Glucosylsphingosine is a key biomarker of Gaucher disease

Abstract

Gaucher disease (GD) leads to accumulation of glucosylceramide (GL1) and its deacylated lysolipid, glucosylsphingosine (lyso-GL1) which is implicated in mediating immune dysregulation and skeletal disease. The aim of our study was to assess plasma Lyso-GL1 as a biomarker of GD and its response to therapy. Plasma lyso-GL1 in 169 patients with GD type 1 (GD1) was measured by LC-MS/MS. Significant predictors of were assessed by Pearson’s correlation coefficient, Wilcoxon Mann Whitney test and multiple linear regression. Propensity scores were used to match patients on treatment mode: Enzyme Replacement Therapy (ERT) vs Eliglustat Tartrate SRT (ELI-SRT). Lyso-GL1 levels in healthy controls on average was 1.5 ng/ml (1.3 – 1.7; 95% CI). In untreated GD patients, the levels were massively elevated (180.9 ng/ml: 95% CI, 145.4 – 216.5) and ERT resulted in marked reduction (89 ng/ml: 95% CI, 69.2 – 129.4) (p<0.001). Lyso-GL1 correlated with chitotriosidase (r=0.59 p<0.001), CCL18 (r= 0.62 p <0.001), hepatomegaly (r=0.28 p<0.001), splenomegaly (r=0.27 p=0.003), splenectomy (p=0.01) and treatment mode (p<0.001). By multiple linear regression, the strongest predictors of lyso-GL1 were age (p<0.001), splenectomy (p=0.02), Chitotriosidase (p<0.001) and CCL18 levels (p=0.001). After propensity score matching to obtain comparable groups of patients on ERT vs ELI-SRT, lyso-GL1 levels were lower among patients receiving ELI-SRT by 113 ng/ml (95% CI: 136 – 90.3 ng/ml p<0.001). Plasma lyso-GL1 is a key biomarker of GD. ERT reduced lyso-GL1 levels. By propensity scoring, ELI-SRT resulted in greater reduction of lyso-GL1 than ERT.

A Review of Gaucher Disease Pathophysiology, Clinical Presentation and Treatments

“…It was recently shown to be very valuable for patient monitoring [146,147,148], but has yet to be assessed on a larger scale. Assays are recommended at the same frequency as the other biomarkers.…”

Blood lysosphingolipids accumulation in patients with parkinson's disease with glucocerebrosidase 1 mutations

“…GlcCer and its deacylated form of glucosylsphingosine (GlcSph) are markedly increased in GD patients . GlcSph levels has been demonstrated to be a highly sensitive and specific GD biomarker . Recently, lysosphingolipids (LysoSLs) have been identified as storage compounds in several sphingolipidoses, including Gaucher, Fabry, and Niemann‐Pick diseases.…”

“…A method of simultaneous LysoSL quantification by liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) has been developed . It is worth noting that GlcSph is the most prevalent plasma sphingolipid compared to GlcCer and is believed to be the most sensitive biomarker of GD …”

A HILIC‐MS/MS method for simultaneous quantification of the lysosomal disease markers galactosylsphingosine and glucosylsphingosine in mouse serum

“…Accumulated GalSph has been suggested as a biomarker for disease progression (Bradbury et al, ; Igisu & Suzuki, ; Turgeon et al, ; Whitfield, Sharp, Taylor, & Meikle, ; Zanfini et al, ; Zhu, Lopez‐Rosas, Qiu, Van Breemen, & Bongarzone, ). Moderate increase of GluSph was also found in plasma from Niemann–Pick C patients (Welford et al, ), and more strikingly in Gaucher disease resulting from glucocerebrosidase deficiency (Brady, Kanfer, Bradley, & Shapiro, ; Dekker et al, ; Murugesan et al, ; Orvisky et al, ; Rolfs et al, ). GluSph has been used for primary diagnosis and long‐term monitoring of the efficacy of therapy in Gaucher disease (Dekker et al, ; Murugesan et al, ; Rolfs et al, ).…”