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1.
Taiwan J Obstet Gynecol ; 56(4): 541-544, 2017 Aug.
Article in English | MEDLINE | ID: mdl-28805615

ABSTRACT

OBJECTIVE: To show the importance of measuring cholesterol precursor levels in amniotic fluid in all pregnancies with ultrasound features (such as holoprosencephaly) suggestive of Smith-Lemli-Opitz syndrome (SLOS), after exclusion of chromosomal anomalies. CASE REPORT: A 28-year-old woman, gravida 1 para 0, performed chorionic villus sampling for fetal karyotyping at 13 weeks of gestation due to positive combined first trimester screening in a fetus with increased nuchal translucency and suspected holoprosencephaly. The result was normal - 46,XX. The diagnosis of alobar holoprosencephaly was confirmed at 15 weeks of gestation, and cardiac and limb defects were also identified. Thus, a syndromic cause was considered, specifically a chromosomal microdeletion syndrome or a monogenic entity such as SLOS. The latter was confirmed by measuring 7-dehydrocholesterol (7DHC) and 8-dehydrocholesterol (8DHC) in amniotic fluid. Molecular analysis of DHCR7 gene identified a homozygous mutation in intron 8, c.964-1G>C, providing molecular confirmation for this diagnosis. CONCLUSION: The differential diagnosis of holoprosencephaly is broad. Identification of the cause of holoprosencephaly aids in establishing the prognosis and is essential to ascertain the mode of inheritance for adequate genetic counseling.


Subject(s)
Holoprosencephaly/diagnosis , Prenatal Diagnosis/methods , Smith-Lemli-Opitz Syndrome/diagnosis , Adult , Amniotic Fluid/chemistry , Cholestadienols/analysis , Chorionic Villi Sampling , Dehydrocholesterols/analysis , Diagnosis, Differential , Female , Holoprosencephaly/embryology , Homozygote , Humans , Karyotype , Mutation , Pregnancy , Smith-Lemli-Opitz Syndrome/embryology
2.
Hum Mol Genet ; 22(6): 1086-96, 2013 Mar 15.
Article in English | MEDLINE | ID: mdl-23221804

ABSTRACT

The srbi gene encodes a lipoprotein receptor with high affinity for high density lipoprotein that is mainly expressed in the liver and in steroidogenic tissues. Disruption of this gene in mice and mutations in humans lead to alterations in lipoprotein metabolism and/or fertility. During murine development, scavenger receptor class B member I (SR-BI) is present in the yolk sac and the placenta and is only expressed in the embryo itself late in gestation. In humans, it has been detected in trophoblast cells and placenta. Although the proportion of mice carrying a null mutation in SR-BI obtained from heterozygous intercrosses is lower than the expected by the Mendelian ratio, suggesting the involvement of this receptor in intrauterine development, the cause of this demise has remained unknown. In this work, we show that embryos lacking SR-BI exhibit a high prevalence of exencephaly with a sex bias toward females. Immunolocalization studies confirmed that SR-BI is not expressed in the embryo at early stages of development and allowed a more detailed description of its localization in the cells that mediate maternal-fetal transport of nutrients. SR-BI-null embryos contain less cholesterol than their wild-type littermates, suggesting the involvement of SR-BI in materno-fetal cholesterol transport. Newborn SR-BI-deficient pups exhibit intrauterine growth restriction, suggesting that this receptor is also important for fetal growth. Altogether, the results of our work suggest that the presence of SR-BI in extraembryonic tissues is involved in the maternal-fetal transport of cholesterol and/or other lipids with a role during neural tube closure and fetal growth.


Subject(s)
Lipoproteins, HDL/deficiency , Receptors, Lipoprotein/deficiency , Scavenger Receptors, Class B/deficiency , Smith-Lemli-Opitz Syndrome/embryology , Smith-Lemli-Opitz Syndrome/metabolism , Animals , Cholesterol/metabolism , Disease Models, Animal , Female , Fetus/abnormalities , Fetus/embryology , Fetus/metabolism , Humans , Lipid Metabolism , Lipoproteins, HDL/genetics , Male , Maternal-Fetal Exchange , Mice , Mice, Inbred C57BL , Mice, Knockout , Pregnancy , Receptors, Lipoprotein/genetics , Scavenger Receptors, Class B/genetics , Smith-Lemli-Opitz Syndrome/genetics
3.
J Lipid Res ; 52(6): 1222-1233, 2011 Jun.
Article in English | MEDLINE | ID: mdl-21402677

ABSTRACT

The level of 7-dehydrocholesterol (7-DHC) is elevated in tissues and fluids of Smith-Lemli-Opitz syndrome (SLOS) patients due to defective 7-DHC reductase. Although over a dozen oxysterols have been identified from 7-DHC free radical oxidation in solution, oxysterol profiles in SLOS cells and tissues have never been studied. We report here the identification and complete characterization of a novel oxysterol, 3ß,5α-dihydroxycholest-7-en-6-one (DHCEO), as a biomarker for 7-DHC oxidation in fibroblasts from SLOS patients and brain tissue from a SLOS mouse model. Deuterated (d7)-standards of 7-DHC and DHCEO were synthesized from d7-cholesterol. The presence of DHCEO in SLOS samples was supported by chemical derivatization in the presence of d7-DHCEO standard followed by HPLC-MS or GC-MS analysis. Quantification of cholesterol, 7-DHC, and DHCEO was carried out by isotope dilution MS with the d7-standards. The level of DHCEO was high and correlated well with the level of 7-DHC in all samples examined (R = 0.9851). Based on our in vitro studies in two different cell lines, the mechanism of formation of DHCEO that involves 5α,6α-epoxycholest-7-en-3ß-ol, a primary free radical oxidation product of 7-DHC, and 7-cholesten-3ß,5α,6ß-triol is proposed. In a preliminary test, a pyrimidinol antioxidant was found to effectively suppress the formation of DHCEO in SLOS fibroblasts.


Subject(s)
Biomarkers/analysis , Brain/metabolism , Cholestenones/analysis , Chromatography, Liquid/methods , Dehydrocholesterols , Embryo, Mammalian/metabolism , Fibroblasts/metabolism , Mass Spectrometry/methods , Oxidoreductases Acting on CH-CH Group Donors/deficiency , Smith-Lemli-Opitz Syndrome/metabolism , Animals , Antioxidants/pharmacology , Biomarkers/chemistry , Brain/embryology , Brain/pathology , Cell Line, Tumor , Cholestenones/chemistry , Chromatography, High Pressure Liquid , Dehydrocholesterols/isolation & purification , Dehydrocholesterols/metabolism , Disease Models, Animal , Embryo, Mammalian/pathology , Female , Fibroblasts/cytology , Humans , Isotope Labeling , Mice , Mice, Knockout , Oxidation-Reduction/drug effects , Oxidoreductases Acting on CH-CH Group Donors/genetics , Pregnancy , Reference Standards , Smith-Lemli-Opitz Syndrome/embryology , Smith-Lemli-Opitz Syndrome/genetics , Smith-Lemli-Opitz Syndrome/pathology
4.
Cesk Fysiol ; 59(2): 37-43, 2010.
Article in Slovak | MEDLINE | ID: mdl-21254658

ABSTRACT

The role of cholesterol in cell biology has been known for years. The sight of cholesteol biological function has changed after the discovery that the genetic disorder Smith-Lemli-Opitz syndrome is caused by a defect in cholesterol biosynthetic pathway. Cholesterol has an important role in regulation and modification of Hedgehog proteins, what links cholesterol to early embryonic development. Hedgehog proteins comprise a family of secreted signaling molecules that are essential for embryonic patterning and morphogenesis. The deficit of cholesterol during embryogenesis causes severe abnormalities in SLOS because of disrupt autoprocessing of hedgehog proteins. SLOS is an autosomal recessive disorder of sterol metabolism. The underlying pathogenetic basis for SLOS has been shown to be a deficiency of 7-dehydrocholesterol reductase, which catalyzes the last step in cholesterol biosynthesis. Reduced enzyme activity leads to a deficit of cholesterol and accumulation of precursor sterols. The human 7-dehydrocholesterol reductase gene (DHCR7) is localized on chromosome 11q 12-13.


Subject(s)
Cholesterol/physiology , Embryonic Development/physiology , Smith-Lemli-Opitz Syndrome/embryology , Female , Hedgehog Proteins/metabolism , Humans , Pregnancy , Smith-Lemli-Opitz Syndrome/metabolism
5.
Hum Mol Genet ; 17(23): 3806-13, 2008 Dec 01.
Article in English | MEDLINE | ID: mdl-18775956

ABSTRACT

Patients with Smith-Lemli-Opitz syndrome (SLOS) are born with multiple congenital abnormalities. Postnatal cholesterol supplementation is provided; however, it cannot correct developmental malformations due to in utero cholesterol deficit. Increased transport of cholesterol from maternal to fetal circulation might attenuate congenital malformations. The cholesterol transporters Abca1, Abcg1, and Sr-b1 are present in placenta; however, their potential role in placental transport remains undetermined. In mice, expression analyses showed that Abca1 and Abcg1 transcripts increased 2-3-fold between embryonic days 13.5 and 18.5 in placental tissue; whereas, Sr-b1 expression decreased. To examine the functional role of Abca1, Abcg1 and Sr-b1 we measured the maternal-fetal transfer of (14)C-cholesterol in corresponding mutant embryos. Disruption of either Abca1 or Sr-b1 decreased cholesterol transfer by approximately 30%. In contrast, disruption of the Abcg1 had no effect. Treatment of pregnant C57Bl/6 female mice with TO901317, an LXR-agonist, increased both Abca1 expression and maternal-fetal cholesterol transfer to the fetus. In an SLOS mouse model (Dhcr7(-/-)), which is incapable of de novo synthesis of cholesterol, in utero treatment with TO901317 resulted in increased cholesterol content in Dhcr7(-/-) embryos. Our data support the hypothesis that Abca1, and possibly Sr-b1, contributes to transport maternal cholesterol to the developing fetus. Furthermore, we show, as a proof of principle, that modulating maternal-fetal cholesterol transport has potential for in utero therapy of SLOS.


Subject(s)
ATP-Binding Cassette Transporters/metabolism , Cholesterol/metabolism , Placenta/metabolism , Smith-Lemli-Opitz Syndrome/metabolism , Smith-Lemli-Opitz Syndrome/therapy , Uterus/metabolism , ATP Binding Cassette Transporter 1 , ATP Binding Cassette Transporter, Subfamily G, Member 1 , ATP-Binding Cassette Transporters/genetics , Animals , Biological Transport , Female , Humans , Hydrocarbons, Fluorinated/therapeutic use , Lipoproteins/genetics , Lipoproteins/metabolism , Mice , Mice, Inbred C57BL , Placental Circulation , Pregnancy , Smith-Lemli-Opitz Syndrome/embryology , Sulfonamides/therapeutic use
6.
Clin Chem ; 54(8): 1317-24, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18556335

ABSTRACT

BACKGROUND: Smith-Lemli-Opitz syndrome (SLOS), a severe disorder of cholesterol synthesis, is classically diagnosed prenatally by GC-MS analysis of sterols in amniotic fluid. Considering the current trend toward tandem mass spectrometry (MS/MS) methodologies, we developed prototype LC-MS/MS methods for accurate diagnosis of the disorder. METHODS: 3beta-Hydroxysterols in amniotic fluid are oxidized with cholesterol oxidase to their corresponding 3-ketones, which are then derivatized with Girard P (GP) hydrazine in a "one-pot" reaction. The resulting GP-hydrazones give an improved response in electrospray (ES)-MS/MS owing to the presence of a charged quaternary nitrogen and are analyzed by reversed-phase LC-ES-MS/MS. Both capillary and conventional LC-MS/MS formats are suitable, and the method is also applicable to paper-absorbed blood spots. RESULTS: In a double-blind analysis of 18 amniotic fluid samples comprising 6 SLOS and 12 controls, the ratio of 7 + 8-dehydrocholesterol (7 + 8-DHC) to cholesterol was <0.02 [range 0.00-0.02, mean (SD) 0.01 (0.007)] in all control samples (intraassay variation 5.91%) and >0.20 [0.20-1.13, 0.79 (0.35)] in SLOS (intraassay variation 4.56%), corresponding to a difference in ratios between the 2 groups of at least a factor of 10. The limit of quantification was equivalent to that of 2 nL amniotic fluid injected on-column. CONCLUSIONS: We describe a proof-of-concept for the prenatal diagnosis of SLOS. Further developments will be necessary to automate sample handling and reduce chromatographic time for the methodology to be used in pre- and postnatal diagnosis.


Subject(s)
Chromatography, Liquid/methods , Prenatal Diagnosis/methods , Smith-Lemli-Opitz Syndrome/diagnosis , Sterols/analysis , Tandem Mass Spectrometry/methods , Amniotic Fluid/chemistry , Double-Blind Method , Female , Humans , Molecular Structure , Pregnancy , Reference Standards , Reproducibility of Results , Sensitivity and Specificity , Smith-Lemli-Opitz Syndrome/embryology , Spectrometry, Mass, Electrospray Ionization/methods , Sterols/chemistry
8.
Ann Pathol ; 25(4): 318-21, 2005 Sep.
Article in French | MEDLINE | ID: mdl-16327658

ABSTRACT

SLO syndrome is an autosomal recessive condition with multiple malformations. This syndrome is ascribed to deficiency of 7 dehydrocholesterol reductase, an enzyme in the cholesterol biosynthetic pathway. The characteristics of this syndrome are facial anomalies, syndactyly of the second and third toe, postaxial polydactyly and genital anomalies with sexual ambiguity. We report a fetal case with intrauterine growth retardation, genital anomalies, multiple malformations with cardiac anomalies, renal aplasia and facial anomalies detected by prenatal ultrasound. Medical abortion was induced at 24 weeks gestation. The diagnosis was considered after complete pathologic examination and biochemical analysis.


Subject(s)
Smith-Lemli-Opitz Syndrome/pathology , Abortion, Induced , Adult , Face/abnormalities , Female , Genotype , Humans , Male , Pregnancy , Sex Determination Processes , Smith-Lemli-Opitz Syndrome/embryology
9.
Am J Clin Nutr ; 82(6): 1155-61, 2005 Dec.
Article in English | MEDLINE | ID: mdl-16332646

ABSTRACT

Cholesterol is required for fetal development. Data obtained from recent studies in humans, rodents, and cell cultures showed that circulating maternal cholesterol can affect fetal metabolism and sterol accretion. Recent studies in our laboratory showed that the efflux of cholesterol from the basolateral side of the placental cells and the secretion of cholesterol from endodermal yolk sac cells to the fetal circulation can be regulated. The ability to manipulate the mass of maternal cholesterol that crosses to the fetus could result in a dramatic improvement in the development of fetuses that lack the ability to synthesize cholesterol, such as those with Smith-Lemli-Opitz syndrome. On the other hand, it could also accelerate the development of various age-related diseases, such as atherosclerosis.


Subject(s)
Cholesterol/metabolism , Fetus/metabolism , Maternal-Fetal Exchange/physiology , Placenta/metabolism , Yolk Sac/metabolism , Biological Transport, Active , Cholesterol/therapeutic use , Female , Fetal Development/physiology , Humans , Pregnancy , Smith-Lemli-Opitz Syndrome/drug therapy , Smith-Lemli-Opitz Syndrome/embryology , Smith-Lemli-Opitz Syndrome/genetics
10.
Med Hypotheses ; 64(3): 563-7, 2005.
Article in English | MEDLINE | ID: mdl-15617867

ABSTRACT

While excess cholesterol may have deleterious consequences, as in the case of atherosclerosis, too little cholesterol may endanger the development of the brain. Different degrees of mental retardation are often observed in inborn errors of cholesterol synthesis, such as the Smith-Lemli-Opitz syndrome or in maternal phenylketonuria, where the metabolite of accumulating phenylalanine, phenylacetate, is an inhibitor of cholesterol synthesis. Lack of cholesterol during brain development as a consequence of these genetic defects leads to severe brain damage, microencephaly and mental retardation, which are also hallmarks of the fetal alcohol syndrome (FAS). The brain relies on the in situ synthesis of cholesterol, which occurs mostly in astrocytes. Astrocyte-produced cholesterol is utilized for cell proliferation, or is released, via astrocyte-secreted high density lipoprotein-like particles containing apolipoprotein E, outside the cell, where it is taken up and utilized by neurons for dendrite outgrowth and to form synapses. We propose the hypothesis that ethanol may disrupt cholesterol homeostasis during brain development, and that this effect may be responsible, at least in part, for the central nervous system dysfunctions observed in the FAS, which include altered astrocyte proliferation, neuronal death and diminished synaptic contacts.


Subject(s)
Brain/embryology , Cholesterol/metabolism , Ethanol/toxicity , Homeostasis , Models, Biological , Alcohol-Induced Disorders, Nervous System/embryology , Alcohol-Induced Disorders, Nervous System/etiology , Apolipoproteins E/metabolism , Astrocytes/metabolism , Ethanol/adverse effects , Female , Fetal Alcohol Spectrum Disorders/embryology , Fetal Alcohol Spectrum Disorders/etiology , Humans , Neurons/metabolism , Neurotoxicity Syndromes/embryology , Neurotoxicity Syndromes/etiology , Phenylketonuria, Maternal/complications , Phenylketonuria, Maternal/metabolism , Pregnancy , Smith-Lemli-Opitz Syndrome/embryology , Smith-Lemli-Opitz Syndrome/etiology
11.
Int J Dev Neurosci ; 21(8): 451-9, 2003 Dec.
Article in English | MEDLINE | ID: mdl-14659996

ABSTRACT

The Smith-Lemli-Opitz syndrome (SLOS) is a malformation/mental retardation syndrome resulting from an inborn error in 3beta-hydroxysteroid Delta7-reductase (DHCR7), the terminal enzyme required for cholesterol biosynthesis. Using a targeting strategy designed to virtually eliminate Dhcr7 activity, we have created a SLOS mouse model that exhibits commissural deficiencies, hippocampal abnormalities, and hypermorphic development of serotonin (5-HT) neurons. The latter is of particular interest with respect to current evidence that serotonin plays a significant role in autism spectrum disorders and the recent clinical observation that 50% of SLOS patients present with autistic behavior. Immunohistochemical analyses have revealed a 306% increase in the area of 5-HT immunoreactivity (5-HT IR) in the hindbrains of mutant (Dhcr7-/-) mice as compared to age-matched wild type animals. Amount of 5-HT IR was measured as total area of IR per histological section. Additionally, a regional increase as high as 15-fold was observed for the most lateral sagittal hindbrain sections. In Dhcr7-/- mice, an expansion of 5-HT IR into the ventricular zone and floor plate region was observed. In addition, the rostral and caudal raphe groups exhibited a radial expansion in Dhcr7-/- mice, with 5-HT IR cells present in locations not seen in wild type mice. This increase in 5-HT IR appears to represent an increase in total number of 5-HT neurons and fibers. These observations may help explain the behavioral phenotype seen in SLOS, and provide clues for future therapeutic interventions that utilize pharmacological modulation of the serotonergic system.


Subject(s)
Autistic Disorder/etiology , Receptors, Serotonin/genetics , Rhombencephalon/abnormalities , Rhombencephalon/metabolism , Serotonin/metabolism , Smith-Lemli-Opitz Syndrome/genetics , Animals , Cell Count , Disease Models, Animal , Embryo, Mammalian , Female , Genotype , Immunohistochemistry , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Neurons/metabolism , Oxidoreductases Acting on CH-CH Group Donors/genetics , Raphe Nuclei/abnormalities , Raphe Nuclei/cytology , Raphe Nuclei/embryology , Raphe Nuclei/metabolism , Receptors, Serotonin/metabolism , Rhombencephalon/pathology , Smith-Lemli-Opitz Syndrome/embryology
12.
Biochim Biophys Acta ; 1529(1-3): 340-56, 2000 Dec 15.
Article in English | MEDLINE | ID: mdl-11111101

ABSTRACT

In recent years, several inherited human disorders caused by defects in cholesterol biosynthesis have been identified. These are characterized by malformations, multiple congenital anomalies, mental and growth retardation and/or skeletal and skin abnormalities indicating a pivotal role of cholesterol in morphogenesis and embryonic development. The first recognized and most common of these developmental disorders is Smith-Lemli-Opitz syndrome, an autosomal recessive trait caused by mutations in the DHCR7 gene resulting in a deficiency of the encoded sterol Delta(7)-reductase, alternatively called 7-dehydrocholesterol reductase (EC 1.3.1.21). This enzyme catalyzes the final step in cholesterol biosynthesis, which is the reduction of the Delta(7) double bond of 7-dehydrocholesterol to produce cholesterol.


Subject(s)
Cholesterol/biosynthesis , Mutation , Oxidoreductases Acting on CH-CH Group Donors , Oxidoreductases/deficiency , Oxidoreductases/genetics , Smith-Lemli-Opitz Syndrome/enzymology , Animals , Biomarkers/blood , Cholesterol/blood , Chromosome Mapping , Cloning, Molecular , DNA, Complementary/biosynthesis , Dehydrocholesterols/blood , Dehydrocholesterols/metabolism , Disease Models, Animal , Heterozygote , Humans , Models, Chemical , Models, Molecular , Oxidoreductases/metabolism , Signal Transduction , Smith-Lemli-Opitz Syndrome/embryology , Smith-Lemli-Opitz Syndrome/genetics , Smith-Lemli-Opitz Syndrome/pathology
13.
Am J Clin Nutr ; 71(5 Suppl): 1270S-9S, 2000 05.
Article in English | MEDLINE | ID: mdl-10799401

ABSTRACT

We showed previously that 3 distal inhibitors of cholesterol synthesis are highly teratogenic in rats. AY 9944 and BM 15766 inhibit 7-dehydrocholesterol reductase, which catalyzes the last step of cholesterol synthesis, and triparanol inhibits Delta(24)-dehydrocholesterol reductase, which catalyzes the last step in another pathway. These molecules cause holoprosencephalic brain anomalies. Under certain experimental conditions, other anomalies (of the limbs and male genitalia) are also observed. Assays performed by gas chromatography-mass spectrometry (GC-MS) show hypocholesterolemia and an accumulation of precursors. These data indicate that this animal model can be considered a model of Smith-Lemli-Opitz syndrome. Smith-Lemli-Opitz syndrome is a recessive autosomal genetic disease characterized by malformations (microcephaly, corpus callosum agenesis, holoprosencephaly, and mental retardation), male pseudohermaphroditism, finger anomalies, and failure to thrive. The syndrome has been attributed to a deficit in 7-dehydrocholesterol reductase. As assayed by GC-MS, the sterol status of these patients indicates severe hypocholesterolemia and an accumulation of precursors: 7-dehydrocholesterol, 8-dehydrocholesterol, and oxidized derivatives. The presence of 7-dehydrocholesterol in the serum of patients is pathognomonic of the disease. The developmental gene Shh (sonic hedgehog) plays a key role in brain, limb, and genital development; it was shown recently that the Shh protein has to be covalently linked to cholesterol to be active. This is the first time that a posttranslational function has been attributed to cholesterol. There is an obvious relation between Shh dysfunction and the malformations observed in our experiments and in patients with Smith-Lemli-Opitz syndrome. However, the exact relation remains to be clarified. It is clear, however, that the role of cholesterol in embryonic development must be taken into account.


Subject(s)
Anticholesteremic Agents/toxicity , Cholesterol/physiology , Dehydrocholesterols/antagonists & inhibitors , Embryonic and Fetal Development/drug effects , Fetus/metabolism , Smith-Lemli-Opitz Syndrome/embryology , Animals , Disease Models, Animal , Piperazines/toxicity , Rats , Smith-Lemli-Opitz Syndrome/chemically induced , Smith-Lemli-Opitz Syndrome/metabolism , Triparanol/toxicity , trans-1,4-Bis(2-chlorobenzaminomethyl)cyclohexane Dihydrochloride/toxicity
14.
J Clin Endocrinol Metab ; 84(3): 1157-9, 1999 Mar.
Article in English | MEDLINE | ID: mdl-10084612

ABSTRACT

The equine-type estriols 1,3,5(10),7-estratetraene-3,16alpha,17beta-triol (16alpha-hydroxy-17beta-dihydroequilin) and 1,3,5(10),6,8-estrapentaene-3,16alpha,17beta-triol (16alpha-hydroxy-17beta-dihydroequilenin) constituted over half of the estrogens excreted by a woman carrying a Smith-Lemli-Opitz syndrome (SLOS) affected fetus. The steroids were characterized by gas chromatography-mass spectrometry (GC/MS), and mass spectra of the dehydro estriols as trimethylsilyl ethers are illustrated. SLOS is associated with 7-dehydrocholesterol (7DHC), delta 7-reductase deficiency; the enzyme catalyzing the final step in cholesterol biosynthesis. Identification of these equine estrogens show that an estrogen biosynthetic pathway parallel to normal is functional in the feto-placental unit and uses 7DHC as precursor, therefore P450scc, P450c17, and 3betaHSD and P450arom are all active on 7-dehydrometabolites. Patients with affected fetuses have low plasma estriol values (probably due to deficient production of the cholesterol precursor) and this is often a warning sign which instigates further evaluation for SLOS. The estriol deficiency is not quantitatively made up by the dehydrometabolites, and the combined excretion was found to be about one-third of the mean of gestational age matched controls. The importance of these findings lies in the potential value of dehydroestriol measurement for non-invasive diagnosis of SLOS at mid-gestation. Currently diagnosis relies on imaging, since SLOS is a malformation syndrome, and measurement of 7DHC levels in amniotic fluid and chorionic villus tissue.


Subject(s)
Estriol/urine , Horses/metabolism , Pregnancy/urine , Smith-Lemli-Opitz Syndrome/embryology , Adult , Animals , Female , Humans
15.
Am J Med Genet ; 58(4): 374-6, 1995 Sep 25.
Article in English | MEDLINE | ID: mdl-8533850

ABSTRACT

Routine ultrasound examination at 11 weeks of gestation in a woman with no family history of genetic disease demonstrated increased accumulation of fluid in the fetal nuchal region. In view of the association of this defect with chromosomal abnormalities, fetal karyotyping was performed by chorion villus sampling and this demonstrated a normal 46,XY karyotype. Subsequent scans showed resolution of the nuchal fluid, and at the 20-week scan the fetal genitalia appeared to be female. Fetal blood sampling confirmed a normal male karyotype and fetoscopy confirmed the presence of female external genitalia. The parents elected to terminate the pregnancy, and postmortem findings were indicative of Smith-Lemli-Opitz syndrome. This was confirmed by the finding of increased levels of 7-dehydrocholesterol in cultured skin fibroblasts.


Subject(s)
Fetal Diseases/diagnostic imaging , Neck/diagnostic imaging , Oxidoreductases Acting on CH-CH Group Donors , Smith-Lemli-Opitz Syndrome/diagnostic imaging , Adult , Cells, Cultured , Chorionic Villi Sampling , Dehydrocholesterols/analysis , Female , Fetal Diseases/embryology , Fetoscopy , Fibroblasts/chemistry , Humans , Karyotyping , Male , Oxidoreductases/deficiency , Pregnancy , Smith-Lemli-Opitz Syndrome/embryology , Ultrasonography
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