Biosynthesis of 5α-Cholestan-3β-ol in Cerebrotendinous Xanthomatosis

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Abstract
Cerebrotendinous Xanthomatosis is a rare, inherited disease characterized by an extraordinary accumulation of cholestanol in all tissues, xanthomatous deposits in the brain, lungs, and Achilles tendons, premature atherosclerosis, and low plasma cholesterol concentrations. In two patients with the disease, the biosynthesis of cholestanol was examined by different techniques. After cholesterol-4-14C was injected intravenously into one patient, cholestanol and cholesterol isolated from the bile on 3 different days over the ensuing week contained significant radioactivity. The specific radioactivity-time curves for cholesterol-14C and cholestanol-14C suggested a precursor product relationship and provided additional evidence for the transformation of cholesterol into cholestanol. The second patient received intravenously a mixture of mevalonate-2-14C and stereospecifically labeled mevalonate-3R,4R-3H. Again cholesterol and cholestanol were isolated from the bile, and the 3H/14C ratio in both sterols was almost the same. This experiment again demonstrated that the biosynthetic path of cholestanol proceeded through cholesterol and not directly from earlier 5α-H-saturated precursors. These two independent lines of evidence indicate that the extraordinary deposition of cholestanol in Cerebrotendinous Xanthomatosis arises from cholesterol presumably through the accentuation of the normal biosynthetic pathway.