Background: Niemann-Pick disease type C (NPC) is a rare lipid storage disorder characterized by progressive neurological deterioration. Diagnosing NPC is challenging as clinical signs and symptoms are variable and non-specific. Two oxysterols, cholestane-3β,5α,6β-triol (triol) and 7-ketocholesterol (7KC), have been proposed as biomarkers for aiding diagnosis of NPC. This study evaluated the use of triol and 7KC as biomarkers in cholestatic neonates with suspected NPC.
Methods: Plasma triol and 7KC were analysed as dimethylglycine esters using an liquid chromatography – tandem mass spectrometry (LC-MS/MS) assay in selected neonates with severe cholestasis and suspected NPC (n=7), adults with cholestasis (n=15), patients with confirmed NPC (positive controls; n=11 [one child and 10 adults]), healthy subjects (negative controls; n=40 [20 children and 20 adults]), and cholestatic adults (comparative reference; n=15). The LC-MS/MS method was subjected to a number of tests for accuracy and consistency.
Results: Triol and 7KC levels were substantially and significantly increased in NPC positive patients compared with healthy controls (p<0.001). However, positive results (markedly increased levels of both oxysterols) were identified in 6/7 (86%) neonates with cholestasis. Genetic testing confirmed NPC only in one neonate who had increased triol and 7KC, and increased oxysterol levels among neonates with no identified NPC gene mutations were considered likely due to biliary atresia (BA).
Conclusions: While the potential of oxysterols as NPC biomarkers has been well evaluated in older patient populations (without cholestasis), our data suggest that cholestasis might represent a pitfall in oxysterol measurements intended to aid diagnosis of NPC in affected patients.
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