A blood test for cerebrotendinous xanthomatosis with potential for disease detection in newborns

Andrea De Barber, Jenny Luo, Michal Star-Weinstock, Subhasish Purkayastha, Michael T. Geraghty, Pei-Wen Chiang, Louise S. Merkens, Anuradha Pappu, Robert D. Steiner

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Cerebrotendinous xanthomatosis (CTX) is a rare, diffi cult-to-diagnose genetic disorder of bile acid (BA) synthesis that can cause progressive neurological damage and premature death. Detection of CTX in the newborn period would be benefi cial because an effective oral therapy for CTX is available to prevent disease progression. There is no suitable test to screen newborn dried bloodspots (DBS) for CTX. Blood screening for CTX is currently performed by GC-MS measurement of elevated 5 - -cholestanol. We present here LC-ESI/MS/MS methodology utilizing keto derivatization with ( O -(3-trimethylammonium-propyl) hydroxylamine) reagent to enable sensitive detection of ketosterol BA precursors that accumulate in CTX. The availability of isotopically enriched derivatization reagent allowed ready tagging of ketosterols to generate internal standards for isotope dilution quantifi cation. Ketosterols were quantifi ed and their utility as markers for CTX was compared with 5 - -cholestanol. 7 - ,12 - - Dihydroxy-4-cholesten-3-one provided the best discrimination between CTX and unaffected samples. In two CTX, newborn DBS concentrations of this ketosterol (120-214 ng/ml) were - 10-fold higher than in unaffected newborn DBS (16.4 ± 6.0 ng/ml), such that quantifi cation of this ketosterol provides a test with potential to screen newborn DBS for CTX. Early detection and intervention through newborn screening would greatly benefi t those affected with CTX by preventing morbidity and mortality.

Original languageEnglish (US)
Pages (from-to)146-154
Number of pages9
JournalJournal of Lipid Research
Volume55
Issue number1
DOIs
StatePublished - Jan 2014

Fingerprint

Cerebrotendinous Xanthomatosis
Cholestanol
Hematologic Tests
Bile Acids and Salts
Cations
Screening
Blood
Hydroxylamine
Isotopes
Dilution
Availability
Inborn Genetic Diseases
Premature Mortality
Disease Progression

Keywords

  • Bile acid
  • CYP27A1
  • Derivatization
  • Ketosterol
  • LC-ESI-MS/MS
  • Leukodystrophy
  • Newborn screening

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Endocrinology

Cite this

De Barber, A., Luo, J., Star-Weinstock, M., Purkayastha, S., Geraghty, M. T., Chiang, P-W., ... Steiner, R. D. (2014). A blood test for cerebrotendinous xanthomatosis with potential for disease detection in newborns. Journal of Lipid Research, 55(1), 146-154. https://doi.org/10.1194/jlr.P043273

A blood test for cerebrotendinous xanthomatosis with potential for disease detection in newborns. / De Barber, Andrea; Luo, Jenny; Star-Weinstock, Michal; Purkayastha, Subhasish; Geraghty, Michael T.; Chiang, Pei-Wen; Merkens, Louise S.; Pappu, Anuradha; Steiner, Robert D.

In: Journal of Lipid Research, Vol. 55, No. 1, 01.2014, p. 146-154.

Research output: Contribution to journalArticle

De Barber, A, Luo, J, Star-Weinstock, M, Purkayastha, S, Geraghty, MT, Chiang, P-W, Merkens, LS, Pappu, A & Steiner, RD 2014, 'A blood test for cerebrotendinous xanthomatosis with potential for disease detection in newborns', Journal of Lipid Research, vol. 55, no. 1, pp. 146-154. https://doi.org/10.1194/jlr.P043273
De Barber A, Luo J, Star-Weinstock M, Purkayastha S, Geraghty MT, Chiang P-W et al. A blood test for cerebrotendinous xanthomatosis with potential for disease detection in newborns. Journal of Lipid Research. 2014 Jan;55(1):146-154. https://doi.org/10.1194/jlr.P043273
De Barber, Andrea ; Luo, Jenny ; Star-Weinstock, Michal ; Purkayastha, Subhasish ; Geraghty, Michael T. ; Chiang, Pei-Wen ; Merkens, Louise S. ; Pappu, Anuradha ; Steiner, Robert D. / A blood test for cerebrotendinous xanthomatosis with potential for disease detection in newborns. In: Journal of Lipid Research. 2014 ; Vol. 55, No. 1. pp. 146-154.
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N2 - Cerebrotendinous xanthomatosis (CTX) is a rare, diffi cult-to-diagnose genetic disorder of bile acid (BA) synthesis that can cause progressive neurological damage and premature death. Detection of CTX in the newborn period would be benefi cial because an effective oral therapy for CTX is available to prevent disease progression. There is no suitable test to screen newborn dried bloodspots (DBS) for CTX. Blood screening for CTX is currently performed by GC-MS measurement of elevated 5 - -cholestanol. We present here LC-ESI/MS/MS methodology utilizing keto derivatization with ( O -(3-trimethylammonium-propyl) hydroxylamine) reagent to enable sensitive detection of ketosterol BA precursors that accumulate in CTX. The availability of isotopically enriched derivatization reagent allowed ready tagging of ketosterols to generate internal standards for isotope dilution quantifi cation. Ketosterols were quantifi ed and their utility as markers for CTX was compared with 5 - -cholestanol. 7 - ,12 - - Dihydroxy-4-cholesten-3-one provided the best discrimination between CTX and unaffected samples. In two CTX, newborn DBS concentrations of this ketosterol (120-214 ng/ml) were - 10-fold higher than in unaffected newborn DBS (16.4 ± 6.0 ng/ml), such that quantifi cation of this ketosterol provides a test with potential to screen newborn DBS for CTX. Early detection and intervention through newborn screening would greatly benefi t those affected with CTX by preventing morbidity and mortality.

AB - Cerebrotendinous xanthomatosis (CTX) is a rare, diffi cult-to-diagnose genetic disorder of bile acid (BA) synthesis that can cause progressive neurological damage and premature death. Detection of CTX in the newborn period would be benefi cial because an effective oral therapy for CTX is available to prevent disease progression. There is no suitable test to screen newborn dried bloodspots (DBS) for CTX. Blood screening for CTX is currently performed by GC-MS measurement of elevated 5 - -cholestanol. We present here LC-ESI/MS/MS methodology utilizing keto derivatization with ( O -(3-trimethylammonium-propyl) hydroxylamine) reagent to enable sensitive detection of ketosterol BA precursors that accumulate in CTX. The availability of isotopically enriched derivatization reagent allowed ready tagging of ketosterols to generate internal standards for isotope dilution quantifi cation. Ketosterols were quantifi ed and their utility as markers for CTX was compared with 5 - -cholestanol. 7 - ,12 - - Dihydroxy-4-cholesten-3-one provided the best discrimination between CTX and unaffected samples. In two CTX, newborn DBS concentrations of this ketosterol (120-214 ng/ml) were - 10-fold higher than in unaffected newborn DBS (16.4 ± 6.0 ng/ml), such that quantifi cation of this ketosterol provides a test with potential to screen newborn DBS for CTX. Early detection and intervention through newborn screening would greatly benefi t those affected with CTX by preventing morbidity and mortality.

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