TY - JOUR
T1 - A useful multi-analyte blood test for cerebrotendinous xanthomatosis
AU - DeBarber, Andrea E.
AU - Luo, Jenny
AU - Giugliani, Roberto
AU - Souza, Carolina F.M.
AU - Chiang, John (Pei Wen)
AU - Merkens, Louise S.
AU - Pappu, Anuradha S.
AU - Steiner, Robert D.
N1 - Funding Information:
The authors would like to thank the Bioanalytical Shared Resource at OHSU for providing technical assistance and access to analytical instrumentation. AED has been supported as a KL2 awardee by the Oregon Clinical and Translational Research Institute (OCTRI), grant number (KL2TR000152) from the National Center for Advancing Translational Sciences (NCATS) at the National Institutes of Health (NIH) and also as a training grant awardee by the Sterol and Isoprenoid Diseases (STAIR) consortium. STAIR is part of the NIH Rare Diseases Clinical Research Network (RDCRN). Funding and/or programmatic support for this project has been provided by a grant ( 1U54HD061939 ) from the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and the NIH Office of Rare Diseases Research (ORDR) .
PY - 2014/6
Y1 - 2014/6
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.
KW - Bile acids
KW - CYP27A1
KW - Cerebrotendinous xanthomatosis
KW - Cholestanol
KW - Ketosterols
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U2 - 10.1016/j.clinbiochem.2014.04.017
DO - 10.1016/j.clinbiochem.2014.04.017
M3 - Article
C2 - 24769274
AN - SCOPUS:84902678677
SN - 0009-9120
VL - 47
SP - 860
EP - 863
JO - Clinical Biochemistry
JF - Clinical Biochemistry
IS - 9
ER -