Is globotriaosylceramide a useful biomarker in Fabry disease?

Abstract

Aim: The aim of this study was to determine whether globotriaosylceramide (Gb3) is a useful biomarker in Fabry disease. Methods: The levels of Gb3 were measured in plasma and urine by tandem mass spectrometry in untreated hemizygotes and heterozygotes with Fabry disease and in healthy controls, and the levels were monitored in patients on treatment with enzyme replacement therapy (ERT). Results: Hemizygotes with classic Fabry disease showed elevated levels of Gb3 in both plasma and urine and could readily be distinguished from normal controls. Male patients with the N215S mutation had normal levels in their plasma but 50% had marginally elevated levels in their urine. Thirty‐three percent of proven heterozygotes had elevated Gb3 concentrations in plasma but 97% of those without the N215S mutation (36/37) had an elevated level in urine. The four heterozygotes with the N215S mutation had normal Gb3 levels in urine. The level of Gb3 in plasma initially fell following the start of ERT in all patients who had an elevated level before treatment. However, in a few patients the level subsequently rose. Similar results were found for the levels of Gb3 in urine. Conclusion: Gb3 is not an ideal marker of Fabry disease or the response to treatment in all patients. Plasma and urine levels of Gb3 cannot be used as a marker of Fabry disease in patients with the N215S mutation and many heterozygotes do not have elevated Gb3 levels in plasma. The urine concentration is more informative in heterozygotes and can be used as a measure of the response to therapy. The fall in Gb3 levels in patients receiving ERT was not sustained in some patients, despite a clinical improvement. Additionally, Gb3 cannot be used to monitor the response to treatment in patients who initially have normal plasma and urine concentrations of this glycolipid.

Elevated globotriaosylsphingosine is a hallmark of Fabry disease

“…The absence of infantile manifestations in Fabry patients completely lacking ␣-galactosidase A activity indicates that Gb3 accumulation does not cause immediate, and perhaps does not even directly cause, signs of disease. Consistent with this notion, plasma or urinary levels of Gb3 in neither hemizygotes nor heterozygotes correlate with the severity of disease manifestations (12,15,16). Plasma Gb3 concentrations in some presymptomatic boys may exceed those in symptomatic adult hemizygotes.…”

A Fast Determination of Globotriaosylsphingosine in Plasma for Screening Fabry Disease Using UPLC-ESI-MS/MS

“…23 The deacylated Gb3 analogue lyso-Gb3 was found remarkably in high amount in plasma and urine of Fabry disesase patient, lyso-Gb3 could be a potential biomarker for the diagnosis and monitoring of Fabry disease. 9,10,18 So far ERT is the only treatment available for Fabry disease however a new approach for the treatment of Fabry disease was investigated using pharmacological chaperone therapy and found to be effective.…”

Changes in plasma and urine globotriaosylceramide levels do not predict Fabry disease progression over 1 year of agalsidase alfa

“…[2][3][4] Plasma Gb 3 concentration has been found to be consistently elevated in hemizygous males with classic Fabry disease but variably elevated in some variant hemizygous males with residual enzyme activity and in heterozygous females. 5,6 No evidence has been published supporting the use of plasma or urine Gb 3 concentrations as a biomarker for disease progression or response to treatment. For patients with elevated plasma or urine Gb 3 concentrations before treatment, enzyme replacement therapy (ERT) results in an initial drop in Gb 3 concentrations.…”

“…For patients with elevated plasma or urine Gb 3 concentrations before treatment, enzyme replacement therapy (ERT) results in an initial drop in Gb 3 concentrations. 5,7 The lower Gb 3 concentrations do not remain low in all patients and do not always coincide with clinical improvement. 8 Biomarkers are generally defined as measurements that reflect the activity of a disease process 9 and can be (i) prognostic, (ii) predictive, or (iii) pharmacodynamic.…”