Plasma lyso-Gb3: a biomarker for monitoring fabry patients during enzyme replacement therapy

Hitoshi Sakuraba,Tadayasu Togawa,Takahiro Tsukimura,Hiroshi Kato

doi:10.1007/s10157-017-1525-3

Abstract

BackgroundRecently, globotriaosylsphingosine (lyso-Gb3) has attracted interest as a biomarker of Fabry disease. However, little is known regarding its utility for the evaluation of the therapeutic efficacy.MethodWe measured plasma lyso-Gb3 concentration in Japanese healthy subjects and Fabry patients by means of liquid chromatography–tandem mass spectrometry (LC–MS/MS). We determined the reference interval in Japanese (UMIN000016854), and examined the effect of enzyme replacement therapy (ERT) with recombinant α-galactosidase A (GLA) and the influence of antibodies against the enzyme on the plasma lyso-Gb3 level in Fabry patients (UMIN000017152).ResultsThe reference interval was determined to be 0.35–0.71 nmol/L, this being almost the same as the normal range in a non-Japanese population previously reported. The analysis revealed that the plasma lyso-Gb3 level was strikingly increased in classic Fabry males, and to a lesser extent in later-onset Fabry males and Fabry females. The elevation of the plasma lyso-Gb3 level was related to renal involvement in the Fabry females. ERT gave a rapid reduction in the elevated plasma lyso-Gb3 level in the classic Fabry males, and a gradual one or stabilization in most of the later-onset Fabry males and Fabry females. However, formation of antibodies against the recombinant GLA had a negative effect on the reduction of plasma lyso-Gb3.ConclusionsRegular observation of plasma lyso-Gb3 and antibodies is useful for monitoring of Fabry patients during ERT.

Highlights

Fabry disease (OMIM 301500) is an X-linked genetic disorder characterized by deficient activity of α-galactosidase A (GLA, EC 3.2.1.22)
There was a tendency that the mean plasma lyso-Gb3 level in the Fabry females who developed cardiac involvement was moderately higher than in those without it, but no statistical difference could be found between the two groups (Student’s t test, p > 0.05)
We tried to determine the reference interval of plasma lyso-Gb3 in Japanese using a sufficient number of proper samples, because it had not been previously determined, there was a report describing the mean plasma lyso-Gb3 level ± standard deviation (SD) in apparently healthy subjects (0.37 ± 0.11 nmol/L, n = 40) [6]

Summary

Introduction

Fabry disease (OMIM 301500) is an X-linked genetic disorder characterized by deficient activity of α-galactosidase A (GLA, EC 3.2.1.22). Systemic analysis revealed that Gb3 was not an ideal biomarker of this disease, because most of the later-onset Fabry males and Fabry females did not exhibit a high plasma Gb3 concentration [3]. Plasma globotriaosylsphingosine (lyso-Gb3) has attracted interest instead of Gb3 as a surrogate biomarker of Fabry disease [3], and a lot of papers reported that the plasma lysoGb3 level is increased in Fabry patients, especially in classic Fabry males [4,5,6]. We determined the reference interval in Japanese (UMIN000016854), and examined the effect of enzyme replacement therapy (ERT) with recombinant α-galactosidase A (GLA) and the influence of antibodies against the enzyme on the plasma lyso-Gb3 level in Fabry patients (UMIN000017152). Conclusions Regular observation of plasma lyso-Gb3 and antibodies is useful for monitoring of Fabry patients during ERT

Methods

Results

Conclusion