Submitted on July 10, 2006
Revised on September 18, 2006
Accepted on September 18, 2006
Increased non-sterol isoprenoids, dolichol and ubiquinone in Smith-Lemli-Opitz syndrome: Effects of dietary cholesterol
Anuradha S. Pappu, William E. Connor, Louise M. Merkens, Julia M. Jordan, Jennifer A. Penfield, D. Roger Illingworth, and Robert D. Steiner
Medicine. L-465, Oregon Health &Science University, Portland, OR 97239
Corresponding Author: pappua{at}ohsu.edu
The Smith-Lemli-Opitz syndrome is an inherited autosomal recessive cholesterol deficiency disorder. Studies in our laboratory have shown that in SLOS children, urinary mevalonate excretion is normal and reflects hepatic HMG CoA reductase activity but not ultimate sterol synthesis. We hypothesized that the combination of low plasma cholesterol levels in SLOS with normal urinary mevalonate excretion may indicate increased diversion of mevalonate to synthesis of non-sterol isoprenoids, which could be responsible for some of the clinical manifestations. To test our hypothesis, we measured urinary dolichol and ubiquinone, two non-sterol isoprenoids, in 16 children with SLOS and 15 controls, all fed a low cholesterol diet. Urinary mevalonate excretion was similar in SLOS subjects and control children. Urinary dolichol excretion in SLOS children was 213 ± 298 versus 31.5 ±17.6 (ng/mg creatinine) in control children. Urinary ubiquinone excretion in SLOS children was 618 ± 857 versus 87.5 ± 87.8 (ng/mg creatinine) in controls. Thus, the urinary excretion of both dolichol (p<0.002) and ubiquinone (p<0.02) in SLOS children was seven-fold higher than in control children. In a subset of twelve SLOS children, a high cholesterol diet decreased urinary mevalonate excretion by 61% (p<0.001), dolichol by 70% (p< 0.001) and ubiquinone by 67% (p<0.03). Our hypothesis that in SLOS children, normal urinary mevalonate excretion results from increased diversion of mevalonate into the production of non-sterol isoprenoids is supported. Dietary cholesterol supplementation reduced urinary mevalonate and non-sterol isoprenoid excretion but did not change the relative ratios of their excretion. In SLOS, a secondary peripheral regulation of isoprenoid synthesis may be stimulated.
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