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.
Smith-Lemli-Opitz syndrome (SLOS, RSH, OMIM #270400) is an autosomal recessive, multiple malformation, mental retardation syndrome due to an inborn error of cholesterol biosynthesis. Specifically, these patients have a deficiency of 3 beta-hydroxysterol Delta 7-reductase activity due to mutation of the 3 beta-hydroxysterol delta 7-reductase gene (DHCR7). This enzymatic deficiency impairs the conversion of 7-dehydrocholesterol (7-DHC) to cholesterol in the last step of cholesterol biosynthesis via the Kandutch-Russel biosynthetic pathway. The clinical manifestations of SLOS are extremely variable and the phenotypic spectrum is broad. At the severe end of the spectrum SLOS is a lethal disorder with multiple major congenital anomalies, and in mild cases SLOS combines minor physical stigmata with behavioral and learning disabilities. Based on clinical studies, the incidence of SLOS is on the order of 1/10,000 to 1/60,000. Molecular studies have shown a carrier frequency of about 1% for the most common SLOS mutant allele in North American populations. Currently therapy is based on dietary cholesterol supplementation. Although clinical improvement has been noted, serum cholesterol levels are rarely normalized and elevated serum 7-DHC levels persist. Because elevated 7-DHC levels may have toxic effects, treatment of SLOS patients with an HMG-CoA reductase inhibitor has been proposed. Two small (two-patient) open trials of simvastatin therapy in SLOS have been reported. One of these trials showed improved clinical status, decreased 7-DHC levels and increased cholesterol levels. The second trial showed decreased 7-DHC levels; however, treatment had to be discontinued in one patient with preexisting liver disease. The goal of this clinical research protocol will be to test the clinical efficacy and safety of simvastatin therapy in mild to classical SLOS patients using a double blinded, crossover design.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
TRIPLE
Enrollment
23
During the simvastatin phase of the trial, therapy will be initiated at 0.5 mg/kg/day for six weeks and then increased to 1.0 mg/kg/day if adverse side effects are minimal or absent.
During this trial and for two months prior, patients will be maintained on 150 mg/kg/day of dietary cholesterol (150 mg/ml in OraPlus) for the duration of the trial
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States
Serum Cholesterol to Total Sterol Ratio
Total serum cholesterol (mg/dL) divided by the sum of all sterols (cholesterol plus its precursors, 7-dehydrocholesterol - 7DHC, and 8-dehydrocholesterol- 8DHC - in mg/dL).
Time frame: 1 year after therapy.
Cerebral Spinal Fluid Dehydrocholesterol to Total Sterol Ratio
Percent of 7-dehydrocholesterol + 8-dehydrocholesterol as a fraction of the total sterols (cholesterol + 7-dehydrocholesterol + 8-dehydrocholesterol measured in cerebral spinal fluid
Time frame: 12 months
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