Research
Print page Print page
Switch language
The Capital Region of Denmark - a part of Copenhagen University Hospital
Published

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

Research output: Contribution to journalJournal articleResearchpeer-review

  1. The need for widely available genomic testing in rare eye diseases: an ERN-EYE position statement

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Data from the European registry for patients with McArdle disease and other muscle glycogenoses (EUROMAC)

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. Creation and implementation of a European registry for patients with McArdle disease and other muscle glycogenoses (EUROMAC registry)

    Research output: Contribution to journalJournal articleResearchpeer-review

  4. The SPARKLE registry: protocol for an international prospective cohort study in patients with alpha-mannosidosis

    Research output: Contribution to journalJournal articleResearchpeer-review

  1. Case report: ‘AARS2 leukodystrophy’

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Paroxysmal Cranial Dyskinesia and Nail-Patella Syndrome Caused by a Novel Variant in the LMX1B Gene

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. Expanding the cerebrovascular phenotype of the p.R258H variant in ACTA2 related hereditary thoracic aortic disease (HTAD)

    Research output: Contribution to journalJournal articleResearchpeer-review

  4. Clinical and biochemical improvement with galactose supplementation in SLC35A2-CDG

    Research output: Contribution to journalJournal articleResearchpeer-review

  • Eugen Mengel
  • Bruno Bembi
  • Mireia Del Toro
  • Federica Deodato
  • Matthias Gautschi
  • Stephanie Grunewald
  • Sabine Grønborg
  • Bénédicte Héron
  • Esther M Maier
  • Agathe Roubertie
  • Saikat Santra
  • Anna Tylki-Szymanska
  • Simon Day
  • Tara Symonds
  • Stacie Hudgens
  • Marc C Patterson
  • Christina Guldberg
  • Linda Ingemann
  • Nikolaj H T Petersen
  • Thomas Kirkegaard
  • Christine Í Dali
View graph of relations

BACKGROUND: 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 Trials.gov 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.

RESULTS: 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).

CONCLUSIONS: 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.

TRIAL REGISTRATION: CT-ORZY-NPC-001: ClincalTrials.gov NCT02435030, Registered 6 May 2015, https://clinicaltrials.gov/ct2/show/NCT02435030 ; EudraCT 2014-005,194-37, Registered 28 April 2015, https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-005194-37/DE . OR-REL-NPC-01: Unregistered.

Original languageEnglish
Article number328
JournalOrphanet Journal of Rare Diseases
Volume15
Issue number1
Pages (from-to)328
ISSN1750-1172
DOIs
Publication statusPublished - Dec 2020

    Research areas

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

ID: 61984605