Plasma glucosylceramide and ceramide in type 1 Gaucher disease patients: Correlations with disease severity and response to therapeutic intervention J.E.M. Groener a, ⁎ , B.J.H.M. Poorthuis a , S. Kuiper a , C.E.M. Hollak b , J.M.F.G. Aerts a a Department of Medical Biochemistry, Academic Medical Center, Amsterdam, the Netherlands b Department of Internal Medicine, Academic Medical Center, Amsterdam, the Netherlands Received 17 July 2007; received in revised form 16 November 2007; accepted 28 November 2007 Available online 5 December 2007 Abstract The concentrations of plasma glucosylceramide (GlcCer) and ceramide (Cer) were determined in a cohort of type 1 Gaucher disease patients. In plasma of untreated patients, GlcCer concentrations were on average 3-fold increased (median Gaucher: 17.5 nmol/ml, range: 6.5–45.5 (n = 27); median control: 5.9 nmol/ml, range 4.0–8.6 (n = 15)). Although plasma Cer concentrations were not significantly different between the two groups (median Gaucher: 7.2 nmol/ml, range: 4.2–10.9 (n = 27); median control: 7.8 nmol/ml, range 5.7–11.9 (n = 15)) in individual patients plasma GlcCer/Cer ratio yields slightly better discrimination between Gaucher disease patients and normal individuals than the GlcCer levels. Positive correlations were detected between plasma GlcCer concentration and GlcCer/Cer ratio and severity of disease, plasma chitotriosidase and CCL18, surrogate markers of storage cells. Gaucher disease is treated by enzyme replacement and substrate reduction therapy. Both therapies were found to result in decreases in plasma GlcCer already within 6 months, without causing abnormal plasma GlcCer or Cer concentrations. The corrections in plasma GlcCer were most robust in patients with a pronounced clinical response. In conclusion, plasma GlcCer concentration and GlcCer/Cer ratio is of value to monitor Gaucher disease manifestation and response to therapeutic intervention. © 2007 Elsevier B.V. All rights reserved. Keywords: Glucosylceramide; Ceramide; Chitotriosidase; Enzyme replacement therapy; Gaucher disease type I; Substrate reduction therapy 1. Introduction Gaucher disease is a lysosomal storage disorder caused by deficiency of the lysosomal enzyme glucocerebrosidase (E.C. 3.2.1.45) and is characterized by the accumulation of glucosyl- ceramide (GlcCer) primarily in macrophages (Gaucher cells) [1]. In the non-neuronopathic Gaucher disease patients (the type 1 variant) GlcCer accumulation is restricted to visceral tissues, predominantly liver and spleen, and bone marrow, without in- volvement of the central nervous system. Increased concentra- tions of GlcCer have been detected in plasma of symptomatic Gaucher disease patients [2–5]. Two distinct therapies exist for treatment of type 1 Gaucher disease: enzyme replacement the- rapy (ERT) and substrate reduction therapy (SRT). ERT is based on chronic intravenous administration of a recombinant gluco- cerebrosidase (imiglucerase, Genzyme) [6]. More recently SRT has been developed as an alternative treatment for Gaucher disease [7]. Partial inhibition of glycosphingolipid synthesis with N-butyl-deoxynojirimycin (miglustat, Actelion) is employed in an effort to balance the reduced catabolic capacity in Gaucher disease patients. Both therapies generally result in marked clinical improvements such as reduction in hepatosplenomegaly, correc- tions in hematological abnormalities, stabilization or improve- ment in skeletal deterioration. Reduction of storage cells in tissues can be conveniently monitored by measurement of sur- rogate markers of Gaucher cells like chitotriosidase and CCL18 [8,9]. Despite the wide-spread application of two therapies that aim to correctively manipulate GlcCer metabolism in different ways surprisingly little is known about the plasma levels of Available online at www.sciencedirect.com Biochimica et Biophysica Acta 1781 (2008) 72 – 78 www.elsevier.com/locate/bbalip Abbreviations: Cer, ceramide; Chito, chitotriosidase; ERT, enzyme replace- ment therapy; SRT, substrate reduction therapy; GlcCer, glucosylceramide; HPLC, high performance liquid chromatography; SSI, Severity Index Score ⁎ Corresponding author. Department of Medical Biochemistry, University of Amsterdam, Academic Medical Center, P.O. Box 22700, 1100 DE Amsterdam, The Netherlands. Tel.: +31 20 5665157; fax: +31 20 6915519. E-mail address: j.e.groener@amc.uva.nl (J.E.M. Groener). 1388-1981/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.bbalip.2007.11.004