Short-term Behavioral Effects of Cholesterol Therapy in Smith-Lemli-Opitz Syndrome

Study Overview
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Brief Summary
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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
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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: To quantitatively evaluate behavior, in a blinded study, of SLOS children on and off dietary cholesterol supplementation. 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

Official Title
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Short-Term Behavioral Effects of Cholesterol Therapy in Smith-Lemli-Opitz Syndrome

Conditions
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Smith-Lemli-Opitz Syndrome

Intervention / Treatment
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* Dietary Supplement: Egg yolk preparation with cholesterol
* Dietary Supplement: Egg substitute, without cholesterol


Participation Criteria
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Eligibility Criteria
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Inclusion This study will include pediatric patients, ages 4-17 years old with a biochemical diagnosis of Smith-Lemli-Opitz Syndrome (SLOS). Only mild and classical patients will be enrolled. This study will be open to include SLOS patients regardless of whether or not they are participating in another NIH protocol. Exclusion Patients with a history of egg allergy or intolerance will be excluded from this study. Subjects must be well enough to be in a home setting. Patients participating in our simvastatin protocol (03-CH-3225) will be excluded from this study.

Ages Eligible for Study
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Minimum Age: 4 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Egg yolk preparation with cholesterol<br>Dietary cholesterol in the form of liquid egg yolk | Dietary Supplement: Egg yolk preparation with cholesterol<br>* Egg yolk preparation with cholesterol<br>|
| Placebo Comparator: Egg yolk preparation without cholesterol<br>No dietary cholesterol supplementation (egg substitute) Papetti Foods Better 'n Eggs egg substitute | Dietary Supplement: Egg substitute, without cholesterol<br>* Placebo control. Egg substitute, without cholesterol<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Hyperactivity Sub-scale of the Aberrant Behavior Checklist-Community (ABC-C). | The Aberrant Behavior Checklist-Community (ABC-C) is a measure used to identify treatment efficacy among intellectually impaired individuals. ABC Subscale IV (Hyperactivity) has 16 items, each can be rated from 0 to 3, with 0 equal to not at all a problems, one the problem is the behavior but slight in degree, to the problem is moderately serious, 3 the problem is severe in degree. For this subscale, score can go from 0 - 48. The higher the score, the worse the hyperactivity. The comparison in this study was made between the blinded phases when patients received either egg yolk (treated, +cholesterol) or egg substitute (untreated, -cholesterol). Order was randomized. | 2 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| ABC Irritability Sub-scale | ABC Subscale I (Irritability) has 15 items, each can be rated from 0 to 3, with 0 equal to not at all a problem, 1 the problem is the behavior but slight in degree, 2 the problem is moderately serious, 3 the problem is severe in degree. For this subscale, score can go from 0 - 45 | 2 weeks | 
| ABC Lethargy Sub-scale | ABC Subscale II (Lethargy) has 16 items, each can be rated from 0 to 3, with 0 equal to not at all a problems, 1 the problem is the behavior but slight in degree,2 the problem is moderately serious, 3 the problem is severe in degree. For this subscale, score can go from 0 - 48. | 2 weeks | 
| ABC Stereotypy Sub-scale | ABC Subscale III (Stereotypy) has 7 items, each can be rated from 0 to 3, with 0 equal to not at all a problems, 1 the problem is the behavior but slight in degree, 2 the problem is moderately serious, 3 the problem is severe in degree. For this subscale, score can go from 0 - 21. | 2 weeks | 
| ABC Inappropriate Behavior Sub-scale | ABC Subscale V (Inappropriate speech) has 4 items, each can be rated from 0 to 3, with 0 equal to not at all a problems, 1 the problem is the behavior but slight in degree, 2 the problem is moderately serious, 3 the problem is severe in degree. For this subscale, score can go from 0 - 12. | 2 weeks | 
| ABC Total Score | ABC total score includes all the questions from subscales, with range of 0 to 174. Higher the score , the greater the problem. | 2 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SLOS, RSH syndrome, ABC Checklist, Cholesterol supplementation, Egg yolk, Smith-Lemli-Opitz Syndrome