A novel, highly sensitive and specific biomarker for Niemann-Pick type C1 disease

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Abstract

Background

Lysosomal storage disorders (LSDs), are a heterogeneous group of rare disorders caused by defects in genes encoding for proteins involved in the lysosomal degradation of macromolecules. They occur at a frequency of about 1 in 5,000 live births, though recent neonatal screening suggests a higher incidence. New treatment options for LSDs demand a rapid, early diagnosis of LSDs if maximal clinical benefit is to be achieved.

Methods

Here, we describe a novel, highly specific and sensitive biomarker for Niemann-Pick Type C disease type 1 (NPC1), lyso-sphingomyelin-509. We cross-validate this biomarker with cholestane-3β,5α,6β-triol and relative lysosomal volume. The primary cohort for establishment of the biomarker contained 135 NPC1 patients, 66 NPC1 carriers, 241 patients with other LSDs and 46 healthy controls.

Results

With a sensitivity of 100.0% and specificity of 91.0% a cut-off of 1.4 ng/ml was established. Comparison with cholestane-3β,5α,6β-triol and relative acidic compartment volume measurements were carried out with a subset of 125 subjects. Both cholestane-3β,5α,6β-triol and lyso-Sphingomyelin-509 were sufficient in establishing the diagnosis of NPC1 and correlated with disease severity.

Conclusion

In summary, we have established a new biomarker for the diagnosis of NPC1, and further studies will be conducted to assess correlation to disease progress and monitoring treatment.

Electronic supplementary material

The online version of this article (doi:10.1186/s13023-015-0274-1) contains supplementary material, which is available to authorized users.

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Most cited references 21

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Elevated globotriaosylsphingosine is a hallmark of Fabry disease.

S Kuiper, C. E. M. Hollak, Astrid Linthorst … (2008)

Fabry disease is an X-linked lysosomal storage disease caused by deficiency of alpha-galactosidase A that affects males and shows disease expression in heterozygotes. The characteristic progressive renal insufficiency, cardiac involvement, and neuropathology usually are ascribed to globotriaosylceramide accumulation in the endothelium. However, no direct correlation exists between lipid storage and clinical manifestations, and treatment of patients with recombinant enzymes does not reverse several key signs despite clearance of lipid from the endothelium. We therefore investigated the possibility that globotriaosylceramide metabolites are a missing link in the pathogenesis. We report that deacylated globotriaosylceramide, globotriaosylsphingosine, and a minor additional metabolite are dramatically increased in plasma of classically affected male Fabry patients and plasma and tissues of Fabry mice. Plasma globotriaosylceramide levels are reduced by therapy. We show that globotriaosylsphingosine is an inhibitor of alpha-galactosidase A activity. Furthermore, exposure of smooth muscle cells, but not fibroblasts, to globotriaosylsphingosine at concentrations observed in plasma of patients promotes proliferation. The increased intima-media thickness in Fabry patients therefore may be related to the presence of this metabolite. Our findings suggest that measurement of circulating globotriaosylsphingosine will be useful to monitor Fabry disease and may contribute to a better understanding of the disorder.

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Glucosylsphingosine Is a Highly Sensitive and Specific Biomarker for Primary Diagnostic and Follow-Up Monitoring in Gaucher Disease in a Non-Jewish, Caucasian Cohort of Gaucher Disease Patients

Arndt Rolfs, Anne-Katrin Giese, Ulrike Grittner … (2013)

Background Gaucher disease (GD) is the most common lysosomal storage disorder (LSD). Based on a deficient β-glucocerebrosidase it leads to an accumulation of glucosylceramide. Standard diagnostic procedures include measurement of enzyme activity, genetic testing as well as analysis of chitotriosidase and CCL18/PARC as biomarkers. Even though chitotriosidase is the most well-established biomarker in GD, it is not specific for GD. Furthermore, it may be false negative in a significant percentage of GD patients due to mutation. Additionally, chitotriosidase reflects the changes in the course of the disease belatedly. This further enhances the need for a reliable biomarker, especially for the monitoring of the disease and the impact of potential treatments. Methodology Here, we evaluated the sensitivity and specificity of the previously reported biomarker Glucosylsphingosine with regard to different control groups (healthy control vs. GD carriers vs. other LSDs). Findings Only GD patients displayed elevated levels of Glucosylsphingosine higher than 12 ng/ml whereas the comparison controls groups revealed concentrations below the pathological cut-off, verifying the specificity of Glucosylsphingosine as a biomarker for GD. In addition, we evaluated the biomarker before and during enzyme replacement therapy (ERT) in 19 patients, demonstrating a decrease in Glucosylsphingosine over time with the most pronounced reduction within the first 6 months of ERT. Furthermore, our data reveals a correlation between the medical consequence of specific mutations and Glucosylsphingosine. Interpretation In summary, Glucosylsphingosine is a very promising, reliable and specific biomarker for GD.

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Miglustat for treatment of Niemann-Pick C disease: a randomised controlled study.

Richard L. Abel, Helena Prady, D Vecchio … (2007)

Niemann-Pick type C disease (NPC) is an inherited neurodegenerative disorder characterised by an intracellular lipid-trafficking defect with secondary accumulation of glycosphingolipids. Miglustat, a small iminosugar, reversibly inhibits glucosylceramide synthase, which catalyses the first committed step of glycosphingolipid synthesis. Miglustat is able to cross the blood-brain barrier, and is thus a potential therapy for neurological diseases. We aimed to establish the effect of miglustat on several markers of NPC severity. Patients aged 12 years or older who had NPC (n=29) were randomly assigned to receive either miglustat 200 mg three times a day (n=20) or standard care (n=9) for 12 months. 12 children younger than 12 years of age were included in an additional cohort; all received miglustat at a dose adjusted for body surface area. All participants were then treated with miglustat for an additional year in an extension study. The primary endpoint was horizontal saccadic eye movement (HSEM) velocity, based on its correlation with disease progression. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN26761144. At 12 months, HSEM velocity had improved in patients treated with miglustat versus those receiving standard care; results were significant when patients taking benzodiazepines were excluded (p=0.028). Children showed an improvement in HSEM velocity of similar size at 12 months. Improvement in swallowing capacity, stable auditory acuity, and a slower deterioration in ambulatory index were also seen in treated patients older than 12 years. The safety and tolerability of miglustat 200 mg three times a day in study participants was consistent with previous trials in type I Gaucher disease, where half this dose was used. Miglustat improves or stabilises several clinically relevant markers of NPC. This is the first agent studied in NPC for which there is both animal and clinical data supporting a disease modifying benefit.

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Author and article information

Contributors

Anne-Katrin Giese: anne-katrin.giese@med.uni-rostock.de

Hermann Mascher: hermann.mascher@pharm-analyt.at

Ulrike Grittner: ulrike.grittner@charite.de

Sabrina Eichler: sabrina.eichler@centogene.de

Guido Kramp: Guido.Kramp@centogene.com

Jan Lukas: jan.lukas@med.uni-rostock.de

Danielle te Vruchte: danielle.tevruchte@pharm.ox.ac.uk

Nada Al Eisa: nada.aleisa@wolfson.ox.ac.uk

Mario Cortina-Borja: m.cortina@ucl.ac.uk

Forbes D Porter: fdporter@mail.nih.gov

Frances M Platt: frances.platt@pharm.ox.ac.uk

Arndt Rolfs: arndt.rolfs@med.uni-rostock.de

Journal

Journal ID (nlm-ta): Orphanet J Rare Dis

Journal ID (iso-abbrev): Orphanet J Rare Dis

Title: Orphanet Journal of Rare Diseases

Publisher: BioMed Central (London )

ISSN (Electronic): 1750-1172

Publication date (Electronic): 17 June 2015

Publication date PMC-release: 17 June 2015

Publication date Collection: 2015

Volume: 10

Electronic Location Identifier: 78

Affiliations

[ ]Albrecht-Kossel-Institute for Neuroregeneration, Medical University of Rostock, Gehlsheimer Str. 20, 18147 Rostock, Germany

[ ]PharmAnalyt Labor GmbH, Ferdinand-Pichler Gasse 2, 2500 Baden, Austria

[ ]Department for Biostatistics and Clinical Epidemiology, Charité-University Medical Centre, Berlin, Germany

[ ]Centogene AG, Schillingallee 68, 18055 Rostock, Germany

[ ]Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT UK

[ ]Population, Policy and Practice Programme, Institute of Child Health, University College London, 30 Guilford Street, London, WC1N 1EH UK

[ ]Eunice Kennedy Shriver National Institute of Child Health and Development, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892 USA

Article

Publisher ID: 274

DOI: 10.1186/s13023-015-0274-1

PMC ID: 4479076

PubMed ID: 26082315

SO-VID: 6edd243a-d7fc-43d8-9a32-f53bf88781b1

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.