title: Diagnostic tests for Niemann-Pick disease type C (NP-C): A critical review.
abstract: Niemann-Pick disease type C (NP-C) is a neurovisceral lysosomal cholesterol trafficking and lipid storage disorder caused by mutations in one of the two genes, NPC1 or NPC2. Diagnosis has often been a difficult task, due to the wide range in age of onset of NP-C and clinical presentation of the disease, combined with the complexity of the cell biology (filipin) laboratory testing, even in combination with genetic testing. This has led to substantial delays in diagnosis, largely depending on the access to specialist centres and the level of knowledge about NP-C of the physician in the area. In recent years, advances in mass spectrometry has allowed identification of several sensitive plasma biomarkers elevated in NP-C (e.g. cholestane-3β,5α,6β-triol, lysosphingomyelin isoforms and bile acid metabolites), which, together with the concomitant progress in molecular genetic technology, have greatly impacted the strategy of laboratory testing. Specificity of the biomarkers is currently under investigation and other pathologies are being found to also result in elevations. Molecular genetic testing also has its limitations, notably with unidentified mutations and the classification of new variants. This review is intended to increase awareness on the currently available approaches to laboratory diagnosis of NP-C, to provide an up to date, comprehensive and critical evaluation of the various techniques (cell biology, biochemical biomarkers and molecular genetics), and to briefly discuss ongoing/future developments. The use of current tests in proper combination enables a rapid and correct diagnosis in a large majority of cases. However, even with recent progress, definitive diagnosis remains challenging in some patients, for whom combined genetic/biochemical/cytochemical markers do not provide a clear answer. Expertise and reference laboratories thus remain essential, and further work is still required to fulfill unmet needs.
authors.affiliation: INSERM Unit 820, 7 Rue Guillaume Paradin, 69008 Lyon, France; Laboratoire Gillet-Mérieux, Centre de Biologie et Pathologie Est, Hospices Civils de Lyon, 69500 Bron, France. Electronic address: marie-t.vanier@inserm.fr.
authors.forename: Marie T
authors.initials: MT
authors.lastname: Vanier
authors.affiliation: UCL Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK; Great Ormond Street Hospital, London WC1N 3JH, UK. Electronic address: p.gissen@ucl.ac.uk.
authors.forename: Paul
authors.initials: P
authors.lastname: Gissen
authors.affiliation: Institute of Medical Genetics and Applied Genomics, University Hospital of Tübingen, 72076 Tübingen, Germany. Electronic address: peter.bauer@med.uni-tuebingen.de.
authors.forename: Peter
authors.initials: P
authors.lastname: Bauer
authors.affiliation: Inborn Errors of Metabolism Section, Biochemistry and Molecular Genetics Service, Hospital Clínic of Barcelona, 08036 Barcelona, Spain; CIBERER, Spain. Electronic address: mjcoll@clinic.ub.es.
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Coll
authors.affiliation: Division of Inherited Metabolic Diseases, Department of Pediatrics, University Hospital, 35129 Padova, Italy. Electronic address: alberto.burlina@unipd.it.
authors.forename: Alberto
authors.initials: A
authors.lastname: Burlina
authors.affiliation: The Mark Holland Metabolic Unit, Salford Royal Foundation NHS Trust, Salford, Manchester M68HD, UK; University of Pretoria, Steve Biko Academic Hospital, Department of Paediatrics and Child Health, Pretoria 0001, South Africa. Electronic address: chris.hendriksz@srft.nhs.uk.
authors.forename: Christian J
authors.initials: CJ
authors.lastname: Hendriksz
authors.affiliation: UF de Neurogénétique Moléculaire, Centre de Biologie et Pathologie Est, Hospices Civils de Lyon, 69500 Bron, France. Electronic address: philippe.latour@chu-lyon.fr.
authors.forename: Philippe
authors.initials: P
authors.lastname: Latour
authors.affiliation: CHU Bordeaux, Department of Medical Genetics, 33076 Bordeaux, France; INSERM Unit 1211, University of Bordeaux, 33076 Bordeaux, France. Electronic address: cyril.goizet@chu-bordeaux.fr.
authors.forename: Cyril
authors.initials: C
authors.lastname: Goizet
authors.affiliation: Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, 4123 Allschwil, Switzerland. Electronic address: richard.welford@actelion.com.
authors.forename: Richard W D
authors.initials: RW
authors.lastname: Welford
authors.affiliation: Unit for Inborn Errors of Metabolism, University Hospital Münster, 48149 Münster, Germany. Electronic address: thorsten.marquardt@ukmuenster.de.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Marquardt
authors.affiliation: Actelion Pharmaceuticals Ltd., Gewerbestrasse 16, 4123 Allschwil, Switzerland. Electronic address: stefan.kolb@actelion.com.
authors.forename: Stefan A
authors.initials: SA
authors.lastname: Kolb
mesh_terms: D017668:Age of Onset; D001647:Bile Acids and Salts / Q000097:blood; D015415:Biomarkers / Q000097:blood*; D002352:Carrier Proteins / Q000235:genetics*; D002776:Cholestanes / Q000097:blood; D005820:Genetic Testing; D006023:Glycoproteins / Q000235:genetics*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000235:genetics*; D000077296:Niemann-Pick C1 Protein; D052556:Niemann-Pick Disease, Type C / Q000097:blood / Q000235:genetics* / Q000503:physiopathology; D010767:Phosphorylcholine / Q000031:analogs & derivatives / Q000097:blood; D013110:Sphingosine / Q000031:analogs & derivatives / Q000097:blood; D033921:Vesicular Transport Proteins
chemical_list: D001647:Bile Acids and Salts; D015415:Biomarkers; D002352:Carrier Proteins; D002776:Cholestanes; D006023:Glycoproteins; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; C106881:NPC1 protein, human; C104585:NPC2 protein, human; D000077296:Niemann-Pick C1 Protein; D033921:Vesicular Transport Proteins; C005356:sphingosine phosphorylcholine; D010767:Phosphorylcholine; D013110:Sphingosine
keywords: Filipin; Lysosphingomyelin; NPC1 gene; NPC2 gene; Niemann-Pick disease type C; Oxysterol