DEFECTIVE CHOLESTEROL-BIOSYNTHESIS ASSOCIATED WITH THE SMITH-LEMLI-OPITZ SYNDROME
DEFECTIVE CHOLESTEROL-BIOSYNTHESIS ASSOCIATED WITH THE SMITH-LEMLI-OPITZ SYNDROME
复制标题
DOI：
10.1056/nejm199401133300205
复制
发表时间：
1994-01-13
影响因子：
158.5
通讯作者：
SALEN, G
中科院分区：
文献类型：
--
作者：
TINT, GS;IRONS, M;SALEN, G
背景Smith-Lemli-Opitz综合征（发生率为1：20，000至1：40，000）是一组严重的出生缺陷，影响大多数器官系统。自闭症通常包括严重的智力迟钝，严重的发育不良和高婴儿死亡率。迄今为止，该综合征仅从其临床表现诊断。采用毛细管柱气相色谱-质谱联用技术，检测了5名儿童（3名女孩，2名男孩）的血浆、红细胞、透镜、培养的成纤维细胞和粪便中的甾醇成分。每例患者的血浆胆固醇水平都异常低（8 ~ 101 mg/dl [0.20 ~ 2.60 mmol/L]），远低于年龄和性别匹配的对照组的第5百分位数。胆固醇前体7-脱氢胆固醇（胆甾-5，7-二烯-3 β-醇）的浓度在我们的大多数对照中检测不到，但升高（11至31 mg/dl）超过正常值的2000倍，与所有患者所有组织中的胆固醇水平相似。还检测到一种与7-脱氢胆固醇结构相似的异构体脱氢胆固醇。异常低的血浆胆固醇水平和高浓度的胆固醇前体7-脱氢胆固醇的组合表明胆固醇生物合成中的主要阻断在7-脱氢胆固醇的C-7（8）双键被还原形成胆固醇的步骤中。这种阻断可能足以剥夺胚胎或胎儿的胆固醇并阻止正常发育，而7-脱氢胆固醇掺入所有膜可能会干扰正常的膜功能。
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-3beta-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.