Oxysterol/chitotriosidase based selective screening for Niemann-Pick type C in infantile cholestasis syndrome patients

Anna V Degtyareva,Tatiana Y Proshlyakova,Elena A Kamenets,Dmitry N Degtyarev,Galina V Baydakova,Ekaterina Y Zakharova,Denis V Rebrikov,Marina S Gautier

doi:10.1186/s12881-019-0857-0

Abstract

BackgroundNiemann-Pick disease type C (NP-C) is an inherited neurodegenerative disease (1 per 100 000 newborns) caused by NPC proteins impairment that leads to unesterified cholesterol accumulation in late endosomal/lysosomal compartments. To date the NP-C diagnostics is usually based on cholesterol detection in fibroblasts using an invasive and time-consuming Filipin staining and we need more arguments to widely introduce oxysterols as a biomarkers in NP-C.MethodsInsofar as NP-C represents about 8% of all infant cholestases, in this prospective observational study we tried to re-assess the specificity plasma oxysterol and chitotriosidase as a biochemical screening markers of NP-C in children with cholestasis syndrome of unknown origin. For 108 patients (aged from 2 weeks to 7 years) the levels of cholestane-3β,5α,6β-triol (C-triol) and chitotriosidase (ChT) were measured. For patients with elevated C-triol and/or ChT the NPC1 and NPC2 genes were Sanger-sequenced and 47 additional genes (from the custom liver damage panel) were NGS-sequenced.ResultsIncreased C-triol level (> 50 ng/ml) was detected in 4 (of 108) infants with cholestasis syndrome of unknown origin, with following molecular genetic NP-C diagnosis for one patient. Plasma cholesterol significantly correlates with C-triol (p < 0.05). NGS of high C-triol infants identified three patients with mutations in JAG1 (Alagille syndrome) and ABCB11 (Byler disease) genes. Increased ChT activity was detected in 8 (of 108) patients with various aetiologies, including NP-C, Byler disease and biliary atresia.ConclusionCombined analysis of ChT activity and C-triol levels is an effective method for identifying NP-C.

Highlights

Niemann-Pick disease type C (NP-C) is an inherited neurodegenerative disease (1 per 100 000 newborns) caused by NPC proteins impairment that leads to unesterified cholesterol accumulation in late endosomal/lysosomal compartments
95% of NP-C cases are caused by mutations in the NPC1 gene, with approximately 5% caused by mutations in the NPC2 gene
Patients and study design The blood samples were obtained from 108 infants with cholestasis syndrome of unknown origin in Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology (Moscow, Russia) and Research Centre for Medical Genetics (Moscow, Russia) between January 2014 and May 2017

Summary

Introduction

Niemann-Pick disease type C (NP-C) is an inherited neurodegenerative disease (1 per 100 000 newborns) caused by NPC proteins impairment that leads to unesterified cholesterol accumulation in late endosomal/lysosomal compartments. Niemann-Pick disease type C (NP-C) is a rare progressive neurodegenerative disease with an incidence of one per 89 000–150 000 live births among the Western European population [1, 2]. The clinical symptoms of NP-C are highly variable and can be divided into three categories: visceral, neurological, and psychiatric [3]. The earliest clinical symptoms of the NP-C among all the patients are neonatal cholestasis syndrome, isolated splenomegaly and hepatosplenomegaly [1, 3, 7]. Some cases of nonimmune hydrops and ascites have been reported [8, 9].

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