Defective cholesterol biosynthesis associated with the Smith-Lemli-Opitz syndrome
Open accessAbstract
BACKGROUND: The Smith-Lemli-Opitz syndrome (frequency, 1:20,000 to 1:40,000) is defined by a constellation of severe birth defects affecting most organ systems. Abnormalities frequently include profound mental retardation, severe failure to thrive, and a high infant-mortality rate. The syndrome has heretofore been diagnosed only from its clinical presentation. METHODS: Using capillary-column gas chromatography-mass spectrometry, we measured the sterol composition of plasma, erythrocytes, lens, cultured fibroblasts, and feces from five children with the syndrome (three girls and two boys). RESULTS: Plasma cholesterol levels were abnormally low (8 to 101 mg per deciliter [0.20 to 2.60 mmol per liter]) in every patient, being well below the 5th percentile for age- and sex-matched controls. Concentrations of the cholesterol precursor 7-dehydrocholesterol (cholesta-5,7-dien-3 beta-ol), which was not detectable in most of our controls, were elevated (11 to 31 mg per deciliter) more than 2000-fold above normal and were similar to the levels of cholesterol in all tissues from all patients. An isomeric dehydrocholesterol with a structure similar to that of 7-dehydrocholesterol was also detected. CONCLUSIONS: The combination of abnormally low plasma cholesterol levels and a high concentration of the cholesterol precursor 7-dehydrocholesterol points to a major block in cholesterol biosynthesis at the step in which the C-7(8) double bond of 7-dehydrocholesterol is reduced, forming cholesterol. The block may be sufficient to deprive an embryo or fetus of cholesterol and prevent normal development, whereas the incorporation of 7-dehydrocholesterol into all membranes may interfere with proper membrane function.
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CYP11A1 action on 7DHC in vivo is supported by detection of Δ7-steroids in Smith-Lemli-Opitz syndrome patients.
“CYP11A1 action on 7DHC in vivo is further supported by detection of Δ7steroids in Smith-Lemli-Opitz syndrome patients.”
From Novel activities of CYP11A1 and their potential physiological significance (2015) · cites this paper as [59]
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- Authors
- Tint, G. S., Irons, M., Elias, E. R., Batta, A. K., Frieden, R., Chen, T. S., & Salen, G.
- Affiliations
- East Orange VA Medical Center (US)
- Tufts University (US)
- Elliot Hospital (US)
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 1994-01-13
- Volume
- 330
- Issue
- 2
- Pages
- 107-113
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W1964390696
- Cited by
- 798
- References
- 34
- Citations by year
- 2026: 6 · 2025: 10 · 2024: 10 · 2023: 16 · 2022: 8 · 2021: 16 · 2020: 12 · 2019: 14 · 2018: 17 · 2017: 19 · 2016: 22 · 2015: 14 · 2014: 26 · 2013: 20 · 2012: 33
- FWCI
- 28.55
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01dk018707-15)
- National Heart, Lung, and Blood Institute (HL 17818)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK-18707)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Metabolism and Genetic Disorders
- Health Sciences › Medicine › Surgery › Cholesterol and Lipid Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and rare skin diseases.
- Keywords
- Smith-Lemli-Opitz syndrome, cholesterol biosynthesis, 7-dehydrocholesterol, sterol composition, membrane cholesterol, intellectual disability, failure to thrive
- MeSH terms
- Abnormalities, Multiple, Adolescent, Bile Acids and Salts, Child, Child, Preschool, Cholesterol, Dehydrocholesterols, Erythrocytes, Failure to Thrive, Feces, Female, Humans, Infant, Male, Microcephaly, Sterols, Limb Deformities, Congenital
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