Cerebrotendinous xanthomatosis (CTX) is a treatable neurodegenerative metabolic disorder of bile acid synthesis in which symptoms can be prevented if treatment with chenodeoxycholic acid supplementation is initiated early in life, making CTX an excellent candidate for newborn screening. We developed a new dried blood spot (DBS) screening assay for this disorder on the basis of different ratios between the accumulating cholestanetetrol glucuronide (tetrol) and specific bile acids/bile acid intermediates, without the need for derivatization. A quarter-inch DBS punch was extracted with methanol, internal standards were added, and after concentration the extract was injected into the tandem mass spectrometer using a 2 min flow injection analysis for which specific transitions were measured for cholestanetetrol glucuronide, taurochenodeoxycholic acid (t-CDCA), and taurotrihydroxycholestanoic acid (t-THCA). A proof-of-principle experiment was performed using 217 Guthrie cards from healthy term/preterm newborns, CTX patients, and Zellweger patients. Using two calculated biomarkers, tetrol:t-CDCA and t-THCA:tetrol, this straightforward method achieved an excellent separation between DBSs of CTX patients and those of controls, Zellweger patients, and newborns with cholestasis. The results of this small pilot study indicate that the tetrol:t-CDCA ratio is an excellent derived biomarker for CTX that has the potential to be used in neonatal screening programs.

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Keywords Bile acid metabolism, Bile acids and salts biosynthesis, CYP27A1, Inborn errors of metabolism, Tandem mass spectrometry
Persistent URL dx.doi.org/10.1194/jlr.P075051, hdl.handle.net/1765/99863
Journal Journal of Lipid Research
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Vaz, F.M, Bootsma, A.H, Kulik, W, Verrips, A, Wevers, R.A, Schielen, P.C.J.I, … Huidekoper, H.H. (2017). A newborn screening method for cerebrotendinous xanthomatosis using bile alcohol glucuronides and metabolite ratios. Journal of Lipid Research, 58(5), 1002–1007. doi:10.1194/jlr.P075051