Expanding the clinical utility of glucosylsphingosine for Gaucher disease

Abstract

Gaucher disease (GD) is an inherited metabolic disorder characterised by impaired catabolism of the glycosphingolipid, glucosylceramide. The deacetylated derivative, glucosylsphingosine (GluSph, lyso-Gb1) has materialised as a biomarker for GD. Further appraisal of the clinical utility of GluSph is required in terms of its prognostic power to inform disease course and pre-symptomatic testing. In this study, we show that plasma GluSph concentrations are significantly higher in GD patients with neuronopathic disease compared with nonneuronopathic disease, even in the neonatal period. A neonate diagnosed at 1 day of age (homozygous for N370S) due to an affected older sibling, returned GluSph of 70 nmol/L compared with 1070-2620 nmol/L for four neuronopathic patients diagnosed <20 days of age. Given this result shows promise for newborn screening, we developed a rapid, simple, and robust assay for GluSph in dried filter paper blood spots (DBS) and were able to detect 23 GD patients from 220 unaffected individuals. Neuronopathic GD patients also had significantly higher DBS concentrations of GluSph than their non-neuronopathic counterparts. We went on to measure GluSph in tissue extracts prepared from chorionic villus sampling and confirmed concentrations were undetectable in unaffected tissue but elevated in GD tissue demonstrating utility in the prenatal setting. Additionally, GluSph is a pharmacodynamic biomarker, revealing a precipitous drop following initiation of enzyme replacement therapy. In conclusion, GluSph is a reliable and specific biomarker for GD and shows promise for prenatal diagnosis and DBS screening programmes. K E Y W O R D Sbiomarker, dried blood spot, Gaucher disease, glucosylsphingosine, prenatal diagnosis, screening

Value of Glucosylsphingosine (Lyso-Gb1) as a Biomarker in Gaucher Disease: A Systematic Literature Review

“…Lyso-Gb1 measured in dried blood spots was found to be highly sensitive and specific for GD in a case-control study conducted in the Russian Federation [ 118 ]. Further, the diagnostic laboratory work-up by Fuller et al [ 41 ] showing the capacity of elevated plasma lyso-Gb1 to identify patients with GD with 100% sensitivity and specificity was extended successfully to testing using dried blood spots and, additionally, samples in a prenatal setting [ 119 ]. On the basis of a normal lyso-Gb1 reference interval of <0.16 pmol per dried blood spot, all patients with GD were differentiated from control samples and patients with other inherited metabolic disorders [ 119 ].…”

“…Further, the diagnostic laboratory work-up by Fuller et al [ 41 ] showing the capacity of elevated plasma lyso-Gb1 to identify patients with GD with 100% sensitivity and specificity was extended successfully to testing using dried blood spots and, additionally, samples in a prenatal setting [ 119 ]. On the basis of a normal lyso-Gb1 reference interval of <0.16 pmol per dried blood spot, all patients with GD were differentiated from control samples and patients with other inherited metabolic disorders [ 119 ]. Indeed, Saville et al report that in utero lyso-Gb1 quantitation (limit of detection, 1 pmol/mg protein) facilitates GD diagnosis in the prenatal setting [ 119 ].…”

“…On the basis of a normal lyso-Gb1 reference interval of <0.16 pmol per dried blood spot, all patients with GD were differentiated from control samples and patients with other inherited metabolic disorders [ 119 ]. Indeed, Saville et al report that in utero lyso-Gb1 quantitation (limit of detection, 1 pmol/mg protein) facilitates GD diagnosis in the prenatal setting [ 119 ]. Further, Polo et al reported a significant elevation of lyso-Gb1 in neonatal dried blood spots using a newly developed and validated assay [ 120 ].…”

“…Data from these studies additionally suggest that lyso-Gb1 concentrations measured in dried blood spots have prognostic power [ 118 , 119 ]. Plasma lyso-Gb1 concentrations were found to be significantly higher in patients with neuronopathic GD than in those with non-neuronopathic disease, even in the neonatal period [ 119 ].…”

“…Data from these studies additionally suggest that lyso-Gb1 concentrations measured in dried blood spots have prognostic power [ 118 , 119 ]. Plasma lyso-Gb1 concentrations were found to be significantly higher in patients with neuronopathic GD than in those with non-neuronopathic disease, even in the neonatal period [ 119 ]. A neonate diagnosed at 1 day of age (homozygous for N370S), owing to an affected older sibling, had a plasma lyso-Gb1 level of 70 nmol/L compared with 1070–2620 nmol/L for four neuronopathic patients diagnosed at <20 days of age [ 119 ].…”