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Previous Volume 330:107-113 January 13, 1994 Number 2 Next

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ABSTRACT

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 (cholest-5,7-dien-3-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.

Source Information

From the Departments of Medicine (GS.T., A.K.B., G.S.) and Pathology (T.S.C.), Veteran Affairs Medical Center, East Orange, N.J., and the University of Medicine and Dentistry-New Jersey Medical School, Newark; the Section of Clinical Genetics, Department of Pediatrics, New England Medical Center, Tufts University School of Medicine, Boston (M.I., E.R.E.); and Elliot Hospital, Manchester, N.H. (R.F.).

Address reprint requests to Dr. Tint at the Veterans Affairs Medical Center, 385 Tremont Ave., East Orange, NJ 07018-1095.

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Diagnosis of Smith-Lemli-Opitz Syndrome
McGaughran J., Donnai D., Clayton P., Mills K., Seedorf U., Walter M., Assmann G., Tint G. S., Salen G., Irons M.
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N Engl J Med 1994; 330:1685-1687, Jun 9, 1994. Correspondence

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