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

Orphanet J Rare Dis. 2020 Nov 23;15(1):328. doi: 10.1186/s13023-020-01616-0.

PMID: 33228797

Eugen Mengel, Bruno Bembi, Mireia del Toro, Federica Deodato, Matthias Gautschi, Stephanie Grunewald, Sabine Gronborg, Benedicte Heron, 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 and Christine i Dali

Summary: A multicentre, prospective observational study was conducted to characterize and measure NPC disease progression and to investigate potential NPC-related biomarkers versus healthy individuals.

Abstract

Background: Niemann–Pick disease type C (NPC) is a rare, progressive, neurodegenerative disease. A multicentre, prospective observational study 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.

Methods: 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 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 progression of 2.7 (±4.0) was reported. Compared with healthy individuals, the NPC population had significantly lower levels of cholesterol esterification, HSP70 and skin unesterified cholesterol. Cholestane-triol levels were significantly higher in individuals with NPC versus healthy individuals and correlated with the 5-domain NPCCSS. The 5-domain NPCCSS showed high ICC agreement in inter-rater reliability and intra-rater reliability.

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.