A useful multi-analyte blood test for cerebrotendinous xanthomatosis

作者：DeBarber Andrea E^*; Luo Jenny; Giugliani Roberto; Souza Carolina F M; Chiang John; Merkens Louise S; Pappu Anuradha S; Steiner Robert D

来源：Clinical Biochemistry, 2014, 47(9): 860-863.

DOI：10.1016/j.clinbiochem.2014.04.017

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

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 5 alpha-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 5 alpha-cholestanol that, although elevated, was below the cut-off used for diagnosis of CTX (10 mu g/mL or 1.0 mg/dL). %26lt;br%26gt;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. %26lt;br%26gt;Results: Quantification of plasma ketosterol BA precursors (7 alpha-hydroxy-4-cholesten-3-one, 7 alpha,12 alpha-dihydroxy-4-cholesten-3-one and 7 alpha,12 alpha-dihydroxy-5 beta-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 5 alpha-cholestanol alone. %26lt;br%26gt;Conclusions: Quantification of plasma ketosterol BA precursors provides a more sensitive biochemical approach to discriminate between CIX 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.

• 出版日期2014-6