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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Forbes Porter, M.D., National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:
NCT00114634
First received: June 15, 2005
Last updated: March 3, 2014
Last verified: March 2014
  Purpose

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.


Condition Intervention Phase
Smith-Lemli-Opitz Syndrome
Drug: Dietary cholesterol supplementation
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: Short-Term Behavioral Effects of Cholesterol Therapy in Smith-Lemli-Opitz Syndrome

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Hyperactivity Sub-scale of the Aberrant Behavior Checklist-Community (ABC-C). [ Time Frame: 2 weeks ] [ Designated as safety issue: No ]
    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.


Secondary Outcome Measures:
  • ABC Irritability Sub-scale [ Time Frame: 2 weeks ] [ Designated as safety issue: No ]
    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

  • ABC Lethargy Sub-scale [ Time Frame: 2 weeks ] [ Designated as safety issue: No ]
    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.

  • ABC Stereotypy Sub-scale [ Time Frame: 2 weeks ] [ Designated as safety issue: No ]
    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.

  • ABC Inappropriate Behavior Sub-scale [ Time Frame: 2 weeks ] [ Designated as safety issue: No ]
    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.

  • ABC Total Score [ Time Frame: 2 weeks ] [ Designated as safety issue: No ]
    ABC total score includes all the questions from subscales, with range of 0 to 174. Higher the score , the greater the problem.


Enrollment: 13
Study Start Date: June 2005
Study Completion Date: February 2009
Primary Completion Date: February 2009 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Dietary cholesterol supplementation
Dietary cholesterol in the form of liquid egg yolk
Drug: Dietary cholesterol supplementation
Compare behavior on and off dietary cholesterol supplementation
Placebo Comparator: Egg substitute
No dietary cholesterol supplementation (egg substitute) Papetti Foods "Better 'n Eggs" egg substitute

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

Ages Eligible for Study:   4 Years to 17 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00114634

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, United States, 20892
Sponsors and Collaborators
Investigators
Principal Investigator: Forbes D Porter, MD NIH/NICHD
  More Information

Publications:
Responsible Party: Forbes Porter, M.D., Senior Investigator, National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier: NCT00114634     History of Changes
Other Study ID Numbers: 050168, 05-CH-0168
Study First Received: June 15, 2005
Results First Received: March 19, 2010
Last Updated: March 3, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
SLOS
RSH syndrome
ABC Checklist
Cholesterol supplementation
Egg yolk
Smith-Lemli-Opitz Syndrome

Additional relevant MeSH terms:
Syndrome
Cleft Palate
Hypertelorism
Hypospadias
Genetic Diseases, X-Linked
Smith-Lemli-Opitz Syndrome
Disease
Pathologic Processes
Jaw Abnormalities
Jaw Diseases
Musculoskeletal Diseases
Maxillofacial Abnormalities
Craniofacial Abnormalities
Musculoskeletal Abnormalities
Stomatognathic Diseases
Mouth Abnormalities
Mouth Diseases
Stomatognathic System Abnormalities
Congenital Abnormalities
Craniofacial Dysostosis
Dysostoses
Bone Diseases, Developmental
Bone Diseases
Penile Diseases
Genital Diseases, Male
Urogenital Abnormalities
Genetic Diseases, Inborn
Abnormalities, Multiple
Lipid Metabolism, Inborn Errors
Metabolism, Inborn Errors

ClinicalTrials.gov processed this record on September 18, 2014