A useful multi-analyte blood test for cerebrotendinous xanthomatosis

Andrea De Barber, Jenny Luo, Roberto Giugliani, Carolina F M Souza, Pei-Wen Chiang, Louise S. Merkens, Anuradha Pappu, Robert D. Steiner

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

Objectives: Cerebrotendinous xanthomatosis (CTX) is a rare genetic disorder of bile acid (BA) synthesis that can cause progressive neurological damage and premature death. Blood (normally serum or plasma) testing for CTX is performed by a small number of specialized laboratories, routinely by gas chromatography-mass spectrometry (GC-MS) measurement of elevated 5α-cholestanol. We report here on a more sensitive biochemical approach to test for CTX particularly useful for confirmation of CTX in the case of a challenging diagnostic sample with 5α-cholestanol that, although elevated, was below the cut-off used for diagnosis of CTX (10. μg/mL or 1.0. mg/dL). Design and methods: We have previously described liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) methodology utilizing keto derivatization to enable the sensitive quantification of plasma ketosterol BA precursors that accumulate in CTX. We have expanded this methodology to perform isotope dilution LC-ESI-MS/MS quantification of a panel of plasma ketosterol BA precursors, with internal standards readily generated using isotopically-enriched derivatization reagent. Results: Quantification of plasma ketosterol BA precursors (7α-hydroxy-4-cholesten-3-one, 7α,12α-dihydroxy-4-cholesten-3-one and 7α,12α-dihydroxy-5β-cholestan-3-one) in a single LC-ESI/MS/MS test provided better discrimination between a CTX-positive and negative samples analyzed (n = 20) than measurement of 5α-cholestanol alone. Conclusions: Quantification of plasma ketosterol BA precursors provides a more sensitive biochemical approach to discriminate between CTX negative and positive samples. A multiplexed LC-ESI-MS/MS test quantifying a panel of plasma ketosterols, with simple sample preparation, rapid analysis time and readily available internal standards, can be performed by most clinical laboratories. Wider availability of testing will benefit those affected with CTX.

Original languageEnglish (US)
Pages (from-to)860-863
Number of pages4
JournalClinical Biochemistry
Volume47
Issue number9
DOIs
StatePublished - 2014

Fingerprint

Cerebrotendinous Xanthomatosis
Hematologic Tests
Bile Acids and Salts
Blood
Cholestanol
Plasmas
Mass spectrometry
Clinical laboratories
Electrospray ionization
Liquid chromatography
Testing
Isotopes
Gas chromatography
Dilution
Inborn Genetic Diseases
Premature Mortality
Electrospray Ionization Mass Spectrometry
Availability
Tandem Mass Spectrometry
Liquid Chromatography

Keywords

  • Bile acids
  • Cerebrotendinous xanthomatosis
  • Cholestanol
  • CYP27A1
  • Ketosterols

ASJC Scopus subject areas

  • Clinical Biochemistry
  • Medicine(all)

Cite this

De Barber, A., Luo, J., Giugliani, R., Souza, C. F. M., Chiang, P-W., Merkens, L. S., ... Steiner, R. D. (2014). A useful multi-analyte blood test for cerebrotendinous xanthomatosis. Clinical Biochemistry, 47(9), 860-863. https://doi.org/10.1016/j.clinbiochem.2014.04.017

A useful multi-analyte blood test for cerebrotendinous xanthomatosis. / De Barber, Andrea; Luo, Jenny; Giugliani, Roberto; Souza, Carolina F M; Chiang, Pei-Wen; Merkens, Louise S.; Pappu, Anuradha; Steiner, Robert D.

In: Clinical Biochemistry, Vol. 47, No. 9, 2014, p. 860-863.

Research output: Contribution to journalArticle

De Barber, A, Luo, J, Giugliani, R, Souza, CFM, Chiang, P-W, Merkens, LS, Pappu, A & Steiner, RD 2014, 'A useful multi-analyte blood test for cerebrotendinous xanthomatosis', Clinical Biochemistry, vol. 47, no. 9, pp. 860-863. https://doi.org/10.1016/j.clinbiochem.2014.04.017
De Barber A, Luo J, Giugliani R, Souza CFM, Chiang P-W, Merkens LS et al. A useful multi-analyte blood test for cerebrotendinous xanthomatosis. Clinical Biochemistry. 2014;47(9):860-863. https://doi.org/10.1016/j.clinbiochem.2014.04.017
De Barber, Andrea ; Luo, Jenny ; Giugliani, Roberto ; Souza, Carolina F M ; Chiang, Pei-Wen ; Merkens, Louise S. ; Pappu, Anuradha ; Steiner, Robert D. / A useful multi-analyte blood test for cerebrotendinous xanthomatosis. In: Clinical Biochemistry. 2014 ; Vol. 47, No. 9. pp. 860-863.
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abstract = "Objectives: Cerebrotendinous xanthomatosis (CTX) is a rare genetic disorder of bile acid (BA) synthesis that can cause progressive neurological damage and premature death. Blood (normally serum or plasma) testing for CTX is performed by a small number of specialized laboratories, routinely by gas chromatography-mass spectrometry (GC-MS) measurement of elevated 5α-cholestanol. We report here on a more sensitive biochemical approach to test for CTX particularly useful for confirmation of CTX in the case of a challenging diagnostic sample with 5α-cholestanol that, although elevated, was below the cut-off used for diagnosis of CTX (10. μg/mL or 1.0. mg/dL). Design and methods: We have previously described liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) methodology utilizing keto derivatization to enable the sensitive quantification of plasma ketosterol BA precursors that accumulate in CTX. We have expanded this methodology to perform isotope dilution LC-ESI-MS/MS quantification of a panel of plasma ketosterol BA precursors, with internal standards readily generated using isotopically-enriched derivatization reagent. Results: Quantification of plasma ketosterol BA precursors (7α-hydroxy-4-cholesten-3-one, 7α,12α-dihydroxy-4-cholesten-3-one and 7α,12α-dihydroxy-5β-cholestan-3-one) in a single LC-ESI/MS/MS test provided better discrimination between a CTX-positive and negative samples analyzed (n = 20) than measurement of 5α-cholestanol alone. Conclusions: Quantification of plasma ketosterol BA precursors provides a more sensitive biochemical approach to discriminate between CTX negative and positive samples. A multiplexed LC-ESI-MS/MS test quantifying a panel of plasma ketosterols, with simple sample preparation, rapid analysis time and readily available internal standards, can be performed by most clinical laboratories. Wider availability of testing will benefit those affected with CTX.",
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AU - Luo, Jenny

AU - Giugliani, Roberto

AU - Souza, Carolina F M

AU - Chiang, Pei-Wen

AU - Merkens, Louise S.

AU - Pappu, Anuradha

AU - Steiner, Robert D.

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N2 - Objectives: Cerebrotendinous xanthomatosis (CTX) is a rare genetic disorder of bile acid (BA) synthesis that can cause progressive neurological damage and premature death. Blood (normally serum or plasma) testing for CTX is performed by a small number of specialized laboratories, routinely by gas chromatography-mass spectrometry (GC-MS) measurement of elevated 5α-cholestanol. We report here on a more sensitive biochemical approach to test for CTX particularly useful for confirmation of CTX in the case of a challenging diagnostic sample with 5α-cholestanol that, although elevated, was below the cut-off used for diagnosis of CTX (10. μg/mL or 1.0. mg/dL). Design and methods: We have previously described liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) methodology utilizing keto derivatization to enable the sensitive quantification of plasma ketosterol BA precursors that accumulate in CTX. We have expanded this methodology to perform isotope dilution LC-ESI-MS/MS quantification of a panel of plasma ketosterol BA precursors, with internal standards readily generated using isotopically-enriched derivatization reagent. Results: Quantification of plasma ketosterol BA precursors (7α-hydroxy-4-cholesten-3-one, 7α,12α-dihydroxy-4-cholesten-3-one and 7α,12α-dihydroxy-5β-cholestan-3-one) in a single LC-ESI/MS/MS test provided better discrimination between a CTX-positive and negative samples analyzed (n = 20) than measurement of 5α-cholestanol alone. Conclusions: Quantification of plasma ketosterol BA precursors provides a more sensitive biochemical approach to discriminate between CTX negative and positive samples. A multiplexed LC-ESI-MS/MS test quantifying a panel of plasma ketosterols, with simple sample preparation, rapid analysis time and readily available internal standards, can be performed by most clinical laboratories. Wider availability of testing will benefit those affected with CTX.

AB - Objectives: Cerebrotendinous xanthomatosis (CTX) is a rare genetic disorder of bile acid (BA) synthesis that can cause progressive neurological damage and premature death. Blood (normally serum or plasma) testing for CTX is performed by a small number of specialized laboratories, routinely by gas chromatography-mass spectrometry (GC-MS) measurement of elevated 5α-cholestanol. We report here on a more sensitive biochemical approach to test for CTX particularly useful for confirmation of CTX in the case of a challenging diagnostic sample with 5α-cholestanol that, although elevated, was below the cut-off used for diagnosis of CTX (10. μg/mL or 1.0. mg/dL). Design and methods: We have previously described liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) methodology utilizing keto derivatization to enable the sensitive quantification of plasma ketosterol BA precursors that accumulate in CTX. We have expanded this methodology to perform isotope dilution LC-ESI-MS/MS quantification of a panel of plasma ketosterol BA precursors, with internal standards readily generated using isotopically-enriched derivatization reagent. Results: Quantification of plasma ketosterol BA precursors (7α-hydroxy-4-cholesten-3-one, 7α,12α-dihydroxy-4-cholesten-3-one and 7α,12α-dihydroxy-5β-cholestan-3-one) in a single LC-ESI/MS/MS test provided better discrimination between a CTX-positive and negative samples analyzed (n = 20) than measurement of 5α-cholestanol alone. Conclusions: Quantification of plasma ketosterol BA precursors provides a more sensitive biochemical approach to discriminate between CTX negative and positive samples. A multiplexed LC-ESI-MS/MS test quantifying a panel of plasma ketosterols, with simple sample preparation, rapid analysis time and readily available internal standards, can be performed by most clinical laboratories. Wider availability of testing will benefit those affected with CTX.

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