Plasma LysoGb3: A useful biomarker for the diagnosis and treatment of Fabry disease heterozygotes

Background: Fabry disease (FD) is a rare X-linked lysosomal storage disorder due to mutations in the cc-galactosidase A gene (CIA) that result in absent or markedly reduce alpha-galactosidase A (alpha-GalA) enzymatic activity. As a result, the major glycosphingolipid substrates, globotriaosylceramide (Gb3) and globotriaosylsphingosine (LysoGb3) accumulate in plasma, urine and tissue lysosomes. In females, the diagnosis can be complicated by the fact that 40-50% of GLA-mutation confirmed heterozygotes have normal or only slightly decreased leukocyte alpha-Ga1A activities. Recently, LysoGb3 has been appreciated as a novel FD biomarker, especially for therapeutic monitoring. Methods: Among our GIA-mutation proven FD patients, we screened 18 heterozygotes whose leukocyte alpha-GalA activity was determined at initial diagnosis. For these females, we measured their serum LysoGb3 levels using highly-sensitive electrospray ionization liquid chromatography tandem mass spectrometry. Results: We identified three unrelated females in whom the accumulating LysoGb3 was increased, whereas their leukocyte alpha-GalA activities were in the normal range. Conclusion: LysoGb3 serves as an useful biomarker to improve the diagnosis of FD heterozygotes and for therapeutic evaluation and monitoring. (C) 2016 The Authors. Published by Elsevier Inc.