, KANESKI, Christine R, SCHIFFMANN, Raphael, SEMINO-MORA, Cristina, DESAI, Priya, ANG, Agnes, KLEINER, David E, PERLEE, Lorah T, QUEZADO, Martha, SPOLLEN, Linda E, WUSTMAN, Brandon A
Format: Article
Language:English
Subjects:
Adult
Biological and medical sciences
Brain - metabolism
Brain - pathology
Cell Membrane - metabolism
Cell Membrane - pathology
Cell Membrane - ultrastructure
Cell Nucleus - metabolism
Cell Nucleus - pathology
Cell Nucleus - ultrastructure
Cells, Cultured
Cellular biology
Endoplasmic Reticulum - metabolism
Endoplasmic Reticulum - pathology
Endoplasmic Reticulum - ultrastructure
Errors of metabolism
Fabry Disease - etiology
Fabry Disease - metabolism
Fabry Disease - pathology
Humans
Investigative techniques, diagnostic techniques (general aspects)
Kidney - metabolism
Kidney - pathology
Lipids (lysosomal enzyme disorders, storage diseases)
Lysosomes - metabolism
Lysosomes - pathology
Lysosomes - ultrastructure
Medical sciences
Metabolic diseases
Middle Aged
Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques
Proteins
Skin - metabolism
Skin - pathology
Trihexosylceramides - metabolism
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Summary:The pathogenesis of Fabry disease is poorly understood. We used a variety of immunohistological techniques to localize globotriaosylceramide, the main glycolipid that accumulates in Fabry disease. Globotriaosylceramide immunoreactivity in a heterogenous pattern was present in all organs examined of a patient on long-term enzyme replacement therapy. In the brain, immmunopositivity was found only in the parahippocampal region. Globotriaosylceramide immunostaining was present in the cell membrane and cytoplasm of endothelial cells, even in the absence of lysosomal inclusions. In kidney tissue, globotriaosylceramide colocalized with lysosomal, endoplasmic reticulum, and nuclear markers. Pre- and postembedding immunogold electron microscopy of skin biopsies and untreated patient cultured skin fibroblasts confirmed the presence of globotriaosylceramide in the cell membrane, in various cytoplasmic structures, and in the nucleus. Control organ tissues and cultured fibroblasts from five unaffected subjects were uniformly negative for globotriaosylceramide by immunohistochemistry and immunogold electron microscopy. We conclude that a substantial amount of lysosomal and extralysosomal globotriaosylceramide immunoreactivity remains in cells and tissues even after years of enzyme replacement therapy in Fabry disease. These findings are crucial for the understanding of the disease mechanism and suggest the usefulness of immunostaining for globotriaosylceramide as a means to assess response to novel, specific therapies.
ISSN:0945-6317
1432-2307
DOI:10.1007/s00428-007-0468-6