title: Plasma lysosphingomyelin demonstrates great potential as a diagnostic biomarker for Niemann-Pick disease type C in a retrospective study.
abstract: Niemann-Pick disease type C (NP-C) is a devastating, neurovisceral lysosomal storage disorder which is characterised by variable manifestation of visceral signs, progressive neuropsychiatric deterioration and premature death, caused by mutations in the NPC1 and NPC2 genes. Due to the complexity of diagnosis and the availability of an approved therapy in the EU, improved detection of NP-C may have a huge impact on future disease management. At the cellular level dysfunction or deficiency of either the NPC1 or NPC2 protein leads to a complex intracellular endosomal/lysosomal trafficking defect, and organ specific patterns of sphingolipid accumulation. Lysosphingolipids have been shown to be excellent biomarkers of sphingolipidosis in several enzyme deficient lysosomal storage disorders. Additionally, in a recent study the lysosphingolipids, lysosphingomyelin (SPC) and glucosylsphingosine (GlcSph), appeared to be elevated in the plasma of three adult NP-C patients. In order to investigate the clinical utility of SPC and GlcSph as diagnostic markers, an in-depth fit for purpose biomarker assay validation for measurement of these biomarkers in plasma by liquid chromatography-tandem mass spectrometry was performed. Plasma SPC and GlcSph are stable and can be measured accurately, precisely and reproducibly. In a retrospective analysis of 57 NP-C patients and 70 control subjects, median plasma SPC and GlcSph were significantly elevated in NP-C by 2.8-fold and 1.4-fold respectively. For miglustat-naïve NP-C patients, aged 2-50 years, the area under the ROC curve was 0.999 for SPC and 0.776 for GlcSph. Plasma GlcSph did not correlate with SPC levels in NP-C patients. The data indicate excellent potential for the use of lysosphingomyelin in NP-C diagnosis, where it could be used to identify NP-C patients for confirmatory genetic testing.
authors.affiliation: Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors.forename: Richard W D
authors.initials: RW
authors.lastname: Welford
authors.affiliation: Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors.forename: Marco
authors.initials: M
authors.lastname: Garzotti
authors.affiliation: Hospital das Clínicas de Ribeirão Preto, São Paulo, Brazil.
authors.forename: Charles
authors.initials: C
authors.lastname: Marques Lourenço
authors.affiliation: Department of Lysosomal Storage Disorder, Villa Metabolica, Center for Paediatric and Adolescent Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
authors.forename: Eugen
authors.initials: E
authors.lastname: Mengel
authors.affiliation: Klinik für Kinder- und Jugendmedizin, Münster, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Marquardt
authors.affiliation: Klinik für Kinder- und Jugendmedizin, Münster, Germany.
authors.forename: Janine
authors.initials: J
authors.lastname: Reunert
authors.affiliation: Department of Lysosomal Storage Disorder, Villa Metabolica, Center for Paediatric and Adolescent Medicine, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
authors.forename: Yasmina
authors.initials: Y
authors.lastname: Amraoui
authors.affiliation: Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Kolb
authors.affiliation: Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors.forename: Olivier
authors.initials: O
authors.lastname: Morand
authors.affiliation: Actelion Pharmaceuticals Ltd, Allschwil, Switzerland.
authors.forename: Peter
authors.initials: P
authors.lastname: Groenen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood*; D001800:Blood Specimen Collection / Q000379:methods; D016022:Case-Control Studies; D004492:Edetic Acid / Q000737:chemistry; D005260:Female; D006493:Heparin / Q000737:chemistry; D006801:Humans; D008297:Male; D052556:Niemann-Pick Disease, Type C / Q000097:blood* / Q000175:diagnosis; D010767:Phosphorylcholine / Q000031:analogs & derivatives* / Q000097:blood; D011609:Psychosine / Q000031:analogs & derivatives / Q000097:blood; D015203:Reproducibility of Results; D012189:Retrospective Studies; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000097:blood; D053719:Tandem Mass Spectrometry / Q000379:methods; D055815:Young Adult
chemical_list: D015415:Biomarkers; C005356:sphingosine phosphorylcholine; D010767:Phosphorylcholine; D011609:Psychosine; C035742:sphingosyl beta-glucoside; D006493:Heparin; D004492:Edetic Acid; D013110:Sphingosine