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Journal of Lipid Research, Vol. 43, 1661-1669, October 2002
Copyright © 2002 by Lipid Research, Inc.

Feedback inhibition of the cholesterol biosynthetic pathway in patients with Smith-Lemli-Opitz syndrome as demonstrated by urinary mevalonate excretion

Anuradha S. Pappu^1,2,*, Robert D. Steiner^1,, Sonja L. Connor^*, Donna P. Flavell^*, Don S. Lin^*, Lauren Hatcher^*, D. Roger Illingworth^* and William E. Connor^*

^* Division of Endocrinology, Diabetes and Clinical Nutrition, Department of Medicine, Oregon Health & Science University, Portland, Oregon 97201
Departments of Pediatrics and Molecular and Medical Genetics, Child Development and Rehabilitation Center, Doernbecher Children's Hospital, Oregon Health & Science University, Portland, Oregon 97201

² To whom correspondence should be addressed. e-mail: pappua{at}ohsu.edu

Smith-Lemli-Opitz syndrome (SLOS) is a genetic disorder characterized by low plasma cholesterol and high 7-dehydrocholesterol (7-DHC). Synthesis of cholesterol and 7-DHC and its metabolites is regulated by HMG-CoA reductase, whose activity can be measured by 24-h excretion of its product mevalonate. We devised a simple, non-invasive method for collecting 24-h urine in our subjects. With a background of a very low cholesterol diet, mean mevalonate excretion did not differ between controls and SLOS children, indicating that SLOS subjects have normal HMG-CoA reductase activity. In a short term feeding study, the effects of a high cholesterol diet in SLOS subjects include a significant 55% increase in plasma cholesterol levels and 39% decrease in mevalonate excretion and no change in plasma 7-DHC levels. However, in four SLOS subjects, fed a high cholesterol diet for 2–3 years, plasma cholesterol levels continued to increase, urinary mevalonate excretion remained low and total 7-DHC decreased significantly, likely from decreased total sterol synthesis.

Thus, in SLOS subjects, HMG-CoA reductase activity was normal and was subject to normal cholesterol induced feedback inhibition. However, total sterol synthesis in SLOS may still be decreased because of increased diversion of mevalonate into the shunt pathway away from sterol synthesis.

Abbreviations: 7-DHC, 7-dehydrocholesterol; 8-DHC, 8-dehydrocholesterol; SLOS, Smith-Lemli-Opitz syndrome

Supplementary key words 7-dehydrocholesterol • 8-dehydrocholesterol • 3-hydroxy-3-methylglutaryl-coenzyme A reductase • 24-h urine • sterols • mevalonate shunt pathway • 3-methyl glutaconic acid

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