#2401 Association of clinical characteristics with relative changes in plasma lyso-Gb3 levels by enzyme replacement therapy in patients with Fabry disease

Abstract Background and Aims Enzyme replacement therapy (ERT) is an established treatment for Fabry disease (FD), notably for its efficacy in reducing plasma globotriaosylceramide (Gb3) levels. FD is characterized by the accumulation of Gb3 in lysosomes, resulting in the formation of globotriaosylsphingosine (lyso-Gb3), a degradation product associated with disease severity. While numerous studies have demonstrated that ERT can reduce plasma lyso-Gb3 levels, these reductions are usually quantified in absolute terms. This study is the first to explore the relative changes in plasma lyso-Gb3 levels due to ERT and to investigate the association of these changes with patients' clinical characteristics through a retrospective analysis. Method This study included patients with FD who attended the division of Nephrology at our hospital. We excluded patients lacking sufficient clinical data or without plasma lyso-Gb3 measurements both before and after initiating ERT. We considered pre-ERT plasma lyso-Gb3 concentrations as the baseline and evaluated the relative changes at one year post-ERT and at the lowest recorded lyso-Gb3 level after ERT. These variations were compared across various clinical backgrounds to assess their correlation with clinical factors including age, gender, type of ERT medication (agalsidase α or β), and disease severity, as determined by the FASTEX score. Results This study included twelve patients with FD (5 males, 7 females). We observed significantly greater relative declining changes in plasma lyso-Gb3 concentration among males compared to females (one year: −71.9 ± 4.5% in males vs. −20.6 ± 13.7% in females, p 0.01; minimum levels: −78.5 ± 8.9% in males vs. −48.4 ± 19.6% in females, p = 0.01). No significant difference emerged in lyso-Gb3 reduction between agalsidase α and β treatments over all. One year after treatment, the relative changes in the levels were −45.1 ± 32.6% for agalsidase α and −37.7 ± 24.2% for agalsidase β (p = 0.68). The minimum levels followed suit, with −59.4 ± 26.8% for agalsidase α and −63.2 ± 15.2% for agalsidase β (p = 0.78). Lastly, the relative changes in lyso-Gb3 one year after initiating ERT were significantly associated with age (r = −0.873, p 0.001), FASTEX score (r = 0.814, p = 0.001), baseline α-galactosidase A activity (r = −0.833, p = 0.001), and baseline lyso-Gb3 levels (r = 0.877, p 0.001). Additionally, at the lowest levels, the relative changes in lyso-Gb3 showed a significant association with baseline α-galactosidase A activity (r = −0.887, p 0.001), and baseline lyso-Gb3 levels (r = 0.702, p = 0.011). Conclusion The findings of our study suggest that relative changes in lyso-Gb3 are more pronounced in male patients, those with lower baseline α-galactosidase A activity, and those with higher baseline plasma lyso-Gb3 levels. Patients exhibiting severe α-galactosidase A deficiency and more severe clinical symptoms may experience greater relative declines in plasma lyso-Gb3 concentration following ERT.