Simvastatin Therapy in Smith-Lemli-Opitz Syndrome
Condition: Smith-Lemli-Opitz Syndrome
MeSH terms: Cleft Palate; Hypertelorism; Hypospadias; Genetic Diseases, X-Linked; Smith-Lemli-Opitz Syndrome; Syndrome
Study type: Interventional
Phase: Phase 2

Summary: 
      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.
    

Detailed description: 
      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.
    

Intervention name(s): Simvastatin Susp.; OraPlus
Intervention type(s): Drug; Drug
Intervention description(s): 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
Intervention MeSH terms: Simvastatin
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: Cholesterol; SLOS; HMG-COA Reductase Inhibitor; Malformation Syndrome; Mental Retardation; Smith-Lemli-Opitz Syndrome