Elevated plasma glucosylsphingosine in Gaucher disease: relation to phenotype, storage cell markers, and therapeutic response

Abstract

IntroductionGaucher disease, a relatively common recessively inherited lysosomal storage disorder, is caused by a deficiency in the enzyme glucocerebrosidase, encoded by the GBA gene. 1 Deficient enzymatic activity of glucocerebrosidase results in the lysosomal accumulation of its substrate glucosylceramide, most prominently in macrophages. Three variants of Gaucher disease are generally distinguished based on the absence (type 1) or presence of central nervous system involvement 1 (types 2 and 3). In the much more common type 1 variant of Gaucher disease, glycosphingolipidladen macrophages, referred to as Gaucher cells, accumulate in the visceral tissues liver, spleen, and bone marrow, inducing a pleiotropic array of symptoms, including hepatosplenomegaly and pancytopenia. In addition, type 1 Gaucher patients often develop bone complications: bone pain and crises, avascular necrosis, and pathologic fractures. 1 Two different types of therapeutic intervention are available for type 1 patients. One relies on chronic intravenous administration of recombinant glucocerebrosidase, denoted enzyme replacement therapy (ERT). 2 Two recombinant enzyme preparations are now registered for ERT in type 1 Gaucher disease: imiglucerase (Cerezyme; Genzyme Corp) and velaglucerase alfa (Vpriv; Shire HGT). 3 A third enzyme, a plant-cellexpressed recombinant glucocerebrosidase, is under clinical development (Taliglucerase; Protalix/Pfizer). 3 The other therapeutic intervention is based on oral administration of the iminosugar N-butyldeoxinojirimycin (Miglustat; Zavesca, Actelion). 4 This compound is thought to effectively lower synthesis of the accumulating metabolite, glucosylceramide, by inhibiting its synthesizing enzyme, glucosylceramide synthase. 5 The clinical responses to ERT are fast and impressive, such as significant corrections in hepatosplenomegaly, improvement of hematologic parameters and reduction of bone marrow infiltration as seen by magnetic resonance imaging. 6 The response to miglustat treatment is less prominent, and its use is authorized for mildly to moderately affected patients who are unsuitable for ERT (EMA) or in whom ERT is not a therapeutic option (FDA). 7 Future use of such small compounds for treating patients with a neuronopathic course of Gaucher disease is appealing given their potential to penetrate the brain (in contrast to recombinant enzyme). 8 The availability of costly therapies has stimulated searches for plasma biomarkers that can assist in clinical management of individual patients. Several circulating protein markers for Gaucher cells have meanwhile been identified (for a review see Aerts et al 9 ). It has been demonstrated that the enzyme chitotriosidase 10 and the chemokine CCL18 11 are produced by Gaucher cells and secreted into the circulation. Both proteins are candidate biomarkers since their plasma concentrations are markedly increased in symptomatic type 1 Gaucher patients and vary This article contains a data supplement.The publication costs of this article were defrayed in part b...

Risk factors for fractures and avascular osteonecrosis in type 1 Gaucher disease: A study from the International Collaborative Gaucher Group (ICGG) Gaucher Registry

“…Given the role of osteoblast dysfunction in the development of osteopenia of GD1, (11,17,18) it will be important to determine whether alternative treatments with small molecule substrate reduction therapy, whose volume of distribution includes cells other than macrophages, result in an enhanced therapeutic effect. In a pooled retrospective study of GD1 patients, substrate reduction therapy with miglustat appeared to modestly increase bone mineral density.…”

“…(12,13) Although osteopenia in GD is commonly attributed to increased osteoclastic bone resorption, (14) it is more likely related to impaired osteoblast function (15,16) associated with accumulating lipids. (17,18) Importantly, it is not known whether osteopenia in GD1 increases the risk of fractures as it does in postmenopausal women. (19) Imiglucerase therapy improves bone mass and bone mineral density (12,13,(20)(21)(22)(23) and studies have shown an apparent decrease in reports of bone pain and bone crises.…”

Lysosomal glycosphingolipid catabolism by acid ceramidase: formation of glycosphingoid bases during deficiency of glycosidases

“…Detection of this chitinase and chemokine in plasma of GD1 patients is, therefore, used as biomarker to assess body burden of Gaucher cells. The glycosphingoid base (lyso-GSL) of the primary storage lipid GlcCer, glucosylsphingosine (GlcSph), is also markedly increased in plasma of symptomatic GD1 patients and its potential as a biomarker has been increasingly recognized [4][5][6]. Accumulation of GlcSph in GD patients was firstly documented in brain of neuronopathic patients several decades ago [7,8].…”

“…A sensitive method for accurate quantification of GlcSph in biological samples, employing LC-MS/MS and an isotope-labelled internal standard, has meanwhile been developed [5]. Recent studies suggest that plasma GlcSph levels correlate with disease severity in GD1 patients [4] and its monitoring is considered useful to evaluate disease status and efficacy of therapeutic intervention. In male Fabry patients with classic disease manifestations a reminiscent phenomenon occurs.…”

Unexpected macrophage-independent dyserythropoiesis in Gaucher disease

“…9,10 We previously detected GCerase activity in normal erythroblasts but not in circulating RBCs. 11 High lipid levels have been frequently reported in the plasma and RBCs of GD patients, [22][23][24][25] which raises the possibility that the RBCs are overloaded with lipids due to the passive incorporation of GlcCer and/or that the erythroid progenitors are primarily affected. To evaluate the alterations in the erythroid progenitors, we performed in vitro experiments to study the erythroid differentiation from peripheral blood samples from GD type 1 patients.…”