Clinical trial NCT05047354: Biochemical and Phenotypical Aspects of Smith-Lemli-Opitz Syndrome and Related Disorders of Cholesterol Metabolism
Official title: Natural History Investigation Into Biochemical and Phenotypical Aspects of Smith-Lemli-Opitz Syndrome and Related Disorders of Cholesterol Metabolism
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Smith Lemli Opitz Syndrome
CHILD Syndrome
Lathosterolosis
Desmosterolosis
Keywords: 7-dehydrocholesterol reductase
7-dehydrocholesterol
cholesterol deficiency
Natural History
Lead sponsor: National Institutes of Health Clinical Center (CC)
Sponsor class: NIH
First posted: 2021-09-17
Enrollment: 250
Sex: ALL
Minimum age (years): 1
Maximum age (years): 100
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Male or female of any age with disorder of cholesterol metabolism. No geographic restrictions.

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.

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 affected individuals 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

1. Phenotypic characterization of individuals with SLOS and related inborn errors of cholesterol synthesis. Define and characterize disease related morbidity and mortality.
2. 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. Additional outcomes include assessments of bone health.

Eligibility criteria: * 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

-Biologic parents of affected individuals or known carriers based on previously done genetic testing who are willing and able to provide samples of any or all of the following: blood, urine, a skin biopsy, and/or tissue derived from clinically indicated surgery or autopsy.

EXCLUSION CRITERIA:

* Affected 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.
* Affected 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.

* Carrier adults who are unable to or unwilling to provide any of the following samples: Blood, urine, skin biopsy sample or tissue derived from clinically indicated surgery or skin biopsy.
* 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.

Primary outcomes:
measure: The primary objective of this study is to determine laboratory or clinical outcome measures that could be used in future therapeutic trials.
timeFrame: ongoing
measure: 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...
timeFrame: ongoing
Secondary outcomes:
Other outcomes:
Locations:
city: Bethesda
country: United States
facility: National Institutes of Health Clinical Center
state: Maryland
Study officials:
affiliation: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
name: Samar N Rahhal, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Nowaczyk MJ, Irons MB. Smith-Lemli-Opitz syndrome: phenotype, natural history, and epidemiology. Am J Med Genet C Semin Med Genet. 2012 Nov 15;160C(4):250-62. doi: 10.1002/ajmg.c.31343. Epub 2012 Oct 11.
citation: Irons M, Elias ER, Salen G, Tint GS, Batta AK. Defective cholesterol biosynthesis in Smith-Lemli-Opitz syndrome. Lancet. 1993 May 29;341(8857):1414. doi: 10.1016/0140-6736(93)90983-n. No abstract available.
citation: SMITH DW, LEMLI L, OPITZ JM. A NEWLY RECOGNIZED SYNDROME OF MULTIPLE CONGENITAL ANOMALIES. J Pediatr. 1964 Feb;64:210-7. doi: 10.1016/s0022-3476(64)80264-x. No abstract available.