Prevention of Retinal Degeneration in a Rat Model of Smith-Lemli-Opitz Syndrome.

Smith-Lemli-Opitz Syndrome (SLOS) is a recessive human disease caused by defective cholesterol (CHOL) synthesis at the level of DHCR7 (7-dehydrocholesterol reductase), which normally catalyzes the conversion of 7-dehydrocholesterol (7DHC) to CHOL. Formation and abnormal accumulation of 7DHC and 7DHC-derived oxysterols occur in SLOS patients and in rats treated with the DHCR7 inhibitor AY9944. The rat SLOS model exhibits progressive and irreversible retinal dysfunction and degeneration, which is only partially ameliorated by dietary CHOL supplementation. We hypothesized that 7DHC-derived oxysterols are causally involved in this retinal degeneration, and that blocking or reducing their formation should minimize the phenotype. Here, using the SLOS rat model, we demonstrate that combined dietary supplementation with CHOL plus antioxidants (vitamins E and C, plus sodium selenite) provides better outcomes than dietary CHOL supplementation alone with regard to preservation of retinal structure and function and lowering 7DHC-derived oxysterol formation. These proof-of-principle findings provide a translational, pre-clinical framework for designing clinical trials using CHOL-antioxidant combination therapy as an improved therapeutic intervention over the current standard of care for the treatment of SLOS.

Pregnancy and life after preimplantation genetic diagnosis of Smith-Lemli-Opitz syndrome.

OBJECTIVE: To use preimplantation genetic diagnosis to achieve Smith-Lemli-Opitz syndrome -free pregnancies in two couples at high risk of producing an affected child. DESIGN: Case report. SETTING: A private IVF unit. PATIENT(S): Two couples carrying the W151X mutation in the DHCR7 gene. INTERVENTION(S): Removal and testing for the W151X mutation in blastomeres from embryos after standard IVF. MAIN OUTCOME MEASURE(S): DNA analysis of blastomeres indicating whether corresponding embryos were mutation-free, for the purpose of transferring only unaffected embryos. RESULT(S): Delivery of healthy children without the W151X mutation in the DHCR7 gene. CONCLUSION(S): This is the first report of preimplantation genetic diagnosis for Smith-Lemli-Opitz syndrome, allowing transfer of mutation-free embryos and successful pregnancies.

Major fetal abnormalities associated with positive screening tests for Smith-Lemli-Opitz syndrome (SLOS).

OBJECTIVE: Determine the relationship between positive screening interpretations for Smith-Lemli-Opitz syndrome (SLOS) and other fetal abnormalities, to aid counseling and diagnostic activities. METHODS: An SLOS screening algorithm was incorporated into California's second-trimester screening program for Down syndrome and open neural tube defects (ONTDs). Between 2002 and 2004, 777 088 pregnant women were given an SLOS risk interpretation, using alpha-fetoprotein (AFP), unconjugated estriol (uE3), and human chorionic gonadotrophin (hCG) measurements. Outcomes were obtained in 98.8% of screen-positive pregnancies. RESULTS: SLOS screen positives, alone or in combination with screen positives for other fetal disorders (Down syndrome, trisomy 18, ONTD), were associated with a high risk for fetal pathology. Type and frequency of chromosomal or anatomic abnormalities (or fetal death) varied according to screen-positive combination. Among 2018 screen-positive pregnancies, 644 fetal deaths were identified. Among the 1374 viable pregnancies, 519 were screen positive for SLOS alone; two SLOS cases and 51 other serious abnormalities were identified (14 aneuploidies; 37 anatomic). The remaining 855 were also screen positive for at least one other disorder; two SLOS cases and 327 other abnormalities were identified (180 aneuploidies; 157 anatomic). CONCLUSION: For screening programs implementing the SLOS algorithm, the present data may be useful for counseling and to guide diagnostic studies.