Sterol and Isoprenoid Disease Research Consortium: Smith-Lemli-Opitz Syndrome

Study Overview
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Brief Summary
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The purpose of this study is to learn about Smith-Lemli-Opitz Syndrome (SLOS). SLOS is an inherited condition that is caused by the body not making an enzyme as it should. The body needs the enzyme to help make cholesterol. SLOS can cause many health problems including slow growth and development, eating disorders, sleep disorders, behavior disorders, and eye diseases. Severe SLOS leads to birth defects and mental retardation and in many cases early death. The investigators plan to measure cholesterol and other sterol levels, perform clinical observations, whole body testing and imaging (brain MRIs), to learn more about the disease and its progression, differences in the clinical features among individuals with SLOS, and look at the effect of cholesterol supplementation in this condition. The study is an interventional study to characterize disease progression and correlations between clinical, biochemical and physiological features of the disease. The main hypothesis is that dietary cholesterol supplementation does not improve features of SLOS related to the brain (e.g. IQ, behavior).

Detailed Description
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Smith-Lemli-Opitz syndrome (SLOS) is a disorder of cholesterol synthesis, or production. It is caused by mutations in the DHCR7 gene which encodes for 7-dehydrocholesterol- Δ7-reductase, an enzyme necessary for the production of cholesterol in the body. Affected individuals exhibit multiple malformations and mental retardation. The features of SLOS are thought to be primarily related to cholesterol deficiency and accumulation of cholesterol precursors. However, the clinical phenotype is not well characterized, the biochemical pathogenesis is incompletely understood, and there is no proven therapy for this devastating condition. Thus our primary objective is to better define the clinical and biochemical phenotypes of the disease using a natural history study design. The study will contribute to creating a comprehensive SLOS patient registry, identify biomarkers that can be used for diagnostic testing, screening and outcome measures in future therapeutic trials. All patients with SLOS receive dietary cholesterol supplementation with the hope that cholesterol supplementation will improve the clinical manifestation of the disease. However, there is no evidence supporting a clinical benefit of cholesterol supplementation. Thus a secondary objective of the study is to determine if cholesterol intake correlates with changes in whole body cholesterol homeostasis and clinical end-points.

Official Title
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Smith-Lemli-Opitz Syndrome: A Longitudinal Clinical Study of Patients Receiving Cholesterol Supplementation

Conditions
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Smith-Lemli-Opitz Syndrome

Intervention / Treatment
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* Dietary Supplement: Cholesterol supplementation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed diagnosis of Smith-Lemli-Opitz Syndrome (SLOS) Males and females of all ages Willing and able to travel to OHSU or another STAIR site Exclusion Criteria: Subject does not have Smith-Lemli-Opitz Syndrome (SLOS)

Ages Eligible for Study
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Maximum Age: 85 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cholesterol supplementation<br>All new subjects will come to their first visit with an least 3 weeks of stable cholesterol intake. Typically and preferably this will include egg yolk as cholesterol supplement, but in some instances e.g. intolerance to egg yolk it may include a new encapsulated cholesterol preparation, Sloesterol. | Dietary Supplement: Cholesterol supplementation<br>* Cholesterol supplementation may be achieved with SLOesterol instead of or in combination with egg yolk. SLOesterol is a powder formulation that contains cholesterol and natural emulsifier. It is considered a medical food developed by Solace Nutrition and available by prescription only.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To define the rate of progression of clinical and biochemical measures in patients with Smith Lemli-Opitz syndrome receiving dietary cholesterol supplementation. | This study will measure changes in whole body cholesterol pool size, 24S, cholesterol absorption and synthesis in relation with cholesterol intake and changes in clincal end-points. | Once per year at annual study visit | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Correlate biochemical and clinical phenotypes | To correlate biochemical and clinical phenotypes in SLOS subjects given dietary cholesterol with changes in whole body cholesterol pool size, and with its major determinants (cholesterol synthesis, absorption and intake). | Once per year at annual study visit | 
| Identify clinical or biochemical markers for future therapeutic trials. | To identify clinical or biochemical markers that can be used as outcome measures in a future therapeutic trial. | Once per year at annual study visit | 
| Identify a biochemical marker that can be used for diagnostic testing or screening. | To identify a biochemical marker that can be used for diagnostic testing or screening | Once per year at annual study visit | 
| Develop a registry and repository of biomaterials of SLOS patients | To develop a registry of well characterized SLOS patients and to maintain a repository of biomaterials corresponding to these patients | each subject will be enrolled in the registry at the baseline/initial visit, if they choose to participate in this portion of the study | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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SLOS