Abstract
ABSTRACTIntroduction:Fabry disease (FD) is a disorder caused by mutations in the gene encoding for lysosomal enzyme α-galactosidase A (α-GAL). Reduced α-GAL activity leads to progressive accumulation of globotriaosylceramide (Gb3), also known as CD77. The recent report of increased expression of CD77 in blood cells of patients with FD indicated that this molecule can be used as a potential marker for monitoring enzyme replacement therapy (ERT).Objective:The purpose of this study was to evaluate the CD77 levels throughout ERT in FD patients (V269M mutation).Methods:We evaluated the fluctuations in PBMC (peripheral blood mononuclear cell) membrane CD77 expression in FD patients undergoing ERT and correlated these levels with those observed in different cell types.Results:A greater CD77 expression was found in phagocytes of patients compared to controls at baseline. Interestingly, the variability in CD77 levels is larger in patients at baseline (340 - 1619 MIF) and after 12 months of ERT (240 - 530 MIF) compared with the control group (131 - 331 MFI). Furthermore, by analyzing the levels of CD77 in phagocytes from patients throughout ERT, we found a constant decrease in CD77 levels.Conclusion:The increased CD77 levels in the phagocytes of Fabry carriers together with the decrease in CD77 levels throughout ERT suggest that measuring CD77 levels in phagocytes is a promising tool for monitoring the response to ERT in FD.
Highlights
Fabry disease (FD) is a disorder caused by mutations in the gene encoding for lysosomal enzyme α-galactosidase A (α-GAL)
The biological manifestations observed in FD come from the non-degradation of glycosphingolipids by a-GAL within the lysosomes, which results in the progressive accumulation of compounds, such as globotriaosylceramide (Gb3).[8]
We studied the levels of CD77 in leukocytes of FD patients undergoing or not enzyme replacement therapy (ERT) and in healthy controls
Summary
Fabry disease (FD) is a disorder caused by mutations in the gene encoding for lysosomal enzyme α-galactosidase A (α-GAL). The GLA gene (300644) located at position Xq22.1 on the human X chromosome constitutively encodes the lipase alpha galactosidase A enzyme (EC 3.2.1.22, a-GAL) under normal conditions.[1] Different mutations in this gene may result in a total lack or decreased activity of a-GAL, which results in Fabry Disease (FD; OMIM #301500).[2] This is a rare syndrome in which the average time between the appearance of its first symptoms (acroparesthesia, hypoor anhidrosis, angiokeratoma, abdominal pain, and Fabry-associated pain)[1,3,4,5,6] and the clinical diagnosis is approximately 15 years in men and 40 years in women.[7] The biological manifestations observed in FD come from the non-degradation of glycosphingolipids by a-GAL within the lysosomes, which results in the progressive accumulation of compounds, such as globotriaosylceramide (Gb3).[8]. The use of these biochemical parameters as trustworthy tools for monitoring the effectiveness of ERT in FD was recently questioned by studies showing that (i) there is no correlation between FD severity and Gb3 and lyso-Gb3 levels, and (ii) FD patients may display normal Gb3 and lyso-Gb3 levels in body fluids.[9,10,11,12,13]
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