Diagnostic performance of serum sterols, including oxysterols, for identifying cerebrotendinous xanthomatosis and monitoring treatment efficacy.

BACKGROUND

Cerebrotendinous xanthomatosis (CTX) is caused by biallelic mutations in the CYP27A1 gene, which encodes sterol 27-hydroxylase. Reduced activity of this enzyme decreases bile acid synthesis and increases cholestanol production. Cholestanol, a metabolic intermediate, can be used as a diagnostic marker; however, patients with CTX have been reported to have normal cholestanol levels. Cholesterol and bile acid metabolism is likely to be extensively disrupted even in these patients with CTX.

OBJECTIVE

We aimed to clarify whether sterol markers, including oxysterols, can be used to screen for and diagnose CTX and assess treatment efficacy.

METHODS

Fourteen patients with CTX (homozygotes, n = 7; compound heterozygotes, n = 5; unidentified, n = 2), 6 carriers, and 24 healthy controls were enrolled. We analyzed 9 sterol markers, including 4 oxysterols, using gas chromatography-mass spectrometry. We measured these markers in patients with CTX before and after treatment with chenodeoxycholic acid (CDCA) and/or lipid-lowering agents.

RESULTS

Cholestanol and sterol markers of cholesterol synthesis and absorption were 1.3 to 8.3 times higher in patients with CTX than in carriers and controls. These marker levels decreased significantly in patients with CTX after treatment. Compared to carriers and controls, patients with CTX had extremely low levels of 27-hydroxycholesterol (27-OHC) and extremely high levels of 7α-hydroxycholesterol (7α-OHC). During treatment, 7α-OHC levels decreased significantly, while 27-OHC levels remained low. Receiver operating characteristic analysis demonstrated excellent diagnostic performance. The area under the curve was 1.000 for low 27-OHC and 0.991 for elevated 7α-OHC, outperforming cholestanol (0.903).

CONCLUSION

Sterol markers, including oxysterols, can be used to screen for and diagnose CTX and to assess treatment efficacy with CDCA and/or lipid-lowering agents.