Newborn screening for Cerebrotendinous Xanthomatosis: A retrospective biomarker study using both flow-injection and UPLC-MS/MS analysis in 20,000 newborns

Frédéric M. Vaz*, Youssra Jamal, Rob Barto, Michael H. Gelb, Andrea E. DeBarber, Ron A. Wevers, Marcel R. Nelen, Aad Verrips, Albert H. Bootsma, Marelle J. Bouva, Nick Kleise, Walter van der Zee, Tao He, Gajja S. Salomons, Hidde H. Huidekoper

*Corresponding author for this work

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Background and aims: Cerebrotendinous Xanthomatosis (CTX) is a treatable disorder of bile acid synthesis caused by deficiency of 27-sterol hydroxylase -encoded by CYP27A1- leading to gastrointestinal and progressive neuropsychiatric symptoms. Biochemically, CTX is characterized by accumulation of the bile alcohol cholestanetetrol glucuronide (GlcA-tetrol) and the deficiency of tauro-chenodeoxycholic acid (t-CDCA) and tauro-trihydroxycholestanoic acid (t-THCA). Materials and Methods: To ascertain the feasibility of CTX newborn screening (NBS) we performed a study with deidentified Dutch dried blood spots using reagents and equipment that is frequently used in NBS laboratories. 20,076 deidentified newborn blood spots were subjected to flow-injection (FIA)-MS/MS and UPLC-MS/MS analysis to determine the concentration of GlcA-tetrol and calculate the GlcA-tetrol/t-CDCA and t-THCA/GlcA-tetrol ratios. Results: Using UPLC-MS/MS analysis both GlcA-tetrol concentration and/or metabolite ratios GlcA-tetrol/t-CDCA proved to be informative biomarkers; newborn DBS results did not overlap with those of the CTX patients. For FIA-MS/MS, GlcA-tetrol also was an excellent marker but when using the combination of the GlcA-tetrol/t-CDCA and t-THCA/GlcA-tetrol ratios also did not yield any screen positives. Conclusion: Newborn screening for CTX using only metabolite ratios following the measurement of three CTX biomarkers is possible using either FIA-MS/MS or UPLC-MS/MS, which paves the way for introduction of CTX NBS.

Original languageEnglish
Pages (from-to)170-174
Number of pages5
JournalClinica Chimica Acta
Publication statusPublished - 15 Jan 2023

Bibliographical note

Funding Information:
This work was supported by ZonMw, project “Validation of a newborn screening method for Cerebrotendinous Xanthomatosis”, number 543002008. We would like to thank the Radboud Genome Technology Center (RGTC) for helping with DBS DNA purifications and subsequent whole-exome sequencing. RGTC is part of the Netherlands X-omics Initiative and partially funded by NWO (The Netherlands Organization for Scientific Research; project 184.034.019). We are grateful to Travere Therapeutics for providing GlcA-tetrol and 2H6-GlcA-tetrol internal standard.

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