Clinical disease progression and biomarkers in Niemann-Pick disease type C: a prospective cohort study.

Mengel, Eugen; Bembi, Bruno; Del Toro, Mireia; Deodato, Federica; Gautschi, Matthias; Grunewald, Stephanie; Grønborg, Sabine; Héron, Bénédicte; Maier, Esther M; Roubertie, Agathe; Santra, Saikat; Tylki-Szymanska, Anna; Day, Simon; Symonds, Tara; Hudgens, Stacie; Patterson, Marc C; Guldberg, Christina; Ingemann, Linda; Petersen, Nikolaj H T; Kirkegaard, Thomas; ... (2020). Clinical disease progression and biomarkers in Niemann-Pick disease type C: a prospective cohort study. Orphanet journal of rare diseases, 15(1), p. 328. BioMed Central 10.1186/s13023-020-01616-0

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Niemann-Pick disease type C (NPC) is a rare, progressive, neurodegenerative disease associated with neurovisceral manifestations resulting from lysosomal dysfunction and aberrant lipid accumulation. A multicentre, prospective observational study (Clinical ID: NCT02435030) of individuals with genetically confirmed NPC1 or NPC2 receiving routine clinical care was conducted, to prospectively characterize and measure NPC disease progression and to investigate potential NPC-related biomarkers versus healthy individuals. Progression was measured using the abbreviated 5-domain NPC Clinical Severity Scale (NPCCSS), 17-domain NPCCSS and NPC clinical database (NPC-cdb) score. Cholesterol esterification and heat shock protein 70 (HSP70) levels were assessed from peripheral blood mononuclear cells (PBMCs), cholestane-3β,5α-,6β-triol (cholestane-triol) from serum, and unesterified cholesterol from both PBMCs and skin biopsy samples. The inter- and intra-rater reliability of the 5-domain NPCCSS was assessed by 13 expert clinicians' rating of four participants via video recordings, repeated after ≥ 3 weeks. Intraclass correlation coefficients (ICCs) were calculated.


Of the 36 individuals with NPC (2-18 years) enrolled, 31 (86.1%) completed the 6-14-month observation period; 30/36 (83.3%) were receiving miglustat as part of routine clinical care. A mean (± SD) increase in 5-domain NPCCSS scores of 1.4 (± 2.9) was observed, corresponding to an annualized progression rate of 1.5. On the 17-domain NPCCSS, a mean (± SD) progression of 2.7 (± 4.0) was reported. Compared with healthy individuals, the NPC population had significantly lower levels of cholesterol esterification (p < 0.0001), HSP70 (p < 0.0001) and skin unesterified cholesterol (p = 0.0006). Cholestane-triol levels were significantly higher in individuals with NPC versus healthy individuals (p = 0.008) and correlated with the 5-domain NPCCSS (Spearman's correlation coefficient = 0.265, p = 0.0411). The 5-domain NPCCSS showed high ICC agreement in inter-rater reliability (ICC = 0.995) and intra-rater reliability (ICC = 0.937).


Progression rates observed were consistent with other reports on disease progression in NPC. The 5-domain NPCCSS reliability study supports its use as an abbreviated alternative to the 17-domain NPCCSS that focuses on the most relevant domains of the disease. The data support the use of cholestane-triol as a disease monitoring biomarker and the novel methods of measuring unesterified cholesterol could be applicable to support NPC diagnosis. Levels of HSP70 in individuals with NPC were significantly decreased compared with healthy individuals.


CT-ORZY-NPC-001: NCT02435030, Registered 6 May 2015, ; EudraCT 2014-005,194-37, Registered 28 April 2015, . OR-REL-NPC-01: Unregistered.

Item Type:

Journal Article (Original Article)


04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Paediatric Medicine
04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Institute of Clinical Chemistry
04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Paediatric Medicine > Endocrinology/Metabolic Disorders

UniBE Contributor:

Gautschi, Matthias


600 Technology > 610 Medicine & health




BioMed Central




Anette van Dorland

Date Deposited:

23 Dec 2020 08:03

Last Modified:

05 Dec 2022 15:43

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Uncontrolled Keywords:

Biomarkers Cholestane-triol Heat shock protein Lysosomal storage disease NPC Clinical Severity Scale (NPCCSS) Natural history of disease Niemann–Pick type C (NPC) disease Observational study Reliability




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