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
- 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
- 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.
- INCLUSION CRITERIA:
All patients with biochemically proven SLOS will be considered for this study.
Patients will be excluded if they cannot travel to the NIH because of their medical
Age less than 4 and older than 18.
Weight less than 10 kg.
Developmental delay too severe to obtain adequate behavioral evaluation.
Severe behavioral problems that preclude proper physical and laboratory medicine
SLOS severity score greater than 30.
No biochemical diagnosis of SLOS.
No molecular conformation of SLOS.
Residual fibroblasts enzymatic activity less than 10% of control value (cholesterol
synthesis as a fraction of total sterol synthesis).
Dehydrocholesterol/cholesterol ratio greater than 1.0.
Contraindications for simvastatin use:
History of hypersensitivity to simvastatin or other "statins."
Acute liver disease.
Persistent elevations of serum transaminase levels or persistent elevations of CPK.
Concomitant therapy with tetralol-class calcium channel blockers (such as mibefradil).
Pregnancy or lactation.
History of rhabdomyolysis or myopathy.
Concomitant therapy with other drugs associated with myopathy (such as gemfibrozil or
other fibrates, niacin) or metabolism by the P450 isoform 3A4 system (such as cyclosporin,
itraconazole, ketoconazole, macrolide antibiotics, or nefazodone (Serzone)).
Warfarin-type anticoagulant therapy.