Smith-Lemli-Optiz Syndrome (SLOS) Ana C. Ferreira 1

Smith-Lemli-Opitz Syndrome: The Impact and of Cholesterol Synthesis and Deficiency in Patients 2

What is SLOS? Inborn error of cholesterol synthesis where the body cannot produce cholesterol. It was first described in 1964 by three pediatricians: David Smith, Luc Lemli, and John Opitz. Incidence is of 1/20,000 to 1/60,000. 1 3

How Does It Happen? It is a inherited disorder when both parents are carriers 7-dehydrocolesterol reductase (DHCR7) gene is impaired. In the last step of cholesterol synthesis, 7-dehydrocholesterol (7-DHC) is not converted to cholesterol. 2 As a result: The body accumulates high levels of 7-DHC and low levels of cholesterol. Fig. 1 Fig. 2 4

7-dehydrocholesterol Cholesterol 5 The 7-DHCR gene encodes an enzyme that removes the C(7-8) double bond in the B ring of sterols and catalyzes the conversion of 7-dehydrocholesterol to cholesterol. Fig. 3 Fig. 4

Cholesterol Pathway. 4 37 Complex steps 6 Fig. 5

Cholesterol plays a very important role in human body and a deficiency of this lipid, causes a series of body abnormalities 7 Fig. 6

Features of SLOS in the Patients Typical features include: 5 Microcephaly Small upturned nose Cleft palate and sub-mucosal clefts Limb abnormalities can include extra or fused finders or toes 8 Fig. 7

Study #1 Chan YM, Merkens LS, Connor WE, et al Effects of dietary cholesterol and simvastatin on cholesterol synthesis in SLOS Purpose: To understand and perhaps ameliorate cholesterol deficiency in SLOS individuals, through a cholesterol-rich diet and Simvastatin. Methods: Evaluation of cholesterol synthesis and sterol concentrations in 12 SLOS patients from Oregon Health & Science University. Nine of the subjects received a high cholesterol diet for three years. Three of the subjects received a low cholesterol diet during four weeks. Results: Lower levels of 7-DHC and higher levels of cholesterol in those who received a cholesterol-rich diet plus Simvastatin. Conclusion: Cholesterol-rich diet shows to increase cholesterol levels, which will help cells to work properly. Simvastatin helps to decrease 7-DHC levels in the plasma. This study was important because it is necessary to understand the types of therapy available that SLOS patients should receive to have a healthier life. 9

Study #2 Steiner RD, Link LM, Flavell DP, et al Sterol balance in the Smith-Lemli-Optiz syndrome Purpose: To promote a better understanding of the precursor sterols and bile acids in SLOS subjects in order to provide an effective therapy to the patients. Methods: Researchers measured sterol precursor synthesis and bile acid synthesis of eight SLOS patients. Four of the SLOS subjects were admitted to the research center for one week period after been given a cholesterol-free diet at home for three or more weeks prior. Results: Total sterol synthesis was lower in SLOS subjects vs. control subjects (12.0 vs. 20.2 mg/kg/day). The bile acid synthesis showed to be not significantly lower in SLOS subjects compared to the control group (3.48 vs. 4.64mg/kg/day). Conclusion: Cholesterol affects the production of bile acids, therefore, with lower levels of bile acids in their system, individuals with SLOS cannot absorb fat-soluble vitamins such as vitamin A, D, E and K. Vitamin D plays a leading role helping calcium to build bones, therefore, the lack of vitamin D absorption might explain why children with SLOS do not grow properly. 10

Study #3 Tulenko TN, Boeze BK, Mason RP, et al A membrane defect in the pathogenesis of the Smith-Lemli-Optiz syndrome Purpose: To discuss the possibility that there is a defect in the lipid bilayer of SLOS cells that alters cells function. Methods: Skin fibroblasts cells from five SLOS patients and five control subjects were used. X-ray diffraction was used to measure membrane sterol, membrane fluidity, calcium permeability, folate uptake, and cell proliferation. Results: Membrane fluidity showed to be significantly increased in SLOS fibroblasts. Folate had 50% reduced uptake in SLOS fibroblasts. Decreased cell proliferation Conclusion: Impaired folate uptake across the cell membrane may lead to clef palate in some SLOS. Decreased cell proliferation may explain the failure to grow normally that almost all SLOS patients suffer. 11

Study #4 Wassif CA, Vied D, Tsokos M, et al Cholesterol storage defect in RSH/Smith-Lemli-Optiz syndrome fibroblasts Purpose: To show evidence that intracellular low-density lipoprotein (LDL) cholesterol metabolism and storage are aberrant in SLOS fibroblasts. Methods: Cell lines from SLOS patients and control group. Fibroblasts were grown and supplemented with 5% lipoprotein- deficient serum (LPDS) for four to seven days. Filipin staining, which is a fluorescent polyene antibiotic that binds unesterefied sterols, was the method used. Results: The rate of LDL degradation was decreased in SLOS cell lines compared to the rate of LDL degradation in control cell lines. Conclusion: SLOS individuals were not able to degrade the bad cholesterol in the body. High concentrations of LDL which may lead to atherosclerosis within the walls of arteries and over the years may eventually result in artery rupture. 12

Overall Conclusion SLOS individuals cannot produce cholesterol endogenously. As a result, due to the very important role that cholesterol plays in the human body, children are born with a significant number of abnormalities. Even though there is no currently cure for SLOS patients, researchers are trying to understand the impact and management of cholesterol synthesis in these individuals, to improve their daily lives. Cholesterol-rich diet has been shown, in many studies, to be the most common treatment for SLOS individuals. Simvastatin is also considered in order to help lower 7-DHC levels. 13

Why is this relevant in my opinion? I believe that it is important for health care professionals such as Nutritionists to understand this genetic disorder in order to help patients and their families, by educating them on how to alleviate some of the symptoms. When receiving a proper diet, the hope is to maximize the childrens health. I also think that more studies should be done in order to find better treatments besides cholesterol-rich diet and drugs. More studies related to the diet of SLOS individual should be also considerate, because it can be such an important factor in their health status. Moreover, perhaps through the study of genetics, researchers might be able find a possible cure for the gene mutation. 14 Neena

REFERENCES: 1. Counsyl. Smith-Lemli-Optiz Syndrome. Counsyl. https://www.counsyl.com/services/family-prep-screen/diseases/smith- lemli-opitz-syndrome/ Accessed November 6, 2014. 2. University of Utah Health Science. Smith-Lemli-Opitz Syndrome. Learn Genetics. file:///Users/anaferreira/Desktop/Fall%202014/Nutritional%20Biochem./M acronutrient%20Metabolism/learn%20genetics%20.webarchive Accessed December 2, 2014. APPENDIX: Figure 1 & 2. University of Utah Health Science. Smith-Lemli-Opitz Syndrome. Learn Genetics. file:///Users/anaferreira/Desktop/Fall%202014/Nutritional%20Biochem./ Macronutrient%20Metabolism/learn%20genetics%20.webarchive Accessed December 2, 2014. Figure 3. Wikipedia. 7-dehydrocholesterol. Wikipedia. http://en.wikipedia.org/wiki/7-Dehydrocholesterol. Accessed October 23, 2014. Figure 4. Wikipedia. Cholesterol. Wikipedia. http://en.wikipedia.org/wiki/CholesterolUpdated October 14, 2014. Accessed October 23, 2014. Figure 5. Porter FD, and Herman GE. Malformation syndromes caused by disorders of cholesterol synthesis. J Lipid Res. 2011; 52:6-34. Figure 6. Sheriff DS, Ali EF Perspective on plasma membrane cholesterol efflux and spermatozoal function. J of Human Reproductive System. 2010; 3:2(68-75 ). Figure 7. Porter FD, and Herman GE. Malformation syndromes caused by disorders of cholesterol synthesis. J Lipid Res. 2011; 52:6-34. 15

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Thank You Everyone! Ana C. Ferreira Biochemistry I Prof. Gian Ziza Fall 2014 17

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Smith-Lemli-Optiz Syndrome (SLOS) Ana C. Ferreira 1