Defective cholesterol biosynthesis associated with the Smith-Lemli-Opitz syndrome

N Engl J Med. 1994 Jan 13;330(2):107-13. doi: 10.1056/NEJM199401133300205.


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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Abnormalities, Multiple / blood*
  • Adolescent
  • Bile Acids and Salts / analysis
  • Child
  • Child, Preschool
  • Cholesterol / biosynthesis*
  • Dehydrocholesterols / analysis
  • Erythrocytes
  • Failure to Thrive
  • Feces / chemistry
  • Female
  • Humans
  • Infant
  • Limb Deformities, Congenital*
  • Male
  • Microcephaly / blood*
  • Sterols / blood


  • Bile Acids and Salts
  • Dehydrocholesterols
  • Sterols
  • Cholesterol
  • 7-dehydrocholesterol