Investigation of Simvastatin Therapy in Smith-Lemli-Opitz Syndrome

This study will evaluate the safety and effectiveness of simvastatin in treating children with Smith-Lemli-Opitz syndrome (SLOS). Patients with this inherited disease are deficient in an enzyme that converts a substance called 7-dehydrocholesterol (7-DHC) to cholesterol. Cholesterol synthesis is impaired, causing birth defects and mental retardation. This study will examine whether simvastatin can increase the amount of the deficient enzyme, thereby lowering 7-DHC and increasing cholesterol. It will examine the safety of simvastatin in affected children and its effects on their behavioral problems.

Children between 4 and 18 years of age with mild to typical SLOS may be eligible for this study. Participants will be evaluated at the NIH Clinical Center in Bethesda, MD, and at the Kennedy Krieger Institute in Baltimore, MD, upon admission to the study and again at 6, 12, 20, and 26 months. The visits will last 3 to 4 days, and will include a medical history and physical examination, photographs to document medical findings, and other procedures detailed below. In addition, blood samples will be collected at 1, 3, 9, 14, 15, 17, and 23 months. Parents will complete several questionnaires during the study. Procedures include the following:

• Simvastatin and cholesterol supplementation therapy. Patients take cholesterol supplements (50 milligrams per kilogram per day) plus simvastatin (0.5 mg/kg/day for 6 weeks and then 1 mg/kg/day) for 12 months, and cholesterol supplements plus a placebo for 12 months.
• Blood draws to check liver, muscle, and kidney function, hormone levels, vitamin D levels, blood counts, cholesterol and 7-DHC levels, and lipoprotein levels. Some extra blood is drawn for research purposes.
• Urine collection. Urine is collected using a toilet hat. For children who are not toilet trained, urine is collected in a bag taped to the skin with an adhesive.
• Electroretinogram (ERG) to measure the function of the retina, the light-sensitive tissue at the back of the eye. ERG is done under sedation. After adapting the child's eyes to the dark, an electrode is taped to the child's forehead, the surface of one eye is numbed with eye drops, and a contact lens is placed on the eye. The child looks inside a globe that emits a series of light flashes. The contact lens senses electrical signals generated by the retina when the light flashes. After the ERG, the patient has a full eye exam, including pupil dilation and photographs of the eye.
• Lumbar puncture (spinal tap) to collect a sample of cerebral spinal fluid (CSF). This procedure, done while the patient is sedated for the ERG, shows whether simvastatin affects brain cholesterol and chemical levels. Under local anesthetic, a needle is inserted in the space between the bones in the lower back where the CSF circulates below the spinal cord. A small amount of fluid is collected through the needle.
• CRH stimulation test to detect hormone-related problems in cholesterol synthesis. The patient is given CRH, a hormone involved in cholesterol synthesis, through a plastic tube placed in a vein. Blood samples are collected through the same catheter to measure levels of other hormones involved in cholesterol production.
• Electroencephalogram (EEG) to look at the electrical activity (brain waves) of the child's brain.
• Activity monitoring. An activity monitor, which looks like and is worn like a watch, is used to record the child's level of activity for a 48-hour period.
• Urine pregnancy test at every visit for female patients over age 10.
• Skin swab for sterol (solid alcohol, such as cholesterol) analysis. An alcohol pad is rubbed lightly against the child's arm or thigh to collect skin cells.
• Stool collection. A small stool sample is collected from the child's diaper or, for children who are toilet trained, from a toilet "hat" like that used to collect urine.