title: Elevated plasma glucosylsphingosine in Gaucher disease: relation to phenotype, storage cell markers, and therapeutic response.
abstract: Gaucher disease, caused by a deficiency of the lysosomal enzyme glucocerebrosidase, leads to prominent glucosylceramide accumulation in lysosomes of tissue macrophages (Gaucher cells). Here we show glucosylsphingosine, the deacylated form of glucosylceramide, to be markedly increased in plasma of symptomatic nonneuronopathic (type 1) Gaucher patients (n = 64, median = 230.7 nM, range 15.6-1035.2 nM; normal (n = 28): median 1.3 nM, range 0.8-2.7 nM). The method developed for mass spectrometric quantification of plasma glucosylsphingosine is sensitive and robust. Plasma glucosylsphingosine levels correlate with established plasma markers of Gaucher cells, chitotriosidase (ρ = 0.66) and CCL18 (ρ = 0.40). Treatment of Gaucher disease patients by supplementing macrophages with mannose-receptor targeted recombinant glucocerebrosidase results in glucosylsphingosine reduction, similar to protein markers of Gaucher cells. Since macrophages prominently accumulate the lysoglycosphingolipid on glucocerebrosidase inactivation, Gaucher cells seem a major source of the elevated plasma glucosylsphingosine. Our findings show that plasma glucosylsphingosine can qualify as a biomarker for type 1 Gaucher disease, but that further investigations are warranted regarding its relationship with clinical manifestations of Gaucher disease.
authors.affiliation: Department of Medical Biochemistry, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: Nick
authors.initials: N
authors.lastname: Dekker
authors.forename: Laura
authors.initials: L
authors.lastname: van Dussen
authors.forename: Carla E M
authors.initials: CE
authors.lastname: Hollak
authors.forename: Herman
authors.initials: H
authors.lastname: Overkleeft
authors.forename: Saskia
authors.initials: S
authors.lastname: Scheij
authors.forename: Karen
authors.initials: K
authors.lastname: Ghauharali
authors.forename: Mariëlle J
authors.initials: MJ
authors.lastname: van Breemen
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Ferraz
authors.forename: Johanna E M
authors.initials: JE
authors.lastname: Groener
authors.forename: Mario
authors.initials: M
authors.lastname: Maas
authors.forename: Frits A
authors.initials: FA
authors.lastname: Wijburg
authors.forename: Dave
authors.initials: D
authors.lastname: Speijer
authors.forename: Anna
authors.initials: A
authors.lastname: Tylki-Szymanska
authors.forename: Pramod K
authors.initials: PK
authors.lastname: Mistry
authors.forename: Rolf G
authors.initials: RG
authors.lastname: Boot
authors.forename: Johannes M
authors.initials: JM
authors.lastname: Aerts
mesh_terms: D019742:Chemokines, CC / Q000097:blood; D056947:Enzyme Replacement Therapy; D057487:Enzyme Therapy; D005260:Female; D005776:Gaucher Disease / Q000097:blood* / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D005838:Genotype; D005962:Glucosylceramidase / Q000235:genetics / Q000627:therapeutic use*; D006596:Hexosaminidases / Q000097:blood; D006801:Humans; D008264:Macrophages / Q000166:cytology; D008297:Male; D010641:Phenotype; D011609:Psychosine / Q000031:analogs & derivatives* / Q000097:blood; D011994:Recombinant Proteins / Q000235:genetics / Q000627:therapeutic use; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: C111792:CCL18 protein, human; D019742:Chemokines, CC; D011994:Recombinant Proteins; D011609:Psychosine; C035742:sphingosyl beta-glucoside; D006596:Hexosaminidases; C086400:chitotriosidase; D005962:Glucosylceramidase