Prenatal diagnosis of smith–lemli–opitz syndrome is possible by measurement of 7‐dehydrocholesterol in amniotic fluid

Dallaire, Louis; Mitchell, G. H.; Giguère, Robert; Lefebvre, Françine; Mélançon, S. B.; Lambert, Marie

doi:10.1002/pd.1970150911

Cited by 28 publications

(17 citation statements)

References 7 publications

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“…Recent reports from our laboratory and other investigators indicate that prenatal diagnosis of RSH/SLOS can be performed successfully by quantification of 7DHC in either amniotic fluid (AF) [Abuelo et al, 1995;Dallaire et al, 1995;McGaughran et al, 1995;Rossiter et al, 1995] or chorionic villus (CV) [Mills et al, 1996;Sharp et al, 1997]. An interesting observation in these and other reports was that the maternal serum level of unconjugated estriol (MSuE3) was decreased [Abuelo et al, 1995;Hyett et al, 1995;McKeever and Young, 1990;Rossiter et al, 1995].…”

Section: Introductionmentioning

confidence: 91%

Prenatal diagnosis of the RSH/Smith-Lemli-Opitz syndrome

Kratz

Kelley

1999

Am. J. Med. Genet.

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The RSH/Smith-Lemli-Opitz syndrome (RSH/SLOS) is a relatively common, autosomal recessive malformation syndrome comprising distinctive facial, limb and genital anomalies, and mental retardation. Most patients with a clinical diagnosis of RSH/SLOS have a defect of cholesterol biosynthesis at the level of 3beta-hydroxysteroid-delta7-reductase, resulting in a decreased level of cholesterol and an increased level of 7-dehydrocholesterol (7DHC) in body fluids and tissues. We report on our experience with the prenatal diagnosis of RSH/SLOS by quantitative sterol chromatography in amniotic fluid (AF) and chorionic villus (CV). Of 76 AF and nine CV samples analyzed for various indications, 20 were diagnostic of RSH/SLOS based on an increased level of 7DHC in the fluid or tissue. Of 39 fetuses at a 25% risk for RSH/SLOS, 10(25.6%) were affected. Twenty-nine pregnancies not known to be at risk for RSH/SLOS were studied because of either a fetal abnormality characteristic of RSH/SLOS detected by ultrasound, a low maternal serum uE3 level (MSuE3), or both. None of the pregnancies tested, because of a low MSuE3 but lacking a sonographic abnormality characteristic of RSH/SLOS, was affected. However, three of four pregnancies with a low MSuE3 and an RSH/SLOS-type fetal abnormality were positive. RSH/ SLOS was diagnosed in two additional pregnancies on which MSuE3 data were not available but in which fetal anomalies were identified. Of these five RSH/SLOS fetuses identified in pregnancies not otherwise at risk for RSH/SLOS, the presenting sonographic anomaly was either polydactyly, ambiguous genitalia, or both. Evaluation of the biochemical parameters and clinical severity of RSH/SLOS showed that there was an inverse correlation between clinical severity and both the level of AF 7DHC and the level of MSuE3. Based on these earlier and more extensive studies, we conclude that accurate prenatal diagnosis of RSH/ SLOS is possible by sterol analysis of AF and, most likely, CV specimens as well. Furthermore, our findings suggest that MSuE3 levels in combination with sonography may provide useful diagnostic and prognostic information in the absence of a family history of RSH/SLOS.

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Section: Introductionmentioning

confidence: 91%

Prenatal diagnosis of the RSH/Smith-Lemli-Opitz syndrome

Kratz

Kelley

1999

Am. J. Med. Genet.

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“…Common physical manifestations include: microcephaly; facial dysmorphism; cleft palate and micrognathia; structural central nervous system anomalies; limb defects, primarily syndactyly and polydactyly; urogenital anomalies; and structural cardiac defects. Prenatal diagnosis of SLOS has been based upon measurement of 7-DHC in CV cells (Mills et al, 1996) or amniotic uid (Abuelo et al, 1995;Dallaire et al, 1995;McGaughran et al, 1995;Rossiter et al, 1995). Recently, a new method for the evaluation of DHCR7 activity in cultured ®broblasts has been described which is simpler than previous assays and relies on the conversion of ergosterol (ergosta-5,7,22-trien-3b-ol) to brassicasterol (ergosta-5,22-dien-3b-ol) (Honda et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Fetal demise with Smith-Lemli-Opitz syndrome confirmed by tissue sterol analysis and the absence of measurable 7-dehydrocholesterol ?7-reductase activity in chorionic villi

et al. 2000

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Smith-Lemli-Opitz syndrome (SLOS), an autosomal recessive condition with multiple malformations, mental retardation, and growth failure, results from markedly reduced activity of the final enzyme in the cholesterol biosynthetic pathway, 7-dehydrocholesterol Delta(7)-reductase (DHCR7). We diagnosed SLOS in a fetus following intrauterine demise at 32 weeks' gestation. Chorionic villus (CV) sampling had been performed at 30 weeks because oligohydramnios and atrioventricular septal defect were noted on fetal ultrasound. On fetal post-mortem examination, a midline U-shaped soft palate cleft, micrognathia, postaxial polydactyly of the fingers with single transverse palmar creases bilaterally, and cutaneous syndactyly of toes two-three bilaterally suggested SLOS. We hypothesized that SLOS could be confirmed by analysis of tissue sterols despite extensive autolysis, and by measurement of enzyme activity in CV cells. Measurement of DHCR7 activity in CV cells was undertaken using ergosterol as a substrate. CV cells were unable to convert any ergosterol to brassicasterol after a 72 h incubation period while control CV cells reduced 12.6-71.8% of ergosterol to brassciasterol in a 72 h period. SLOS was confirmed by measurement of elevated 7-dehydrocholesterol (7-DHC) in the CV cells. Measurements of sterols were made in multiple fetal tissues. All tissues analysed showed elevated 7-DHC with markedly increased 7-DHC/cholesterol ratios.

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“…It was determined that this must be caused by defective 7-dehydrosterol-7-reductase, a final step in cholesterol synthesis, and GC-MS of serum cholesterol and 7-DHC became the accepted clinical method for SLOS diagnosis (2,3 ). This method was further developed for prenatal diagnosis by measuring the sterols in amniotic fluid (3)(4)(5)(6)(7)(8)(9) or chorionic villus cells (10,11 ). In addition to 7-DHC, serum and amniotic fluid contain 8-dehydrocholesterol , and this is included in some analyses (12 ).…”

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confidence: 99%

“…Smith-Lemli-Opitz syndrome (SLOS) 5 is a serious disorder associated with dysmorphology and mental retardation. Because of the severity of the condition, development of diagnostic procedures has been critical.…”

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confidence: 99%

Potential of Sterol Analysis by Liquid Chromatography–Tandem Mass Spectrometry for the Prenatal Diagnosis of Smith-Lemli-Opitz Syndrome

et al. 2008

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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: 3β-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.

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Prenatal diagnosis of smith–lemli–opitz syndrome is possible by measurement of 7‐dehydrocholesterol in amniotic fluid

Cited by 28 publications

References 7 publications

Prenatal diagnosis of the RSH/Smith-Lemli-Opitz syndrome

Prenatal diagnosis of the RSH/Smith-Lemli-Opitz syndrome

Fetal demise with Smith-Lemli-Opitz syndrome confirmed by tissue sterol analysis and the absence of measurable 7-dehydrocholesterol ?7-reductase activity in chorionic villi

Potential of Sterol Analysis by Liquid Chromatography–Tandem Mass Spectrometry for the Prenatal Diagnosis of Smith-Lemli-Opitz Syndrome

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