更新于：2024-09-19

Smith-Lemli-Opitz Syndrome

Smith-Lemli-Opitz综合征

更新于：2024-09-19

基本信息

别名

7-Dehydrocholesterol reductase deficiency、7-dehydrocholesterol reductase deficiency、Acrodysgenital Syndrome, Lethal

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简介

An autosomal recessive disorder of CHOLESTEROL metabolism. It is caused by a deficiency of 7-dehydrocholesterol reductase, the enzyme that converts 7-dehydrocholesterol to cholesterol, leading to an abnormally low plasma cholesterol. This syndrome is characterized by multiple CONGENITAL ABNORMALITIES, growth deficiency, and INTELLECTUAL DISABILITY.

关联

项与 Smith-Lemli-Opitz综合征相关的药物

Dalzanemdor

靶点

NMDA receptor

作用机制

NMDA receptor调节剂

在研机构

SAGE Therapeutics, Inc.

原研机构

SAGE Therapeutics, Inc.

在研适应症

亨廷顿舞蹈病 [+4]

非在研适应症

帕金森病

最高研发阶段临床3期

首次获批国家/地区-

首次获批日期1800-01-20

项与 Smith-Lemli-Opitz综合征相关的临床试验

DRKS00033193 / RecruitingN/A

MySyndrome - Rare Disease Patient Registry for Treatability, Natural History, Phenotype and Psychosozial Aspects of Rare Genetic Developmental Diseases - MySyndrome

开始日期2024-01-01

申办/合作机构-

NCT05642221 / RecruitingN/AIIT

Pilot Study of the Use of Functional Near-Infrared Spectroscopy (fNIRS) Combined With Diffuse Correlation Spectroscopy (DCS) in Neurocognitive Disease as Compared to Healthy Neurotypical Controls

Background:
Neurocognitive disorders affect how the brain uses oxygen. They may affect mental development in children. These disorders can be studied with imaging scans that use radiation; however, these methods are not ideal for research on children. Two technologies-functional near-infrared spectroscopy (fNIRS) and diffuse correlation spectroscopy (DCS)-use light to detect changes in brain activity. These methods are safer, and they can be used in a more relaxed setting. In this natural history study, researchers want to find out whether fNIRS and DCS can be a good way to study people with neurocognitive disorders.
Objective:
To find out whether fNIRS and DCS can be useful in measuring brain activity in people with neurocognitive disorders.
Eligibility:
People aged 6 months or older with neurocognitive disorders. These can include Niemann-Pick disease type C1 (NPC1); creatine transporter deficiency (CTD); Smith Lemli Opitz syndrome (SLOS); juvenile neuronal ceroid lipofuscinosis (CLN3 disease); and Pheland-McDermid (PMS) syndrome. Healthy volunteers are also needed.
Design:
Participants will have a physical exam. They will have tests of their memory and thinking.
Participants will sit in a quiet room for the fNIRS and DCS tests. A snug cap (like a cloth swim cap) will be placed on their head. The cap has lights and sensors. Another sensor will be placed on their forehead. Participants will perform tasks on a computer. This testing will take 45 to 60 minutes.
The tests will be repeated within 1 to 4 weeks. Participants will be asked to return for repeat tests 1 year later....

开始日期2023-01-23

申办/合作机构

Eunice Kennedy Shriver National Institute Of Child Health And Human Development

NCT05687474 / RecruitingN/AIIT

Universal Genomic Newborn Screening in the Wallonia-Brussels Federation: Baby Detect

Newborn screening (NBS) is a global initiative of systematic testing at birth to identify babies with pre-defined severe but treatable conditions. With a simple blood test, rare genetic conditions can be easily detected, and the early start of transformative treatment will help avoid severe disabilities and increase the quality of life.
Baby Detect Project is an innovative NBS program using a panel of target sequencing that aims to identify 126 treatable severe early onset genetic diseases at birth caused by 361 genes. The list of diseases has been established in close collaboration with the Paediatricians of the University Hospital in Liege. The investigators use dedicated dried blood spots collected between the first day and 28 days of life of babies, after a consent sign by parents.

开始日期2022-09-01

申办/合作机构

Centre Hospitalier Universitaire de Liege

[+5]

100 项与 Smith-Lemli-Opitz综合征相关的临床结果

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100 项与 Smith-Lemli-Opitz综合征相关的转化医学

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0 项与 Smith-Lemli-Opitz综合征相关的专利（医药）

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1,025

项与 Smith-Lemli-Opitz综合征相关的文献（医药）

2024-01-26·Veterinary journal (London, England : 1997)

Multiple independent de novo mutations are associated with the development of schistosoma reflexum, a lethal syndrome in cattle.

Article

作者: J G P Jacinto ; I M Häfliger ; A Letko ; J Weber ; M Freick ; A Gentile ; C Drögemüller ; J S Agerholm

Schistosoma reflexum (SR) is a lethal congenital syndrome characterized by U-shaped dorsal retroflexion of the spine and exposure of abdominal viscera. SR is usually associated with severe dystocia. The syndrome is thought to be inherited as a Mendelian trait. We collected a series of 23 SR-affected calves from four breeds (20 Holstein, one Red Danish, one Limousin, one Romagnola) and performed whole-genome sequencing (WGS). WGS was performed on 51 cattle, including 14 cases with parents (trio-based; Group 1) and nine single cases (solo-based; Group 2). Sequencing-based genome-wide association studies with 20 Holstein cases and 154 controls showed no association (above Bonferroni threshold; P-value<3×10^-09). Assuming a monogenic recessive inheritance, no region of shared homozygosity was observed, suggesting heterogeneity. Alternatively, the presence of possible dominant acting de novo mutations were assessed. In Group 1, heterozygous private variants, absent in both parents, were found in seven cases. These involved the ACTL6A, FLNA, GLG1, IQSEC2, MAST3, MBTPS2, and MLLT1 genes. In addition, heterozygous private variants affecting the genes DYNC1LI1, PPP2R2B, SCAF8, SUGP1, and UBP1 were identified in five cases from Group 2. The detected frameshift and missense variants are predicted to cause haploinsufficiency. Each of these 12 affected genes belong to the class of haploinsufficient loss-of-function genes or are involved in embryonic and pre-weaning lethality or are known to be associated with severe malformation syndromes in humans and/or mice. This study presents for the first time a detailed genomic evaluation of bovine SR, suggesting that independent de novo mutations may explain the sporadic occurrence of SR in cattle.

2024-01-18·The Journal of clinical investigation

Sterol biosynthesis regulates TLR signaling and the innate immune response in Smith-Lemli-Opitz syndrome model.

Article

作者: Kristin Gabor ; Emily V Mesev ; Jennifer Madenspacher ; Julie M Meacham ; Prashant Rai ; Sookjin Moon ; Christopher A Wassif ; Saame Raza Shaikh ; Charles J Tucker ; Peer W Karmaus ; Simona Bianconi ; Forbes D Porter ; Michael B Fessler

2023-11-21·bioRxiv : the preprint server for biology

Temporal gene expression changes and affected pathways in neurodevelopment of a mouse model of Smith-Lemli-Opitz syndrome.

作者: Amy Li ; Hideaki Tomita ; Libin Xu

Smith-Lemli-Opitz syndrome is an autosomal recessive disorder that arises from mutations in the gene DHCR7 , which encodes the terminal enzyme of cholesterol biosynthesis, leading to decreased production of cholesterol and accumulation of the cholesterol precursor, 7-dehydrocholesterol, and its oxysterol metabolites. The disorder displays a wide range of neurodevelopmental defects, intellectual disability, and behavioral problems. However, an in-depth study on the temporal changes of gene expression in the developing brains of SLOS mice has not been done before. In this work, we carried out the transcriptomic analysis of whole brains from WT and Dhcr7 -KO mice at four-time points through postnatal day 0. First, we observed the expected downregulation of the Dhcr7 gene in the Dhcr7 -KO mouse model, as well as gene expression changes of several other genes involved in cholesterol biosynthesis throughout all time points. Pathway and GO term enrichment analyses revealed affected signaling pathways and biological processes that were shared amongst time points and unique to individual time points. Specifically, the pathways important for embryonic development, including Hippo, Wnt, and TGF-β signaling pathways are the most significantly affected at the earliest time point, E12.5. Additionally, neurogenesis-related GO terms were enriched in earlier time points, consistent with the timing of development. Conversely, pathways related to synaptogenesis, which occurs later in development compared to neurogenesis, are significantly affected at the later time points, E16.5 and PND0, including the cholinergic, glutamatergic, and GABAergic synapses. The impact of these transcriptomic changes and enriched pathways is discussed in the context of known biological phenotypes of SLOS.

项与 Smith-Lemli-Opitz综合征相关的新闻（医药）

2024-02-01

·生物探索

Nature | 同济大学王平团队揭示铁死亡敏感性决定新机制

引言铁死亡是一种受铁依赖性磷脂过氧化作用驱动的细胞死亡形式，与多种疾病有关，包括癌症、退行性疾病和器官缺血再灌注损伤(IRI)。2024年1月31日，同济大学王平团队（李亚旭、冉巧、段秋慧和金佳丽为该论文共同第一作者）在Nature在线发表题为“7-Dehydrocholesterol dictates ferroptosis sensitivity”的研究论文，该研究确定了7-脱氢胆固醇(7-DHC)在保护细胞免受磷脂过氧化和铁死亡中的作用，这突出了远端胆固醇生物合成途径在病理生理条件(如癌症和IRI)中的重要作用。这一重要发现为代谢稳态维持与细胞命运决定之间的调控机制提供了新的理论依据，也为治疗肿瘤及缺血再灌注器官损伤等铁死亡密切相关疾病提供了潜在的靶点和策略。铁死亡是一种独特的受调控的细胞死亡方式，由于其在各种病理生理条件(包括癌症、神经退行性疾病和器官IRI)中的关键作用而受到广泛关注。铁死亡的一个重要标志是铁依赖性磷脂过氧化，这有助于膜损伤。细胞具有内在的防御系统来保护自己免受磷脂过氧化。半胱氨酸/半胱氨酸-谷胱甘肽-谷胱甘肽过氧化物酶4 (GPX4)轴是抑制铁死亡的主要途径，其作用是将过氧化氢磷脂转变为磷脂醇。可选的保护机制包括(1)自由基捕获抗氧化活性介导的机制，如铁死亡抑制蛋白1 (FSP1) -辅酶Q10 (CoQ10，也称为泛素-10)，二氢羟酸脱氢酶(DHODH) -辅酶Q10和GTP环水解酶1 (GCH1) -四氢生物蝶呤(BH4)轴;(2) MBOAT1/2介导的细胞磷脂重塑。7-DHC是远端胆固醇生物合成途径的代谢中间体，通过DHCR7转化为胆固醇。作为一种不饱和甾醇，7-DHC在其B环上含有5,7-二烯，可以作为脂肪酸过氧自由基的有效H原子供体。然而，除了7-DHC衍生的氧甾醇对神经元和视网膜细胞造成的细胞毒性外，7-DHC的生物学作用尚不清楚，尽管DHCR7突变是Smith-Lemli-Opitz综合征的标志，并在Burkitt淋巴瘤患者中被发现。该研究利用全基因组CRISPR-Cas9筛选，发现参与远端胆固醇生物合成的酶通过决定7-脱氢胆固醇(7-DHC)的水平在调节铁死亡中具有关键但相反的作用。7-脱氢胆固醇是远端胆固醇生物合成的中间代谢物，由甾醇C5-去饱和酶(SC5D)合成，并由7-DHC还原酶(DHCR7)代谢，用于胆固醇合成。研究人员发现，MSMO1、CYP51A1、EBP和SC5D等通路组分是铁死亡的潜在抑制因子，而DHCR7则是一个促铁死亡基因。模式图（Credit: Nature）在机制上，7-DHC通过使用共轭二烯发挥其抗磷脂自氧化功能，并保护血浆和线粒体膜免受磷脂自氧化，从而指示铁死亡监测。重要的是，通过药物靶向EBP阻断内源性7-DHC的生物合成可诱导铁死亡并抑制肿瘤生长，而通过抑制DHCR7增加7-DHC水平可有效促进癌症转移并减轻肾脏IRI的进展，支持该调控轴在体内的关键功能。该研究揭示了7-DHC作为一种天然的抗铁毒性代谢物的作用，并表明药理学操纵7-DHC水平是一种很有前景的治疗癌症和IRI的策略。原文链接https://www-nature-com.libproxy1.nus.edu.sg/articles/s41586-023-06983-9责编|探索君排版|探索君文章来源|“iNature”End往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文Science最新发布：全世界最前沿的125个科学问题热文Nature | 2024年值得关注的七项技术热文Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文Nature | 颠覆性发现：我们肠道微生物中隐藏的“奇异RNA碎片”

临床研究

2024-01-12

·生物谷

爱情会扰乱大脑，最新研究揭示背后的原因

众所周知，浪漫的爱情会改变大脑，释放所谓的爱情激素——催产素（oxytocin），这正是我们坠入爱河时所感受到的愉悦感。近日，来自澳大利亚国立大学、堪培拉大学和南澳大利亚大学的研究人员在 Behavioral Sciences 期刊发表了题为：Romantic Love and Behavioral Activation System Sensitivity to a Loved One 的研究论文。众所周知，浪漫的爱情会改变大脑，释放所谓的爱情激素——催产素（oxytocin），这正是我们坠入爱河时所感受到的愉悦感。这项研究进行了世界首个调查人类大脑行为激活系统（BAS）与浪漫爱情之间联系的研究，测量了大脑是如何在第一次浪漫的冲动中将我们所爱之人推上神坛的。在这项研究中，研究团队调查了1556名处于恋爱中的年轻人。调查问题集中在对爱人的情感反应、行为以及他们对爱人的关注程度。事实证明，当我们坠入爱河时，我们的大脑会做出不同的反应，使得我们情感的对象成为我们生活的中心。这项研究表明爱情与行为和情感的变化有关。具体来说，在研究1中，行为激活系统-对爱人的敏感性（BAS-SLO）量表在1556名正处于浪漫爱情中的年轻人中得到验证。在研究2中，使用分层线性回归在812名经历浪漫爱情不到两年的年轻人中确定了BAS-SLO量表与浪漫爱情强度的关联。BAS-SLO量表解释了浪漫爱情强度变异的8.89%。在进一步验证和测试的情况下，BAS-SLO量表可能在未来的神经成像和心理学研究中发挥作用。综合来看，这两项研究表明，大脑的行为激活系统（BAS）对所爱之人的敏感度是一种真实存在的现象，并且浪漫爱情的状态可能与BAS对所爱之人的敏感度有关。这对于理解浪漫爱情的机制和演化历史具有重要意义。众所周知，催产素在浪漫爱情中的重要作用，当我们与所爱之人互动时，催产素会在我们的神经系统和血液中循环。然而，爱上一个人之所以显得特别重要，是因为催产素和多巴胺结合，多巴胺是我们的大脑在浪漫爱情中释放的一种化学物质。从本质上讲，爱情激活了大脑中与积极情绪相关的通路。研究团队表示，我们实际上对爱情的演变知之甚少，因此，每一个告诉我们浪漫爱情演变的发现都是刚刚开始的研究拼图中的重要一块。接下来，研究团队将进一步调查男性和女性在恋爱方式上的差异，并将开展一项全球调查，确定四种不同类型的浪漫恋人。

2023-05-31

·GlobeNewswire-Health Care

Nacuity Pharmaceuticals Achieves Target Enrollment for Phase 1/2 Clinical Trial of NPI-001 for the Treatment of Retinitis Pigmentosa Associated with Usher Syndrome

Phase 1/2 SLO-RP trial completed target enrollment of 48 patients diagnosed with RP associated with USH Interim efficacy data anticipated by year end 2023 FORT WORTH, Texas, May 31, 2023 (GLOBE NEWSWIRE) -- Nacuity Pharmaceuticals, Inc., a clinical stage biopharmaceutical company developing treatments for retinitis pigmentosa, cataracts and other diseases caused by oxidative stress, today announced that target enrollment of 48 patients has been reached in the SLO-RP Phase 1/2 clinical trial of NPI-001 tablets in patients with retinitis pigmentosa (RP) associated with Usher syndrome (USH). “We are pleased to reach our target enrollment, an important step toward our goal to realize the potential of NPI-001 for patients affected by RP,” said Halden Conner, Chairman, CEO and Co-Founder of Nacuity Pharmaceuticals. “We extend our gratitude to the principal investigators, Usher patient advocacy organizations and clinical sites who supported our recruitment efforts, working through challenges including the early days of a global pandemic. We are especially appreciative of the patients who have made this work possible. We look forward to sharing results from an interim analysis including efficacy data by year end 2023.” The SLO-RP trial is a randomized, placebo-controlled, multicenter, double-masked, dose-escalation trial designed to assess the clinical safety, tolerability and efficacy of NPI-001 tablets versus placebo in patients with RP associated with USH. The trial enrolled 48 male and female patients, ages 18 years and older, at its four trial sites in Australia. Patients will be followed for two years in the core study to assess efficacy. The protocol has been amended to allow continued treatment beyond two years for interested participants while the trial is ongoing. To date, all eligible participants have elected to continue on treatment. “The incredible compliance and enthusiasm of participants in the trial is a promising demonstration of the potential of NPI-001 for the treatment of RP,” said Jami Kern, Ph.D., Senior Vice President and Chief Clinical Officer of Nacuity. “We hope to confirm and build upon the encouraging preclinical and Phase 1 results to generate a robust package of data supporting the promise of an oral treatment option for patients with RP, while validating the potential for broader applications in other diseases caused by oxidative stress.” For more information, visit clinicaltrials.gov (NCT04355689). About NPI-001 NPI-001 is a proprietary, GMP-grade formulation of N-acetylcysteine amide (NACA) tablets being developed to target oxidative stress associated with blinding eye diseases, such as retinitis pigmentosa. Preclinical studies indicate that oral NPI-001 protects photoreceptor cones in the eye from oxidative damage by boosting glutathione, the body’s most powerful endogenous antioxidant, to stop chemically aggressive oxygen molecules from damaging eye tissue. NPI-001 and related small molecules have been shown to be potent antioxidants in several preclinical models that may lead to additional indications. NPI-001 has been granted orphan drug designation, which provides seven years of U.S. FDA regulatory exclusivity for the product upon regulatory approval. About Nacuity PharmaceuticalsNacuity Pharmaceuticals is a clinical-stage leader in innovative treatments for oxidative stress. The company’s powerful, targeted therapies aim to stop oxidative tissue damage, a driver of blinding eye diseases and a broad spectrum of serious chronic conditions. Nacuity has three highly differentiated clinical programs ongoing in retinitis pigmentosa, cataracts and cystinosis with the potential to be first-of-a-kind therapies and gateways to wider applications. Based in Fort Worth, TX, the company has extensive managerial and scientific domain expertise as well as backing from Foundation Fighting Blindness (https://www.fightingblindness.org/) and its venture arm RD Fund (https://www.retinaldegenerationfund.org). For more information, please visit www.nacuity.com. Media Contact: Julia Clements6 Degrees PR267.626.1085jclements@6degreespr.com

孤儿药临床研究