In Smith-Lemli-Opitz Syndrome (SLOS) cholesterol levels in plasma and tissue are low, and concentrations of 7-dehyrdocholesterol and other sterols are high. These other sterols are pathologic and are not normally present. Patients with SLOS block the synthesis of cholesterol because of a deficiency in enzyme 7-dehydrocholesterol delta 7-reductase, and it is 7-dehydrocholesterol that converts to cholesterol in the last step of cholesterol synthesis. The principal investigator (PI) has proposed to feed dietary cholesterol from three different sources, egg yolk, crystalline cholesterol and butterfat to SLOS patients. Cholesterol absorption and synthesis will be determined in both very low cholesterol diets and high cholesterol diets. Using three different techniques, the PI will measure whole body cholesterol absorption and synthesis as well as bile acid synthesis in SLOS patients and in control subjects. The three different techniques include measuring cholesterol synthesis and absorption and bile acid synthesis by the sterol balance, determining cholesterol synthesis by measuring the incorporation of deuterated water into erythrocyte cholesterol, and determining sterol synthesis in SLOS patients and control subjects by measuring 24-hour urinary mevalonate excretion. The objective is to fully understand the effects that 7-dehydrocholesterol delta 7-reductase deficiency has on sterol metabolism in SLOS. Long-term dietary cholesterol supplementation feeding studies might produce more definitive results about the effect that 7-dehydrocholesterol delta 7-reductase deficiency has on sterol metabolism than have short-term supplementation feeding studies. Once the optimal dose and best source of dietary cholesterol (egg yolk, crystalline cholesterol or butterfat) is determined, the diets of SLOS patients will be supplemented for one year or longer. Biochemical parameters of these patients will be measured during this time. As a result of these feeding studies, therapies can be devised and applied to SLOS patients immediately following identification of their condition. It is the PI's plan to identify mutations in the 7-dehydrocholesterol delta 7-reductase gene in SLOS patients in order to establish a genotype-phenotype correlation based on dysmorphology and sterol synthesis. Developmental testing will be performed.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
3R01HL064618-03S1
Application #
6664259
Study Section
Nutrition Study Section (NTN)
Program Officer
Ershow, Abby
Project Start
2000-04-01
Project End
2004-03-31
Budget Start
2002-04-01
Budget End
2004-03-31
Support Year
3
Fiscal Year
2002
Total Cost
$153,484
Indirect Cost
Name
Oregon Health and Science University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009584210
City
Portland
State
OR
Country
United States
Zip Code
97239
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Lin, Don S; Steiner, Robert D; Flavell, Donna P et al. (2005) Intestinal absorption of cholesterol by patients with Smith-Lemli-Opitz syndrome. Pediatr Res 57:765-70
Merkens, Louise S; Connor, William E; Linck, Leesa M et al. (2004) Effects of dietary cholesterol on plasma lipoproteins in Smith-Lemli-Opitz syndrome. Pediatr Res 56:726-32
Sikora, Darryn M; Ruggiero, Mark; Petit-Kekel, Kersti et al. (2004) Cholesterol supplementation does not improve developmental progress in Smith-Lemli-Opitz syndrome. J Pediatr 144:783-91
Pappu, Anuradha S; Steiner, Robert D; Connor, Sonja L et al. (2002) Feedback inhibition of the cholesterol biosynthetic pathway in patients with Smith-Lemli-Opitz syndrome as demonstrated by urinary mevalonate excretion. J Lipid Res 43:1661-9
Steiner, R D; Linck, L M; Flavell, D P et al. (2000) Sterol balance in the Smith-Lemli-Opitz syndrome. Reduction in whole body cholesterol synthesis and normal bile acid production. J Lipid Res 41:1437-47
Linck, L M; Lin, D S; Flavell, D et al. (2000) Cholesterol supplementation with egg yolk increases plasma cholesterol and decreases plasma 7-dehydrocholesterol in Smith-Lemli-Opitz syndrome. Am J Med Genet 93:360-5