Sterol concentrations in cultured Smith-Lemli-Opitz syndrome skin fibroblasts: Diagnosis of a biochemically atypical case of the syndrome

✍ Scribed by Honda, Akira; Tint, G. Stephen; Salen, Gerald; Kelley, Richard I.; Honda, Megumi; Batta, Ashok K.; Chen, Thomas S.; Shefer, Sarah

• Publisher: John Wiley and Sons
• Year: 1997
• Tongue: English
• Weight: 154 KB
• Volume: 68
• Category: Article
• ISSN: 0148-7299
• DOI: 10.1002/(sici)1096-8628(19970131)68:3<282::aid-ajmg7>3.0.co;2-o

✦ Synopsis

The Smith-Lemli-Opitz syndrome is a common birth defect syndrome caused by a deficiency of 7-dehydrocholesterol ⌬ 7 -reductase, an essential enzyme in the biosynthesis of cholesterol. The syndrome can usually be diagnosed easily from the plasma markers of markedly elevated 7-dehydrocholesterol and reduced cholesterol concentrations. However, atypical cases with normal plasma levels of cholesterol with only moderately elevated 7-dehydrocholesterol have been reported. To establish a sensitive method for the biochemical diagnosis of the atypical cases of the syndrome, we measured sterol concentrations of cultured skin fibroblasts. 7-Dehydrocholesterol concentrations in patients' fibroblasts grown in the presence of 10% fetal bovine serum were significantly higher than those in controls and parents (P < 0.0005), but they were not elevated proportionately as much as in plasma. To re-produce the accumulation of 7-dehydrocholesterol, the cells were exposed to delipidated medium to induce sterol biosynthesis. After 4 weeks, 7dehydrocholesterol concentrations in patients' fibroblasts increased from 2.8 ؎ 0.3% to 34 ؎ 3% of total sterols (cholesterol ؉ 7dehydrocholesterol ؉ 8-dehydrocholesterol). The increase was also observed in fibro-blasts from an atypical patient who has a normal plasma cholesterol level and a 7dehydrocholesterol concentration of only 0.15 mg/dl. In contrast, cells from parents and controls accumulated very little 7dehydrocholesterol (< 1% of total sterols). These results demonstrate that cultured fibroblasts exhibit abnormally high accumulation of 7-dehydrocholesterol after cells are exposed to delipidated medium not only in typical patients, but also in an atypical case. The present method is a sensitive procedure for the biochemical diagnosis of this syndrome. Am.