Assessment of the Whole Body Cholesterol Pool Size in Smith-Lemli-Opitz Syndrome Patients Receiving Cholesterol Supplementation Alone or Combined with Simvastatin

Smith-Lemli-Opitz syndrome (SLOS) is a multiple congenital/mental retardation syndrome, caused by 7-dehydrocholesterol-?7-reductase (DHCR7) enzyme deficiency. DHCR7 enzyme is involved in the last step conversion of sterol precursors to cholesterol, thus its deficiency results in low plasma cholesterol, high 7-dehydrocholesterol (7DHC) and 8-dehydrocholesterol (8DHC) levels in tissues and plasma.;Since cholesterol supplementation is prescribed routinely for most SLOS patients, it is critical to examine effects of cholesterol supplementation alone (HI) or combined with simvastatin (HI+ST) on maximizing whole body cholesterol pool size (WBCPS) and how other parameters can influence WBCPS in a positive way while down-regulating biosynthesis to decrease the build-up of potentially toxic precursors (7DHC/8DHC).;SLOS patients receiving cholesterol supplementation alone (n=15; mean age: 9.4 +/- 1.9 years) or combined with simvastatin (n=4; mean age: 7.3 +/- 1.2 years) were administered an intravenous injection of [18O]-cholesterol (1.0-1.4 mg/kg bodyweight) or [2H7]-cholesterol (0.9-1.4 mg/kg). Blood samples were collected at baseline and over a 10 weeks period, cholesterol was extracted from red blood cells, derivatized with piconyl ester and analyzed using liquid chromatography-tandem mass spectrometry (LC/MS/MS). Data were analyzed with SPSS statistical software. General linear regression analysis was used to examine associations between WBCPS and various parameters including body weight, cholesterol intake, and plasma levels of cholesterol, and for comparison of WBCPS values between patients on high cholesterol diet with and without simvastatin. Results are reported as mean +/- SEM.;Overall, WBCPS was significantly predicted by body weight (r2=0.65; p<0.05) and age (r2=0.46; p<0.05), but not plasma cholesterol levels (r2=0.10). WBCPS failed to correlate with cholesterol intake. However, plasma cholesterol concentration correlated with cholesterol intake (r2=0.42; p<0.05). WBCPS was higher in HI+ST compared to HI group (2.76 +/- 0.20 vs. 2.53 +/- 0.19 mg/kg bodyweight, respectively; p=0.02). Finally, no significant change in WBCPS was seen over time (p=0.06) in SLOS patients (n=6) re-evaluated after 2.0 +/- 1.1 years of high cholesterol supplementation with and without simvastatin.;Dietary cholesterol supplementation has been used as a standard therapy, aiming to increase plasma and tissue cholesterol concentrations, down regulating 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG CoA R) enzyme activity and perhaps suppressing 7DHC synthesis. HMG CoA R competitive inhibitor (e.g. simvastatin) also has been used in explorative studies in SLOS to decrease toxic build-up of 7DHC and 8DHC.;The findings of this current study increased our knowledge about the effects of interventions such as dietary cholesterol supplementation and simvastatin on the WBCPS in children with SLOS.