Biochemical and Phenotypical Aspects of Smith-Lemli-Opitz Syndrome and Related Disorders of Cholesterol Metabolism

Sponsor

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (NIH)

Overall Status

Recruiting

CT.gov ID

NCT05047354

Collaborator

(none)

250

Enrollment

Location

119.2

Anticipated Duration (Months)

2.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Background:

Smith-Lemli-Opitz Syndrome (SLOS) is a genetic disorder. It can cause birth defects and developmental delays. There is no cure for SLOS or other inherited diseases related to cholesterol production or storage. The data gained in this study may help researchers find ways to measure how well future treatments work.

Objective:

To learn more about SLOS and related disorders and how these diseases affect participants and relatives.

Eligibility:

People of any age who have or are suspected to have SLOS or another inherited disease related to cholesterol production or storage. Relatives are also needed.

Design:

Participants will be screened with a medical record review.

Participants will have visits every 6 to 12 months. They will have a physical exam. They will fill out a survey about their medical and behavioral history. They may have an eye exam. They may have a neurodevelopmental assessment. They may have a hearing test. Their outer and middle ears may be examined. Their ability to speak, understand speech, eat, and swallow may be assessed. They may get X-rays while they chew and swallow. Their functional ability and needs for adaptive devices or braces may be assessed. They may have a lumbar puncture. Photographs may be taken of their face and body.

Participants who cannot visit the NIH and relatives will have a virtual visit once a year. They will talk about their medical history and symptoms. They give blood, urine, and skin samples at a lab near their home. They will fill out a survey about their medical and behavioral history.

Participation will last for several years.

Condition or Disease	Intervention/Treatment	Phase
Smith Lemli Opitz Syndrome CHILD Syndrome Lathosterolosis Desmosterolosis

Detailed Description

Study Description: The objective of this study is to characterize the natural history of Smith-Lemli-Opitz Syndrome (SLOS) and related disorders (such as lathosterolosis, desmosterolosis, X-linked dominant chondrodysplasia punctata (CDPX2), CHILD syndrome, HEM dysplasia, and Antley-Bixler syndrome) by collecting both crosssectional and longitudinal data on individuals with these conditions.

Our goal is to investigate genetic, biochemical, and clinical aspects of SLOS and related disorders in order to facilitate development and implementation of future therapeutic trials. This protocol consists of a main study and two substudies. The main study involves in-person evaluation of patients and carriers of SLOS and related disorders. The first substudy includes collecting biorepository samples from patients and carriers of SLOS and related disorders. The second substudy involves obtaining a telemedicine history and full review of systems for patients with SLOS and related disorders. This protocol will also maintain a database of information collected over the past two decades at the NIH on SLOS trial participants. All individuals with SLOS, related disorders and carriers will be eligible for enrollment.

Objectives: The primary objective of this study is to determine laboratory or clinical outcome measures that could be used in future therapeutic trials. The secondary objectives of these studies are to define comorbidities and mortality of the disease, to identify potential participants for future therapeutic trials and to evaluate possible laboratory outcome measures in carriers and suspected carriers.

Endpoints: Primary endpoints

Phenotypic characterization of individuals with SLOS and related inborn errors of cholesterol synthesis. Define and characterize disease related morbidity and mortality.
Establishing a biomaterial collection (Blood, urine, CSF, DNA/RNA and cell lines) corresponding to well-phenotyped individuals for biomarker discovery and characterization.

Secondary endpoints: Phenotypic history as well as blood and urine biomarkers in individuals heterozygous for pathogenic DHCR7 variants or pathogenic variants in cholesterol synthetic genes.

Study Design

Study Type:

Observational

Anticipated Enrollment :

250 participants

Observational Model:

Cohort

Time Perspective:

Prospective

Official Title:

Natural History Investigation Into Biochemical and Phenotypical Aspects of Smith-Lemli-Opitz Syndrome and Related Disorders of Cholesterol Metabolism

Actual Study Start Date :

Jun 23, 2021

Anticipated Primary Completion Date :

May 31, 2031

Anticipated Study Completion Date :

May 31, 2031

Arms and Interventions

Arm	Intervention/Treatment
1 Subjects with Smith-Lemli-Opitz syndrome
2 Subjects with Disorders of cholesterol synthesis and metabolism

Outcome Measures

Primary Outcome Measures

The primary objective of this study is to determine laboratory or clinical outcome measures that could be used in future therapeutic trials. [ongoing]
We will obtain data from patient evaluations that may be used as therapeutic targets in the fututre.
The secondary objectives of these studies are to define comorbidities and mortality of the disease, to identify potential participants for future therapeutic trials and to evaluate possible laboratory outcome measures in carriers and suspected c... [ongoing]
To describe in more detail long term manifestations of SLOS and disorders of cholesterol synthesis.

Eligibility Criteria

Criteria

Ages Eligible for Study:

1 Day and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

INCLUSION CRITERIA:

Males or females of any age with any one of the following:

Clinical, biochemical, or genetic diagnosis of Smith-Lemli-Opitz Syndrome OR
Clinical, biochemical, or genetic diagnosis of desmosterolosis, lathosterolosis, CHILD syndrome, X-linked dominant chondrodysplasia type2 or another inborn error of cholesterol synthesis OR
Clinical suspicion of an inborn error of cholesterol synthesis, metabolism or impaired cholesterol homeostasis. Clinical observations may include, but are not limited to lipid-laden macrophages, abnormal LDL, HDL, total cholesterol, triglycerides, abnormal lipid electrophoresis, lipid storage in other tissues. OR
Family members of individuals diagnosed with or suspected to have an inborn error of cholesterol synthesis, metabolism or homeostasis.

EXCLUSION CRITERIA:

Individuals who cannot travel to the NIH because of their medical condition will be excluded from on-site participation. They may participate in the telemedicine or in the biomaterials parts of the study.
Individuals who, in the opinion of the investigator, are unable to comply with the protocol or have medical conditions that would potentially increase the risk of participation will be excluded from on-site participation. They may participate in the telemedicine or in the biomaterials parts of the study.
Female participants who are pregnant will be excluded from evaluations requiring sedation, radiation and LP. Total blood draw volumes will be kept at a minimum or if anemia of pregnancy is known, no blood will be taken for research testing.