Fabry disease (OMIM 301500) is an X-linked genetic disorder characterized by deficient activity of α-galactosidase A (GLA, EC 3.2.1.22). The enzymatic defect leads to systemic accumulation of glycolipids, predominantly globotriaosylceramide (Gb3) [
1]. Fabry disease is divided into three subtypes based on gender and manifestations of a patient. Typical male patients with the “classic” form of Fabry disease exhibit pain in the peripheral extremities, hypohidrosis, angiokeratomas, and corneal opacities during childhood or adolescence, and develop renal, cardiac, and cerebrovascular involvement in adulthood, and those with the “later-onset” form of the disease show milder manifestations limited to the heart and/or kidneys in adulthood without the childhood symptoms. The manifestations in “Fabry females” are more heterogeneous than in Fabry males ranging from asymptomatic to severe, depending on random X-chromosomal inactivation [
1].
Plasma Gb3 has been mainly measured as a biomarker of Fabry disease [
2]. However, 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]. Recently, 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 lyso-Gb3 level is increased in Fabry patients, especially in classic Fabry males [
4‐
6]. Furthermore, since enzyme replacement therapy (ERT) involving recombinant human GLAs produced in human fibroblasts (agalsidase alfa) and Chinese hamster ovary cells (agalsidase beta) has been successfully introduced [
7], the importance of biomarkers is increasing more and more for evaluating therapeutic efficacy and monitoring therapy. Some investigators revealed that the elevated plasma lyso-Gb3 level was reduced following ERT and the improvement of some clinical manifestations was associated with it in Fabry patients, suggesting the availability of plasma lyso-Gb3 as an indicator reflecting the efficacy of ERT [
3,
5,
8]. On the other hand, it has been reported that antibodies against recombinant GLAs produced in Fabry patients have a negative impact on the therapeutic effect of the enzymes [
9,
10]. However, there have been few studies on the relationship between antibodies and plasma lyso-Gb3. Recently, Rombach et al. investigated the impact of anti-GLA antibodies on lyso-Gb3 and the clinical outcome in Fabry patients who had received ERT, and reported that the presence of the antibodies was associated with a less drastic decrease in plasma lyso-Gb3, which may reflect the worse treatment outcome [
10]. They emphasized that this issue urgently needed to be addressed and that the findings needed to be confirmed.
Based on their report, we performed a comprehensive study on plasma lyso-Gb3 in Japanese healthy individuals and Fabry patients who had received ERT with agalsidase alfa. In this study, we first determined the reference interval for plasma lyso-Gb3 in Japanese (validation study) and then examined the effect of ERT and the influence of anti-agalsidase alfa antibodies on the plasma lyso-Gb3 concentration in Fabry patients (retrospective study).