SMITH-LEMLI-OPITZ SYNDROME STEROIDOGENESIS

SMITH-LEMLI-OPITZ 综合征 类固醇生成

• 批准号: 6530552
• 负责人: CEDRIC HOWARD SHACKLETON
• 金额: $ 6.26万
• 依托单位: CHILDREN'S HOSPITAL & RES CTR AT OAKLAND
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-01 至 2003-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6530552
• 关键词: adrenocorticotropic hormone; blood chemistry; chemical synthesis; cholesterol; enzyme activity; enzyme mechanism; enzyme structure; excretion; gas chromatography mass spectrometry; gene mutation; high performance liquid chromatography; human subject; hypoadrenalism; hypogonadism; inborn metabolism disorder; inborn metabolism disorder diagnosis; orphan disease /drug; patient oriented research; preschool child (1-5); steroid biosynthesis; steroid hormone metabolism; urinalysis

DESCRIPTION: (Adapted from the applicant's Description) Smith-Lemli-Opitz syndrome (SLOS) is a devastating birth defect associated with mental retardation and multiple physical malformations. Since it is an enzymatic disorder of cholesterol synthesis (7-dehydrocholesterol-7-reductase deficiency) it is likely that steroid hormone synthesis by the adrenal glands and gonads is impacted because all such compounds utilize cholesterol as precursor. SLOS patients may have quantitatively compromised steroid synthesis because of cholesterol deficiency, and in addition novel steroids with unknown pharmacological properties may be produced which retain ring B unsaturation. This application addresses such issues through a study of serum and urinary steroids. About 30 patients are routinely studied for short periods at the NIH and these will be the subjects of the study. The investigators have evidence that 7-dehydrocholesterol overproduced in the disorder can act as precursor for novel C21, C19, and C18 steroids that are produced in adrenals and gonads. Once confirmed structures of urinary metabolites of such compounds have been obtained, it will be possible to state which (if not all) steroid biosynthetic enzymes accept 7- and 8- dehydrocholesterol as precursor. Information on specific steroids produced in SLOS will permit easy diagnosis, maybe leading to future pre- and postnatal screening. Furthermore, is the quantitative production of steroid hormone metabolites reduced in SLOS? If so, does this suggest adrenal insufficiency? The investigators will measure 40 steroid metabolites in urine and relate their excretions to those of age matched controls and to serum hormone measurements obtained in a separate study. In addition, cholesterol is routinely given to SLOS patients for beneficial effect on behavior and growth. Does the cholesterol partially work through the adrenal steroid mechanism by contributing to hormonal synthesis? The investigators will measure steroid hormone metabolites before and after cholesterol administration and determine if there has been a measurable increase in hormonal metabolites concomitant with decreased dehydrometabolite excretion. Finally, if ring B dehydrosteroids are produced, is the ratio of the individual dehydrometabolites to corresponding conventional metabolites related to the dehydrocholesterol to cholesterol ratio and clinical severity?

描述：（改编自申请人的描述）Smith-lemli-Opitz 综合征（SLO）是与精神相关的毁灭性先天缺陷 迟钝和多种身体畸形。 因为它是一种酶 胆固醇合成障碍（7-脱氧胆固醇-7还原酶 缺乏症）可能是肾上腺合成的类固醇激素 性腺受到影响，因为所有这些化合物都使用胆固醇为 前体。 SLOS患者可能已定量损害类固醇 合成由于胆固醇缺乏，此外，新型类固醇 可以生产未知的药理特性，以保留环B 不饱和。 该申请通过血清研究解决此类问题 和尿类固醇。 通常对大约30名患者进行简短研究 NIH的时期将是研究的主题。 这 研究人员有证据表明7-脱氢胆固醇在 疾病可以充当新型C21，C19和C18类固醇的前体 以肾上腺和性腺产生。 一旦确认的尿液结构 已经获得了此类化合物的代谢物，可以说明 哪种（如果不是全部）类固醇生物合成酶接受7-和8-- 脱氢胆固醇作为前体。 有关在中产生的特定类固醇的信息 SLO将允许轻松诊断，也许会导致未来的前后 筛选。 此外，是类固醇激素的定量产生 SLO中的代谢产物减少了？ 如果是这样，这是否表明肾上腺不足？ 研究人员将在尿液中测量40种类固醇代谢物并相关 它们对年龄匹配的对照和血清激素的排泄物排泄 在另一项研究中获得的测量值。 此外，胆固醇是 通常给予SLOS患者对行为和生长的有益影响。 胆固醇是否通过肾上腺类固醇机制部分起作用 有助于激素合成？ 调查人员将测量类固醇 胆固醇给药前后激素代谢物并确定 如果激素代谢物伴有可测量的增加 随着脱氢代谢物排泄减少。 最后，如果响了 产生脱氢类固醇，是个体的比率 脱氢代谢物与相应的常规代谢产物有关 脱氢胆固醇与胆固醇比和临床严重程度？