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First trimester prenatal diagnosis of Smith-Lemli-Opitz syndrome (7-dehydrocholesterol reductase deficiency)
K Mills1, H Mandel, R Montemagno
1Biochemistry Unit, Institute of Child Health, London, United Kingdom.
Insights
First-trimester prenatal diagnosis of Smith-Lemli-Opitz syndrome (SLOs) is possible using chorionic villus (CV) samples. Analysis of 7-dehydrocholesterol (7-DHC) in CV tissue can detect SLOs early in pregnancy.
Area of Science:
- Biochemistry
- Genetics
- Prenatal Diagnosis
Background:
- Smith-Lemli-Opitz syndrome (SLOs) is characterized by 7-dehydrocholesterol (7-DHC) accumulation due to a cholesterol synthesis defect.
- Current prenatal diagnosis for SLOs relies on amniotic fluid analysis at 16-18 weeks of gestation.
Purpose of the Study:
- To investigate 7-DHC and cholesterol concentrations in chorionic villus (CV) samples.
- To establish the feasibility of first-trimester prenatal diagnosis for SLOs.
Main Methods:
- Gas chromatography-mass spectrometry (GC-MS) assay to quantify 7-DHC and cholesterol.
- Analysis of the 7-DHC/cholesterol ratio in CV samples from pregnancies at risk for SLOs.
- Comparison with control ranges for CV samples (8-12 weeks gestation).
Main Results:
- 7-DHC was detectable in CV samples as early as 7 weeks of gestation.
- The 7-DHC/cholesterol ratio in placental tissue remained relatively constant between 7-18 weeks.
- One fetus was diagnosed with SLOs based on an elevated 7-DHC/cholesterol ratio (0.091) in CV samples at 10-12 weeks; two fetuses were diagnosed as unaffected.
Conclusions:
- Cholesterol synthesis via 7-DHC occurs in the placenta and/or fetus by 10 weeks of gestation.
- Prenatal diagnosis of SLOs is achievable in the first trimester using CV biopsy.
Abstract:
In Smith-Lemli-Opitz syndrome (SLOs), 7-dehydrocholesterol (7-DHC) accumulated because there is a block in the pathway for synthesis of cholesterol via 7-DHC. Prenatal diagnosis of SLOs has been achieved by analysis of 7-DHC in amniotic fluid obtained at 16-18 wk from pregnancies at risk. The purpose of this study was to investigate 7-DHC and cholesterol concentrations in chorionic villus (CV) samples with a view to performing first trimester prenatal diagnosis. Using a sensitive gas chromatography-mass spectrometry assay it was possible to detect 7-DHC in CV samples obtained as early as 7 wk of gestation. The ration of 7-DHC to cholesterol in placental tissue was shown to be relatively constant over the gestational period of 7-18 wk. We therefore proceeded to analyze the 7-DHC/cholesterol ration in CV samples taken at 10-12 wk of gestation from three pregnancies at risk for SLOs. The results were as follows: patient A, 1.10 x 10(-3); patient B, 1.80 x 10(-3); patient C, 0.091; control range for CVS (8-12 wk), 3.10 x 10(-4) to 1.62 x 10(-3) (mean +/- 2SD; n = 5). The fetus of patient C was diagnosed as affected by SLOs, and the parents requested termination. Analysis of cultured skin fibroblasts confirmed the diagnosis. Pregnancies A and B were diagnosed unaffected, and this was confirmed first by amniocentesis and then by the birth of normal infants at term. We conclude that synthesis of cholesterol via 7-DHC is occurring in the placenta and/or fetus at 10 wk of gestation and that prenatal diagnosis by CV biopsy is possible.