Abstract
BackgroundGaucher disease (GD) is the most common lysosomal storage disorder (LSD). Based on a deficient β-glucocerebrosidase it leads to an accumulation of glucosylceramide. Standard diagnostic procedures include measurement of enzyme activity, genetic testing as well as analysis of chitotriosidase and CCL18/PARC as biomarkers. Even though chitotriosidase is the most well-established biomarker in GD, it is not specific for GD. Furthermore, it may be false negative in a significant percentage of GD patients due to mutation. Additionally, chitotriosidase reflects the changes in the course of the disease belatedly. This further enhances the need for a reliable biomarker, especially for the monitoring of the disease and the impact of potential treatments.MethodologyHere, we evaluated the sensitivity and specificity of the previously reported biomarker Glucosylsphingosine with regard to different control groups (healthy control vs. GD carriers vs. other LSDs).FindingsOnly GD patients displayed elevated levels of Glucosylsphingosine higher than 12 ng/ml whereas the comparison controls groups revealed concentrations below the pathological cut-off, verifying the specificity of Glucosylsphingosine as a biomarker for GD. In addition, we evaluated the biomarker before and during enzyme replacement therapy (ERT) in 19 patients, demonstrating a decrease in Glucosylsphingosine over time with the most pronounced reduction within the first 6 months of ERT. Furthermore, our data reveals a correlation between the medical consequence of specific mutations and Glucosylsphingosine.InterpretationIn summary, Glucosylsphingosine is a very promising, reliable and specific biomarker for GD.
Highlights
Gaucher disease (GD) is the most common lysosomal storage disorder (LSD), with an estimated prevalence in Caucasians ranging from about 1:40,000 to 1:60,000, a current newborn screening in Szeged, Hungary suggests a higher prevalence of 1:13,341 [1,2]
In 1989 Rosengren and colleagues published a comparative analysis of glycosphingolipid patterns, especially lyso-sulfatide, in the normal brain and in patients suffering from Metachromatic Leukodystrophy [24]
Likewise Lloyd-Evan and colleagues concluded from their experiments with glycosphingolipids and calcium that they may not contribute to disease pathology, but could play a possible role in treatment [25]
Summary
Gaucher disease (GD) is the most common lysosomal storage disorder (LSD), with an estimated prevalence in Caucasians ranging from about 1:40,000 to 1:60,000, a current newborn screening in Szeged, Hungary suggests a higher prevalence of 1:13,341 [1,2]. LSDs are generally characterized by a genetic defect in proteins and enzymes involved in the lysosomal degradation of macromolecules into smaller compounds resulting in the accumulation of non-degraded macromolecules [3]. In GD this results in the accumulation of glucosylceramides as the enzyme b-glucocerebrosidase is impaired This causes a compensatory lipid re-uptake by macrophages which likewise cannot degrade glucosylceramides and enlarge and evolve into the disease-specific ‘‘Gaucher cells’’. They are the hallmark of the disease [4]. Chitotriosidase reflects the changes in the course of the disease belatedly This further enhances the need for a reliable biomarker, especially for the monitoring of the disease and the impact of potential treatments
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