Towards a New Diagnostic Standard for Niemann-Pick C Disease.

Niemann–Pick C (NPC) disease is rare, neurodegenerative, lysosomal cholesterol storage disorder. Diagnosis of the disease is often delayed due to disease heterogeneity, non-specific early visceral and neurological symptoms, and lack of a rapid and reliable diagnostic assay. As a result, the disease progresses and opportunities to intervene tragically are lost. Until recently, the principal diagnostic test for NPC disease was filipin staining of unesterified cholesterol in cultured fibroblasts obtained from a skin biopsy. While the filipin assay is sensitive for diagnosis of “classical” disease, it is unable to provide a firm diagnosis in fibroblasts with “variant” phenotypes that represent N1/3 of NPC cases (Stampfer et al., 2013). Moreover, the test is invasive, performed only at specialized centers, is costly (3000 USD), and generally entails ~3 month turnaround time, all of which are disincentives for broad clinical deployment. Genetic analysis, involving sequencing of the NPC1 and NPC2 genes, is an important diagnostic tool, though, due to cost considerations, it is generally applied as a confirmatory rather than screening test. Furthermore, routine gene sequencing detects mutations on both alleles in only 85% cases and is confounded by the highly polymorphic nature of NPC1 (N400 known mutations), which makes interpretation of new mutations challenging (Stampfer et al., 2013). Over the past several years, biomarker discovery efforts have led to identification of several promising NPC disease biomarkers. One of these markers, cholestane-3β,5α,6β-triol (“triol”), which is a cholesterol oxidation product, has emerged as a sensitive diagnostic for NPC disease (Porter et al., 2010). The application of this biomarker to rapid diagnosis of NPC has been demonstrated at multiple centers and on diverse platforms (Boenzi et al., 2014; Klinke et al., 2015; Pajares et al., 2015; Polo et al., 2015; Jiang et al., 2011). In this issue of EBioMedicine,