title: Comprehensive Evaluation of Plasma 7-Ketocholesterol and Cholestan-3β,5α,6β-Triol in an Italian Cohort of Patients Affected by Niemann-Pick Disease due to NPC1 and SMPD1 Mutations.
abstract: Niemann-Pick C disease (NPCD) is a rare autosomal recessive neurovisceral disorder with a heterogeneous clinical presentation. Cholestan-3β,5α,6β-triol and 7-ketocholesterol have been proposed as biomarkers for the screening of NPCD. In this work, we assessed oxysterols levels in a cohort of Italian patients affected by NPCD and analyzed the obtained results in the context of the clinical, biochemical and molecular data. In addition, a group of patients affected by Niemann-Pick B disease (NPBD) were also analyzed. NPC patients presented levels of both oxysterols way above the cut off value, except for 5 siblings presenting the variant biochemical phenotype who displayed levels of 3β,5α,6β-triol below or just above the cut-off value; 2 of them presented also normal levels of 7-KC. Both oxysterols were extremely high in a patient presenting the neonatal systemic lethal phenotype. All NPB patients showed increased oxysterols levels. In conclusion, the reported LC-MS/MS assay provides a robust non-invasive screening tool for NPCD. However, false negative results can be obtained in patients expressing the variant biochemical phenotype. These data strengthen the concept that the results should always be interpreted in the context of the patients' clinical picture and filipin staining and/or genetic studies might still be undertaken in patients with normal levels of oxysterols if symptoms are highly suggestive of NPCD. Both oxysterols are significantly elevated in NPB patients; thus a differential diagnosis should always be performed in patients presenting isolated hepatosplenomegaly, a common clinical sign of both NPCD and NPBD.
authors.affiliation: Regional Coordinator Centre for Rare Diseases, University Hospital Santa Maria della Misericordia, Udine, Italy. Electronic address: romanello.milena@aoud.sanita.fvg.it.
authors.forename: Milena
authors.initials: M
authors.lastname: Romanello
authors.affiliation: Regional Coordinator Centre for Rare Diseases, University Hospital Santa Maria della Misericordia, Udine, Italy. Electronic address: zampieri.stefania@aoud.sanita.fvg.it.
authors.forename: Stefania
authors.initials: S
authors.lastname: Zampieri
authors.affiliation: Clinical Pathology Institute, University Hospital Santa Maria della Misericordia, Udine, Italy. Electronic address: bortolotti.nadia@aoud.sanita.fvg.it.
authors.forename: Nadia
authors.initials: N
authors.lastname: Bortolotti
authors.affiliation: Regional Coordinator Centre for Rare Diseases, University Hospital Santa Maria della Misericordia, Udine, Italy. Electronic address: deroma.laura@aoud.sanita.fvg.it.
authors.forename: Laura
authors.initials: L
authors.lastname: Deroma
authors.affiliation: Regional Coordinator Centre for Rare Diseases, University Hospital Santa Maria della Misericordia, Udine, Italy. Electronic address: sechi.annalisa@aoud.sanita.fvg.it.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Sechi
authors.affiliation: Department of Pediatrics, Regional Referral Center for Inherited Metabolic Disease, University of Catania, Catania, Italy. Electronic address: agatafiumara@yahoo.it.
authors.forename: Agata
authors.initials: A
authors.lastname: Fiumara
authors.affiliation: Rare Metabolic Diseases Unit, Pediatric Clinic, San Gerardo Hospital, Monza, Italy. Electronic address: rossella.parini@unimib.it.
authors.forename: Rossella
authors.initials: R
authors.lastname: Parini
authors.affiliation: Centre for Ageing Brain and Neurodegenerative Disorders, Neurology Unit, University of Brescia, Brescia, Italy. Electronic address: barbara.borroni@unibs.it.
authors.forename: Barbara
authors.initials: B
authors.lastname: Borroni
authors.affiliation: Medical Genetics Unit, Tor Vergata University, Roma, Italy. Electronic address: f.brancati@igenetica.com.
authors.forename: Francesco
authors.initials: F
authors.lastname: Brancati
authors.affiliation: Regional Neurogenetic Centre, ASPCZ, Lamezia Terme, Italy. Electronic address: bruni@arn.it.
authors.forename: Amalia
authors.initials: A
authors.lastname: Bruni
authors.affiliation: Department of Neurosciences, Reproductive and Odontostomatological Sciences, Federico II University, Naples, Italy. Electronic address: cinziavaleria@hotmail.it.
authors.forename: Cinzia V
authors.initials: CV
authors.lastname: Russo
authors.affiliation: Regional Centre for Newborn Screening, Diagnosis and Treatment of Inherited Metabolic Disorders and Inherited Metabolic Diseases Unit, Department of Pediatrics, Verona, Italy. Electronic address: abordugo@hotmail.com.
authors.forename: Andrea
authors.initials: A
authors.lastname: Bordugo
authors.affiliation: Regional Coordinator Centre for Rare Diseases, University Hospital Santa Maria della Misericordia, Udine, Italy. Electronic address: bembi.bruno@aoud.sanita.fvg.it.
authors.forename: Bruno
authors.initials: B
authors.lastname: Bembi
authors.affiliation: Regional Coordinator Centre for Rare Diseases, University Hospital Santa Maria della Misericordia, Udine, Italy. Electronic address: dardis.andrea@aoud.sanita.fvg.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: Dardis
mesh_terms: D002138:Calibration; D002352:Carrier Proteins / Q000235:genetics*; D002776:Cholestanes / Q000097:blood*; D015331:Cohort Studies; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D007558:Italy; D007653:Ketocholesterols / Q000097:blood*; D008562:Membrane Glycoproteins / Q000235:genetics*; D009154:Mutation; D000077296:Niemann-Pick C1 Protein; D009542:Niemann-Pick Diseases / Q000097:blood* / Q000235:genetics; D015203:Reproducibility of Results; D013108:Sphingomyelin Phosphodiesterase / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; D002776:Cholestanes; D047908:Intracellular Signaling Peptides and Proteins; D007653:Ketocholesterols; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; D000077296:Niemann-Pick C1 Protein; C543066:SMPD1 protein, human; D013108:Sphingomyelin Phosphodiesterase; C003001:7-ketocholesterol
keywords: Liquid chromatography-tandem–mass spectrometry; Niemann-Pick; Oxysterols; Variant biochemical phenotype