Globotriaosylsphingosine (lyso-Gb3) and analogues in plasma and urine of patients with Fabry disease and correlations with long-term treatment and genotypes in a nationwide female Danish cohort

Introduction Recent studies showed the usefulness of globotriaosylsphingosine (lyso-Gb(3)) and related analogues, deacylated forms of globotriaosylceramide (Gb(3)), for high-risk screening, treatment monitoring and follow-up for patients with Fabry disease. Methods We evaluated Gb(3), lyso-Gb(3) and analogues using tandem mass spectrometry in 57 women with Fabry disease followed during a period of 15.4 years. Twenty-one women were never treated and 36 received treatment (agalsidase-beta, n=30; agalsidase-alfa, n=5; or migalastat, n=1). Lyso-Gb(3) and analogues at m/z (-28), (-2), (+16), (+34) and (+50) were analysed in plasma and urine. Total Gb(3) and lyso-Gb(3) analogues at m/z (-12) and (+14) were evaluated in urine while the analogue at m/z (+18) was evaluated in plasma. Results A strong correlation between plasma and urine lyso-Gb(3) and analogue levels was revealed. Plasma and urine lyso-Gb(3) and analogue levels were not statistically different between patients carrying missense (n=49), nonsense (n=6) or deletion mutations (n=2). Never treated patients had lower plasma lyso-Gb(3) and analogues at m/z (-28), (-2), (+16), (+34) and the seven urinary lyso-Gb(3) analogues compared with pretreatment levels of the treated patients. A significant reduction of plasma lyso-Gb(3) and five analogues, as well as urine Gb(3) and six lyso-Gb(3) analogues, but not lyso-Gb(3) and lyso-Gb(3) at m/z (+50), was observed post-treatment with agalsidase-beta. The same tendency was observed with agalsidase-alfa. Conclusion Women with Fabry disease who started treatment based on clinical manifestations had higher lyso-Gb(3) and analogue biomarker levels than never treated women. This indicates that a biomarker cut-off could potentially be a decision tool for treatment initiation in women with Fabry disease.

Automated summary

Recent studies have shown the utility of lyso-Gb(3) and related analogues as biomarkers for Fabry disease patients. This study found a strong correlation between plasma and urine levels of lyso-Gb(3) and analogues, with significant reductions post-treatment in treated patients compared to untreated patients. These findings suggest that biomarker cut-off levels could potentially be a useful tool for treatment initiation in Fabry disease patients.