Sterol concentrations in cultured Smith-Lemli-Opitz syndrome skin fibroblasts: diagnosis of a biochemically atypical case of the syndrome.
The Smith-Lemli-Opitz syndrome is a common birth defect syndrome caused by a deficiency of 7-dehydrocholesterol delta 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, 7-dehydrocholesterol concentrations in patients' fibroblasts increased from 2.8 +/- 0.3% to 34 +/- 3% of total sterols (cholesterol + 7-dehydrocholesterol + 8-dehydrocholesterol). The increase was also observed in fibroblasts from an atypical patient who has a normal plasma cholesterol level and a 7-dehydrocholesterol concentration of only 0.15 mg/dl. In contrast, cells from parents and controls accumulated very little 7-dehydrocholesterol (< 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.
Honda
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Department of Medicine, Veterans Affairs Medical Center, East Orange, New Jersey 07018-1095, USA.
Tint
G S
GS
Salen
G
G
Kelley
R I
RI
Honda
M
M
Batta
A K
AK
Chen
T S
TS
Shefer
S
S
D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D003684:Dehydrocholesterols / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D019082:Smith-Lemli-Opitz Syndrome / Q000175:diagnosis* / Q000378:metabolism; D013261:Sterols / Q000378:metabolism*
D003684:Dehydrocholesterols; D013261:Sterols; C016705:7-dehydrocholesterol