Clinical trial NCT00114634: Short-term Behavioral Effects of Cholesterol Therapy in Smith-Lemli-Opitz Syndrome
Official title: Short-Term Behavioral Effects of Cholesterol Therapy in Smith-Lemli-Opitz Syndrome
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Smith-Lemli-Opitz Syndrome
Keywords: SLOS
RSH syndrome
ABC Checklist
Cholesterol supplementation
Egg yolk
Smith-Lemli-Opitz Syndrome
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2005-06-16
Enrollment: 13
Sex: ALL
Minimum age (years): 4
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief 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

Eligibility criteria: Inclusion

1. This study will include pediatric patients, ages 4-17 years old with a biochemical diagnosis of Smith-Lemli-Opitz Syndrome (SLOS).
2. Only mild and classical patients will be enrolled.
3. This study will be open to include SLOS patients regardless of whether or not they are participating in another NIH protocol.

Exclusion

1. Patients with a history of egg allergy or intolerance will be excluded from this study.
2. Subjects must be well enough to be in a home setting.
3. Patients participating in our simvastatin protocol (03-CH-3225) will be excluded from this study.

Primary outcomes:
measure: Hyperactivity Sub-scale of the Aberrant Behavior Checklist-Community (ABC-C).
timeFrame: 2 weeks
Secondary outcomes:
measure: ABC Irritability Sub-scale
timeFrame: 2 weeks
measure: ABC Lethargy Sub-scale
timeFrame: 2 weeks
measure: ABC Stereotypy Sub-scale
timeFrame: 2 weeks
measure: ABC Inappropriate Behavior Sub-scale
timeFrame: 2 weeks
measure: ABC Total Score
timeFrame: 2 weeks
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center, 9000 Rockville Pike
state: Maryland
Study officials:
affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
name: Forbes D Porter, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Elias ER, Irons MB, Hurley AD, Tint GS, Salen G. Clinical effects of cholesterol supplementation in six patients with the Smith-Lemli-Opitz syndrome (SLOS). Am J Med Genet. 1997 Jan 31;68(3):305-10. doi: 10.1002/(sici)1096-8628(19970131)68:33.0.co;2-x.
citation: Irons M, Elias ER, Abuelo D, Bull MJ, Greene CL, Johnson VP, Keppen L, Schanen C, Tint GS, Salen G. Treatment of Smith-Lemli-Opitz syndrome: results of a multicenter trial. Am J Med Genet. 1997 Jan 31;68(3):311-4.
citation: Kelley RI. A new face for an old syndrome. Am J Med Genet. 1997 Jan 31;68(3):251-6. doi: 10.1002/(sici)1096-8628(19970131)68:33.0.co;2-p. No abstract available.