Virchows Archiv

, Volume 451, Issue 4, pp 823–834 | Cite as

Cellular and tissue localization of globotriaosylceramide in Fabry disease

  • Hasan Askari
  • Christine R. Kaneski
  • Cristina Semino-Mora
  • Priya Desai
  • Agnes Ang
  • David E. Kleiner
  • Lorah T. Perlee
  • Martha Quezado
  • Linda E. Spollen
  • Brandon A. Wustman
  • Raphael SchiffmannEmail author
Original Article


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.


Glycolipids Immunohistochemistry Electron microscopy Lysosomal disorder Lysosome 



We thank the NINDS EM facility for expert technical help in the pre-embedding immunogold technique. This study was funded by the Intramural Program of the National Institute of Neurological Disorders and Stroke and the National Cancer Institute. The authors do not have financial conflict of interest that is relevant to this study. Dr. Brandon A. Wustman is employed by Amicus Therapeutics that develops pharmacological chaperones for the treatment of lysosomal diseases.


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Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Hasan Askari
    • 1
  • Christine R. Kaneski
    • 1
  • Cristina Semino-Mora
    • 2
  • Priya Desai
    • 3
  • Agnes Ang
    • 3
  • David E. Kleiner
    • 4
  • Lorah T. Perlee
    • 3
  • Martha Quezado
    • 4
  • Linda E. Spollen
    • 5
  • Brandon A. Wustman
    • 6
  • Raphael Schiffmann
    • 1
    Email author
  1. 1.Developmental and Metabolic Neurology Branch, NINDSNational Institutes of HealthBethesdaUSA
  2. 2.Laboratory of Gastrointestinal and Liver StudiesUniformed Services University of the Health SciencesBethesdaUSA
  3. 3.HistoRxNew HavenUSA
  4. 4.Laboratory of Pathology, National Cancer InstituteNational Institutes of HealthBethesdaUSA
  5. 5.Department of PathologyUniversity of Missouri Hospitals and ClinicsColumbiaUSA
  6. 6.Amicus TherapeuticsCranburyUSA

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