Short-term Behavioral Effects of Cholesterol 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 10-week study will evaluate and compare behavior changes in children with
      Smith-Lemli-Opitz syndrome (SLOS) who are taking cholesterol supplementation versus those who
      are not on cholesterol supplementation. SLOS is a genetic disorder that affects the
      development of children both before and after birth. An enzyme deficiency in these children
      results in low levels of cholesterol, which can cause a variety of birth defects and
      behavioral problems. Typical abnormal physical features of patients include a small head,
      drooping eyelids, small upturned nose, small chin, cleft palate, heart defects, and extra
      fingers or toes.

      Children between 5 and 17 with mild SLOS who do not have a history of egg allergy or
      intolerance may be eligible for this study. Candidates are screened with a questionnaire
      about the patient's age, genotype (if known), sterol levels, symptoms, current treatment and
      medical history.

      Children participate in two 2-week study phases. Between the study phases the children will
      take 150 mg/kg daily of a cholesterol preparation typically used to supplement cholesterol in
      patients in SLOS studies at NIH. In the study phases, the participants are randomly assigned
      to take either egg yolk or an egg yolk substitute, such as Egg Beaters, that does not contain
      cholesterol. The study is done at the participant's home, and the cholesterol supplementation
      and egg/egg substitute are sent to the home each day with instructions on how to take them.

      The caretakers can stop the study phases after four days if behavior problems occur.

      The children's caretakers fill out a standard behavioral questionnaire, the Aberrant Behavior
      Checklist. The questionnaire is designed to assess the effects of treatment in mentally
      impaired persons.
    

Detailed description: 
      Smith-Lemli- Opitz syndrome (SLOS) is an autosomal recessive genetic condition caused by a
      deficiency of the enzyme 3beta-hydroxysterol delta(7)- reductase (DHCR7). DHCR7 is the final
      enzyme in the sterol synthetic pathway and converts 7- dehydrocholesterol (7DHC) to
      cholesterol. This results in low cholesterol and elevated 7DHC levels. SLOS has a wide
      phenotypic spectrum. Mildly affected individuals may have subtle dysmorphic features along
      with learning and behavioral disabilities. Typical clinical manifestations include
      microcephaly, ptosis, anteversion of the nostrils, micrognathia, high arched or cleft palate,
      congenital heart defects, clinodactyly, post- axial polydactyly, and 2-3 toe syndactyly. More
      severely affected individuals have multiple congenital anomalies, may be miscarried,
      stillborn, or die within the first few weeks of life.

      Dietary cholesterol supplementation in children with SLOS is reported to improve behavior,
      growth and nutritional status. Based upon observational studies, the behavioral changes
      reported with dietary cholesterol supplementation occur rapidly and appear to be reversible.
      Parental reports of improved behavior could be influenced by a placebo effect. Thus, we are
      proposing a blinded study to compare behavioral changes while the patient is on cholesterol
      supplementation (egg yolk) versus no cholesterol supplementation (egg substitute).

      The objectives of this study are:

        1. To quantitatively evaluate behavior, in a blinded study, of SLOS children on and off
           dietary cholesterol supplementation.

        2. To quantitatively evaluate behavior in SLOS children treated with egg yolk compared to
           synthetic dietary cholesterol supplementation.

      Completed study has been published. Tierney, E., Conley, S.K., Goodwin, H., Porter, F.D.
      (2010) Analysis of short-term behavioral effects of dietary cholesterol supplementation in
      Smith-Lemli-Opitz Syndrome. Am. J. Med. Genet. Part A. 152A: 91-95 PMID: 20014133
    

Intervention name(s): Egg yolk preparation with cholesterol; Egg substitute, without cholesterol
Intervention type(s): Dietary Supplement; Dietary Supplement
Intervention description(s): Egg yolk preparation with cholesterol; Placebo control. Egg substitute, without cholesterol
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Care Provider, Investigator)
Primary purpose: Treatment
Keywords: SLOS; RSH syndrome; ABC Checklist; Cholesterol supplementation; Egg yolk; Smith-Lemli-Opitz Syndrome