Abstract
Fabry disease is an X-linked lysosomal storage disorder caused by mutations in the GLA gene encoding the α-galactosidase A enzyme. This enzyme cleaves the last sugar unit of glycosphingolipids, including globotriaosylceramide (Gb3), globotriaosylsphingosine (lyso-Gb3), and galabiosylceramide (Ga2). Enzyme impairment leads to substrate accumulation in different organs, vascular endothelia, and biological fluids. Enzyme replacement therapy (ERT) is a commonly used treatment. Urinary analysis of Gb3 isoforms (different fatty acid moieties), as well as lyso-Gb3 and its analogues, is a reliable way to monitor treatment. These analogues correspond to lyso-Gb3 with chemical modifications on the sphingosine moiety (−C2H4, −C2H4+O, −H2, −H2+O, +O, +H2O2, and +H2O3). The effects of sample collection time on urinary biomarker levels between ERT cycles were not previously documented. The main objective of this project was to analyze the aforementioned biomarkers in urine samples from seven Fabry disease patients (three treated males, three treated females, and one ERT-naïve male) collected twice a day (morning and evening) for 42 days (three ERT cycles). Except for one participant, our results show that the biomarker levels were generally more elevated in the evening. However, there was less variability in samples collected in the morning. No cyclic variations in biomarker levels were observed between ERT infusions.
Highlights
Fabry disease (FD) (OMIM no. 301500) is an X-linked monogenic lysosomal storage disorder
The main objectives of this research project were, to evaluate if the urinary FD biomarker concentrations show statistically significant differences when sampled in the morning compared to the evening, and if the levels fluctuate periodically between Enzyme replacement therapy (ERT) infusions using bi-daily monitoring over three ERT cycles (42 days)
According to the results obtained in this study, there is no cyclic variation of the urinary Fabry disease biomarkers (Lyso-Gb3 and analogues, and Gb3) normalized to creatinine between two ERT cycles
Summary
Fabry disease (FD) (OMIM no. 301500) is an X-linked monogenic lysosomal storage disorder. FD is caused by mutations in the GLA gene encoding the α-galactosidase A enzyme (EC 3.2.1.22). The function of this glycoside hydrolase is to cleave the terminal α-galactosyl moieties from glycoproteins or glycolipids [1]. Previous results showed that FD children with the late-onset cardiac variant p.N215S mutation presented normal urinary levels of lyso-Gb3, but abnormal levels of some lyso-Gb3 analogues [14]. The analysis of urine samples from FD patients with the late-onset IVS4+919G > A cardiac variant mutation prevalent in Taiwan revealed that some lyso-Gb3 analogue levels had a positive association with the left-ventricular mass index and/or the Mainz Severity Score Index [15]. The main objectives of this research project were, to evaluate if the urinary FD biomarker concentrations show statistically significant differences when sampled in the morning compared to the evening, and if the levels fluctuate periodically between ERT infusions using bi-daily monitoring over three ERT cycles (42 days)
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