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Proteomics of specific treatment-related alterations in Fabry disease: a strategy to identify biological

David F Moore1, Oleg V Krokhin, Ronald C Beavis

  • 1Section of Neurology, Manitoba Center for Proteomics and System Biology, University of Manitoba, Winnipeg, Ontario, Canada R3C 4J5.

Proceedings of the National Academy of Sciences of the United States of America
|February 16, 2007
PubMed

Insights

Enzyme replacement therapy (ERT) for Fabry disease in children revealed significant protein changes, including decreased alpha-2-antiplasmin and increased VEGF, suggesting new insights into disease mechanisms and treatment effects.

Area of Science:

  • Biochemistry
  • Genetics
  • Metabolic Disorders

Background:

  • Fabry disease is an X-linked genetic disorder caused by alpha-galactosidase A deficiency.
  • This deficiency leads to abnormal metabolism and multisystemic complications, including renal and cardiac dysfunction, and strokes.
  • Diagnosis is often delayed despite symptom onset in childhood.

Purpose of the Study:

  • To investigate global protein changes in pediatric patients with Fabry disease before and after enzyme replacement therapy (ERT).
  • To identify potential biomarkers and understand previously unknown biological abnormalities related to Fabry disease and its treatment.

Main Methods:

  • A 6-month open-label study involving 13 children with Fabry disease receiving agalsidase alfa ERT.
  • Serum samples were analyzed using differential stable isotope labeling and nanoHPLC-tandem mass spectrometry to compare protein profiles.
  • Alternate methods confirmed low levels of specific proteins in a larger cohort.

Main Results:

  • ERT led to statistically significant decreases in five proteins: alpha(2)-HS glycoprotein, vitamin D-binding protein, transferrin, Ig-alpha-2 C chain, and alpha-2-antiplasmin.
  • Low alpha-2-antiplasmin levels correlated with increased circulating vascular endothelial growth factor (VEGF).
  • Soluble VEGF receptor-2 was elevated in patients and decreased with ERT, indicating altered angiogenesis factors.

Conclusions:

  • ERT in Fabry disease patients induces significant changes in specific serum proteins.
  • Findings suggest previously unrecognized abnormalities in fibrinolysis and angiogenesis pathways in Fabry disease.
  • The study demonstrates the feasibility of using proteomic analysis to detect treatment-specific alterations and uncover novel disease-related biological insights.

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