Newborn screening for cerebrotendinous xanthomatosis is the solution for early identification and treatment

Andrea De Barber, Limor Kalfon, Ayalla Fedida, Vered Fleisher Sheffer, Shani Ben Haroush, Natalia Chasnyk, Efrat Shuster Biton, Hanna Mandel, Krystal Jeffries, Eric S. Shinwell, Tzipora C. Falik-Zaccai

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

Cerebrotendinous xanthomatosis (CTX) is a progressive metabolic leukodystrophy. Early identification and treatment from birth onward effectively provides a functional cure, but diagnosis is often delayed. We conducted a pilot study using a two-tier test for CTX to screen archived newborn dried bloodspots (DBSs) or samples collected prospectively from a high-risk Israeli newborn population. All DBS samples were analyzed with flow injection analysis (FIA)-MS/MS, and 5% of samples were analyzed with LC-MS/MS. Consecutively collected samples were analyzed to identify CTX-causing founder genetic variants common among Druze and Moroccan Jewish populations. First-tier analysis with FIA-MS/MS provided 100% sensitivity to detect CTX-positive newborn DBSs, with a low false-positive rate (0.1-0.5%). LC-MS/MS, as a second-tier test, provided 100% sensitivity to detect CTX-positive newborn DBSs with a false-positive rate of 0% (100% specificity). In addition, 5β-cholestane-3α,7α,12α,25-tetrol-3-O-β-D-glucuronide was identified as the predominant bile-alcohol disease marker present in CTX-positive newborn DBSs. In newborns identifying as Druze, a 1:30 carriership frequency was determined for the c.355delC CYP27A1 gene variant, providing an estimated disease prevalence of 1:3,600 in this population. These data support the feasibility of two-tier DBS screening for CTX in newborns and set the stage for large-scale prospective pilot studies.

Original languageEnglish (US)
Pages (from-to)2214-2222
Number of pages9
JournalJournal of Lipid Research
Volume59
Issue number11
DOIs
StatePublished - Nov 1 2018

Keywords

  • bile acids and salts
  • diagnostic tools
  • inborn errors of metabolism
  • mass spectrometry
  • storage diseases

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

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  • Cite this

    De Barber, A., Kalfon, L., Fedida, A., Fleisher Sheffer, V., Ben Haroush, S., Chasnyk, N., Shuster Biton, E., Mandel, H., Jeffries, K., Shinwell, E. S., & Falik-Zaccai, T. C. (2018). Newborn screening for cerebrotendinous xanthomatosis is the solution for early identification and treatment. Journal of Lipid Research, 59(11), 2214-2222. https://doi.org/10.1194/jlr.M087999