Smith-Lemli-Opitz Syndrome (SLOS) is a genetic disorder (autosomal recessive) caused by an
abnormality in the production of cholesterol. The disorder can occur in both a "mild" or
"severe" form. SLOS is associated with multiple birth defects and mental retardation. Some of
the birth defects include; abnormal facial features, poor muscle tone, poor growth, shortened
life span, and abnormalities of the heart, lungs, brain, gastrointestinal tract, limbs,
genitalia, and kidneys.
There is no known cure for SLOS but recently patients have been treated with increased
amounts of cholesterol in their diet. The cholesterol in a persons diet is unable to correct
the abnormalities in the patient's organs, but researchers hope it will improve growth
failure and mental retardation.
This study was developed to answer questions about the causes and complications of SLOS, as
well as the effectiveness of cholesterol treatment. The study will enroll patients diagnosed
with SLOS, and their mothers. The objectives of the study will be to address the following
1. <TAB> What is the prognosis / natural history of the demyelination in the nervous system
of patients with SLOS?
2. <TAB> Do patients with SLOS have other problems concerning the function of their
3. <TAB>What are the genetic make-ups of patients with SLOS?
4. <TAB>Can further studies of cholesterol metabolism and genetic testing, using SLOS
fibroblasts, increase the understanding of SLOS?<TAB>
Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive multiple congenital
anomaly/mental retardation syndrome. Typical clinical features include a distinctive facial
appearance, mental retardation, autistic behavior, hypotonia, failure to feed, poor growth,
decreased life span, and variable structural anomalies of the heart, lungs, brain,
gastrointestinal tract, limbs, genitalia and kidneys. The SLOS phenotypic spectrum is broad
and variable. At the severe end of the spectrum SLOS is a lethal disorder with multiple major
congenital anomalies; whereas, mild cases of SLOS present with a combination of minor
physical stigmata, behavioral problems, and learning disabilities. SLOS is due to an inborn
error of cholesterol biosynthesis. Biochemically, SLOS patients have a deficiency of
3beta-hydroxysterol delta(7)-reductase activity. 3beta-hydroxysterol delta(7)-reductase is an
NADPH dependent microsomal enzyme that catalyzes the reduction of the C7(8) double bond of
7-dehydrocholesterol (7-DHC) to yield cholesterol in the last step of cholesterol
biosynthesis via the Kandutsch-Russel pathway. This inborn error of cholesterol biosynthesis
results in elevated tissue and serum 7-DHC levels and typically decreased serum and tissue
cholesterol levels. In 1998 we established that the deficiency in 3beta-hydroxysterol
delta(7)-reductase activity is due to mutation of the 3beta-hydroxysterol delta(7)-reductase
gene (DHCR7). Once the biochemical defect in SLOS was identified, dietary cholesterol
supplementation was proposed and employed as a therapeutic approach. Although developmental
malformations remain fixed, dietary cholesterol supplementation appears to improve the
overall health of these patients, and initial results have shown that dietary cholesterol
supplementation has had a positive impact on some of the behavioral manifestations of this
disorder. Although our understanding of this disorder has advanced over the last few years,
many questions remain concerning the effectiveness of cholesterol replacement therapy, the
long term prognosis for individuals on dietary cholesterol supplementation, and the need for
adjunctive measures in the clinical management of SLOS patients. We propose to answer some of
these questions by continuing our longitudinal natural history/prognosis study on patients
The objectives of this study are as follows:
1. To establish the natural history, and thus prognoses, of a cohort of SLOS patients on
dietary cholesterol supplementation.<TAB><TAB>
2. To provide baseline information about SLOS patients on cholesterol supplementation in
order to design and interpret future adjunctive therapies.
3. To function as a screening protocol to recruit patients into other therapeutic or
investigative trials. This protocol provides for phenotypic evaluation, obtaining skin
fibroblasts, initial laboratory testing, and genotyping. This protocol also provides an
alternative for patients who are excluded, or elect not to participate in a future
4. To maintain a large, diverse and well-characterized SLOS cohort to investigate new areas
of clinical concern that arise.
5. To establish a genotype/phenotype correlation for SLOS, to continue to define the SLOS
clinical spectrum and to determine other factors that may significantly influence a
specific patient s phenotype.
6. To use in vitro and in vivo studies of cholesterol metabolism to further our
understanding of the molecular, biochemical, and cellular processes that underlie the
clinical problems encountered in SLOS.
7. To use newer modalities of magnetic resonance imaging (Quantitative MRS and Diffusion
Tensor Imaging) and to correlate findings with both biochemical measures and
- INCLUSION CRITERIA:
- Any patient with biochemically confirmed SLOS will be accepted into this study.
Patients of any age, either gender, or any ethnicity will be accepted into this study.
No exclusions will be made based on race or gender. Historically, more males than
females have been diagnosed as having SLOS. This bias was likely a result of the fact
that genital hypoplasia is readily apparent in a male, and therefore the clinical
diagnosis is easier to make in a male patient. SLOS syndrome appears more commonly in
individuals of Northern European ancestry. Out of 150 biochemically proven cases, only
one was an African American and no patients of Asian descent were reported. One SLOS
mutant allele (R404C) appears to be present in individuals of French Canadian and
Creole heritage. This likely represents a founder effect. One puzzling finding is that
the carrier rate of the most common SLOS mutant allele in Black Canadians from Ontario
and African Americans from Pennsylvania appears to be approximately 0.7%. However,
clinical cases appear to be rare. The predominance of Caucasians reported in the
literature may represent a bias of ascertainment of the disorder, variable
presentation in different ethnic groups, or a founder effect in some ethnic groups.
Because we function as a referral center with respect to recruitment, the ethnic
background of our population is likely going to reflect the overall population of
- Patients will be excluded if they cannot travel to the NIH because of their medical
- Pregnant women will be excluded, and a negative urine pregnancy test will be required
of menstruating women.