A Cholesterol deficiency in Smith-Lemli-Opitz syndrome: clinical and pharmaceutical relevance

Flávia Mendes

doi:10.62741/ahrj.v3iSuppl.2.162

Authors

Flávia Mendes Universidade Fernando pessoa

DOI:

https://doi.org/10.62741/ahrj.v3iSuppl.2.162

Keywords:

Smithe-Lemli-Opitz Syndrome, Cholesterol synthesis, inborn error, hypocholesterolemia, enzyme deficiency

Abstract

Introduction: Hypocholesterolemias, unlike hypercholesterolemias, constitute a heterogeneous group of rare disorders that remain poorly understood and are associated with high morbidity. In individuals with impaired cholesterol biosynthesis, abnormal embryonic development occurs, leading to the appearance of phenotypic alterations already in the prenatal period, since the transfer of cholesterol across the placental barrier is limited. Currently, approximately ten genetic disorders affecting the distal portion of the cholesterol biosynthetic pathway have been described, with Smith-Lemli-Opitz syndrome (SLOS) being the most frequent. This syndrome results from a deficiency of the enzyme 7-dehydrocholesterol reductase, responsible for the conversion of 7-dehydrocholesterol into cholesterol, and presents a very broad phenotypic spectrum, ranging from mild forms to severe cases with lethal congenital malformations. The most frequent clinical manifestations include syndactyly of the second and third toes, microcephaly, retrognathism, and anteverted nares.

Objectives: The aim of this work was to deepen knowledge on hypocholesterolemias, with particular emphasis on SLOS, highlighting the importance of early identification of cholesterol biosynthesis defects in order to improve diagnosis and therapeutic approaches.

Methodology: A narrative literature review was conducted based on scientific articles published between 2018 and 2024, retrieved from the PubMed, ScienceDirect, B-ON, and Google Scholar databases. Searches were performed using combinations of the keywords “Cholesterol synthesis”, “Inborn error”, “Hypocholesterolemias”, “Enzyme deficiency”, and “Smith-Lemli-Opitz syndrome” and their Portuguese equivalents, combined with the Boolean operators AND and OR. Articles were selected according to thematic relevance and alignment with the defined objectives, resulting in the analysis of 87 scientific articles.

Results: There is currently no proven effective treatment for SLOS. Dietary cholesterol supplementation and statin therapy remain controversial approaches. Cholic acid may improve cholesterol absorption, although it is insufficient to reverse the pathology. Miglustat has been considered a promising therapeutic option, particularly due to its potential impact on central nervous system alterations associated with the syndrome. In addition, supplementation with antioxidants such as vitamin E has shown the ability to inhibit the formation of oxysterols derived from 7-dehydrocholesterol, some of which exhibit relevant cellular toxicity. Despite these advances, available evidence remains limited, and continued scientific research is required. These disorders have a significant impact on human health, being associated with high morbidity, premature mortality, and persistent neurological impairments. Early recognition of hypocholesterolemias is essential to optimize clinical follow-up, implement individualized therapeutic strategies, and improve the quality of life of patients and their families.

Conclusion: Life expectancy of individuals with SLOS is often reduced, ranging from a few days to several decades, with premature death frequently resulting from severe congenital malformations. Although some clinical manifestations can be treated, most patients present persistent neurobehavioral abnormalities, reinforcing the need for more effective and targeted therapeutic approaches.

References

Abdel-Khalik, J. et al. (2021). Bile acid biosynthesis in Smith-Lemli-Opitz syndrome bypassing cholesterol: Potential importance of pathway intermediates. J Steroid Biochem Mol Biol, 206, pp. 105794. DOI: https://doi.org/10.1016/j.jsbmb.2020.105794

Abe, R. J. et al. (2022). Free Cholesterol Bioavailability and Atherosclerosis. Curr Atheroscler Rep, 24(5), pp. 323-336. DOI: https://doi.org/10.1007/s11883-022-01011-z

Aguilar-Ballester, M. et al. (2020). Impact of Cholesterol Metabolism in Immune Cell Function and Atherosclerosis. Nutrients, 12(7), pp. 19. DOI: https://doi.org/10.3390/nu12072021

Allen, L. B. et al. (2019). Desmosterolosis and desmosterol homeostasis in the developing mouse brain. J Inherit Metab Dis, 42(5), pp. 934-943. DOI: https://doi.org/10.1002/jimd.12088

Alston, M. C., Redman, L. M. e Sones, J. L. (2022). An Overview of Obesity, Cholesterol, and Systemic Inflammation in Preeclampsia. Nutrients, 14(10), pp. 1-9. DOI: https://doi.org/10.3390/nu14102087

Armistead, B. et al. (2020). Placental Regulation of Energy Homeostasis During Human Pregnancy. Endocrinology, 161(7), pp. 1-14. DOI: https://doi.org/10.1210/endocr/bqaa076

Ayoub, C. et al. (2021). Identification of a Variant in APOB Gene as a Major Cause of Hypobetalipoproteinemia in Lebanese Families. Metabolites, 11(9), pp. 1-13. DOI: https://doi.org/10.3390/metabo11090564

Bai, X. et al. (2022). The role of DHCR24 in the pathogenesis of AD: re-cognition of the relationship between cholesterol and AD pathogenesis. Acta Neuropathol Commun, 10(1), pp. 35. DOI: https://doi.org/10.1186/s40478-022-01338-3

Ballout, R. A. et al. (2020). Statins for Smith-Lemli-Opitz syndrome. Cochrane Database Syst Rev, 2020(1), pp. 1-22. DOI: https://doi.org/10.1002/14651858.CD013521

Begic, N., Begic, Z. e Begic, E. (2021). Smith-Lemli-Opitz syndrome: Bosnian and Herzegovinian experience. Balkan Journal of Medical Genetics, 24(1), pp. 99-102. DOI: https://doi.org/10.2478/bjmg-2021-0002

Berghoff, S. A., Spieth, L. e Saher, G. (2022). Local cholesterol metabolism orchestrates remyelination. Trends Neurosci, 45(4), pp. 272-283. DOI: https://doi.org/10.1016/j.tins.2022.01.001

Bianconi, S. E. et al. (2015). Pathogenesis, Epidemiology, Diagnosis and Clinical Aspects of Smith-Lemli-Opitz Syndrome. Expert Opin Orphan Drugs, 3(3), pp. 267-280. DOI: https://doi.org/10.1517/21678707.2015.1014472

Blassberg, R. et al. (2016). Reduced cholesterol levels impair Smoothened activation in Smith-Lemli-Opitz syndrome. Hum Mol Genet, 25(4), pp. 693-705. DOI: https://doi.org/10.1093/hmg/ddv507

Boland, M. R. e Tatonetti, N. P. (2016). Investigation of 7-dehydrocholesterol reductase pathway to elucidate off-target prenatal effects of pharmaceuticals: a systematic review. Pharmacogenomics J, 16(5), pp. 411-429. DOI: https://doi.org/10.1038/tpj.2016.48

Bredefeld, C. et al. (2022). Guidance for the diagnosis and treatment of hypolipidemia disorders. J Clin Lipidol, 16(6), pp. 797-812. DOI: https://doi.org/10.1016/j.jacl.2022.08.009

Capell-Hattam, I. M. et al. (2020). Twin enzymes, divergent control: The cholesterogenic enzymes DHCR14 and LBR are differentially regulated transcriptionally and post-translationally. J Biol Chem, 295(9), pp. 2850-2865. DOI: https://doi.org/10.1074/jbc.RA119.011323

Cappello, F. et al. (2022). FFPE-Based NGS Approaches into Clinical Practice: The Limits of Glory from a Pathologist Viewpoint. J Pers Med, 12(5), pp. 1-18. DOI: https://doi.org/10.3390/jpm12050750

Chattopadhyay, A. e Sharma, A. (2023). Smith-Lemli-Opitz syndrome: A pathophysiological manifestation of the Bloch hypothesis. Front Mol Biosci, 10, pp. 1120373. DOI: https://doi.org/10.3389/fmolb.2023.1120373

Chatuphonprasert, W., Jarukamjorn, K. e Ellinger, I. (2018). Physiology and Pathophysiology of Steroid Biosynthesis, Transport and Metabolism in the Human Placenta. Front Pharmacol, 9, pp. 1027. DOI: https://doi.org/10.3389/fphar.2018.01027

Cheon, S. Y. (2023). Impaired Cholesterol Metabolism, Neurons, and Neuropsychiatric Disorders. Exp Neurobiol, 32(2), pp. 57-67. DOI: https://doi.org/10.5607/en23010

Dang Do, A. N. et al. (2018). Spontaneously regressing brain lesions in Smith-Lemli-Opitz syndrome. Am J Med Genet A, 176(2), pp. 386-390. DOI: https://doi.org/10.1002/ajmg.a.38563

Daum, H. et al. (2020). Smith-Lemli-Opitz syndrome: what is the actual risk for couples carriers of the DHCR7:c.964-1G>C variant? Eur J Hum Genet, 28(7), pp. 938-942. DOI: https://doi.org/10.1038/s41431-020-0577-0

Delvecchio, M. et al. (2020). Dietary cholesterol supplementation and inhibitory factor 1 serum levels in two dizygotic Smith-Lemli-Opitz syndrome twins: a case report. Ital J Pediatr, 46(1), pp. 161. DOI: https://doi.org/10.1186/s13052-020-00924-2

Dewangan, L. et al. (2019). A colorimetric nanoprobe based on enzyme-immobilized silver nanoparticles for the efficient detection of cholesterol. RSC Adv, 9(72), pp. 42085-42095. DOI: https://doi.org/10.1039/C9RA08328F

Donoghue, S. E. et al. (2018). Smith-Lemli-Opitz syndrome: clinical and biochemical correlates. J Pediatr Endocrinol Metab, 31(4), pp. 451-459. DOI: https://doi.org/10.1515/jpem-2017-0501

Driesen, K. e Witters, P. (2022). Understanding Inborn Errors of Metabolism through Metabolomics. Metabolites, 12(5), pp. 1-19. DOI: https://doi.org/10.3390/metabo12050398

Elias, E. R. et al. (2024). Cholic acid increases plasma cholesterol in Smith-Lemli-Opitz syndrome: A pilot study. Mol Genet Metab Rep, 38, pp. 101030. DOI: https://doi.org/10.1016/j.ymgmr.2023.101030

Eren, E. E. et al. (2021). A Case of Smith-Lemli-Opitz Syndrome Diagnosed with Hypertrophic Pyloric Stenosis. Sisli Etfal Hastan Tip Bul, 55(2), pp. 268-271.

Ertugrul et al. (2022). Liver Transplant and Improvements in Cholesterol Biosynthesis Defect: A Case Report of Smith-Lemli-Opitz Syndrome. Experimental and Clinical Transplantation, 20(1), pp. 104-107. DOI: https://doi.org/10.6002/ect.2018.0131

Escriba, R., Ferrer-Lorente, R. e Raya, A. (2021). Inborn errors of metabolism: Lessons from iPSC models. Rev Endocr Metab Disord, 22(4), pp. 1189-1200. DOI: https://doi.org/10.1007/s11154-021-09671-z

Falsaperla, R. et al. (2021). Neonatal seizures as onset of Inborn Errors of Metabolism (IEMs): from diagnosis to treatment. A systematic review. Metab Brain Dis, 36(8), pp. 2195-2203. DOI: https://doi.org/10.1007/s11011-021-00798-1

Farkas et al. (2022). Morphological, biochemical, and transcriptomic characterization of iPSC-derived human RPE cells from normal and Smith-Lemli-Opitz syndrome patients. Molecular Vision, 28, pp. 394-411.

Fliesler, S. J. e Xu, L. (2018). Oxysterols and Retinal Degeneration in a Rat Model of Smith-Lemli-Opitz Syndrome: Implications for an Improved Therapeutic Intervention. Molecules, 23(10), pp. 1-11. DOI: https://doi.org/10.3390/molecules23102720

Foundation, S.-L.-O. (1990). Fundação Smith-Lemli-Opitz [Em linha]. Disponível em <https://www.smithlemliopitz.org/> [Consultado em 22/11/2023/].

Freel, B. A. et al. (2022). Sterol dysregulation in Smith-Lemli-Opitz syndrome causes astrocyte immune reactivity through microglia crosstalk. Dis Model Mech, 15(12), pp. 1-15. DOI: https://doi.org/10.1242/dmm.049843

Galano, M., Venugopal, S. e Papadopoulos, V. (2022). Role of STAR and SCP2/SCPx in the Transport of Cholesterol and Other Lipids. Int J Mol Sci, 23(20), pp. 1-14. DOI: https://doi.org/10.3390/ijms232012115

Garcia-Ruiz, C. et al. (2021). Mitochondrial Cholesterol and Cancer. Semin Cancer Biol, 73, pp. 76-85. DOI: https://doi.org/10.1016/j.semcancer.2020.07.014

Genaro-Mattos, T. C. et al. (2019). Maternal aripiprazole exposure interacts with 7-dehydrocholesterol reductase mutations and alters embryonic neurodevelopment. Mol Psychiatry, 24(4), pp. 491-500. DOI: https://doi.org/10.1038/s41380-019-0368-6

Genaro-Mattos, T. C. et al. (2021). Sterol Biosynthesis Inhibition in Pregnant Women Taking Prescription Medications. ACS Pharmacol Transl Sci, 4(2), pp. 848-857. DOI: https://doi.org/10.1021/acsptsci.1c00012

Genaro-Mattos, T. C. et al. (2018). Dichlorophenyl piperazines, including a recently-approved atypical antipsychotic, are potent inhibitors of DHCR7, the last enzyme in cholesterol biosynthesis. Toxicol Appl Pharmacol, 349, pp. 21-28. DOI: https://doi.org/10.1016/j.taap.2018.04.029

Gerrick, K. Y. et al. (2018). Transcriptional profiling identifies novel regulators of macrophage polarization. PLoS One, 13(12), pp. e0208602. DOI: https://doi.org/10.1371/journal.pone.0208602

Gibbins, K. J. et al. (2018). Smith-Lemli-Opitz Mutations in Unexplained Stillbirths. Am J Perinatol, 35(10), pp. 936-939. DOI: https://doi.org/10.1055/s-0038-1626705

Gumus, E. (2019). A Novel Frameshift Homozygous Mutation in DHCR7 with a Known Missense Homozygous Mutation in the PROC in a 6-Year-Old Boy: A Child with Two Rare Genetic Diseases. J Pediatr Genet, 8(3), pp. 168-171. DOI: https://doi.org/10.1055/s-0039-1685171

Gunda, V. et al. (2022). Ubiquitous Aberration in Cholesterol Metabolism across Pancreatic Ductal Adenocarcinoma. Metabolites, 12(1), pp. 1-14. DOI: https://doi.org/10.3390/metabo12010047

Hofmaenner, D. A. et al. (2022). The Many Roles of Cholesterol in Sepsis: A Review. Am J Respir Crit Care Med, 205(4), pp. 388-396. DOI: https://doi.org/10.1164/rccm.202105-1197TR

Hryniewicz-Jankowska, A., Augoff, K. e Sikorski, A. F. (2019). The role of cholesterol and cholesterol-driven membrane raft domains in prostate cancer. Exp Biol Med (Maywood), 244(13), pp. 1053-1061. DOI: https://doi.org/10.1177/1535370219870771

Jayamanne, C. et al. (2018). Smith-Lemli-Opitz syndrome presenting as acute adrenal crisis in a child: a case report. J Med Case Rep, 12(1), pp. 217. DOI: https://doi.org/10.1186/s13256-018-1738-4

Jezela-Stanek, A. et al. (2020). GC-MS as a tool for reliable non-invasive prenatal diagnosis of Smith-Lemli-Opitz syndrome but essential also for other cholesterolopathies verification. Ginekol Pol, 91(5), pp. 287-293. DOI: https://doi.org/10.5603/GP.2020.0049

Jiang, K. et al. (2020). Evolution, Expression Profile, Regulatory Mechanism, and Functional Verification of EBP-Like Gene in Cholesterol Biosynthetic Process in Chickens (Gallus Gallus). Front Genet, 11, pp. 587546. DOI: https://doi.org/10.3389/fgene.2020.587546

Kanuri, B. et al. (2021). Generation and validation of a conditional knockout mouse model for the study of the Smith-Lemli-Opitz syndrome. J Lipid Res, 62, pp. 100002. DOI: https://doi.org/10.1194/jlr.RA120001101

Kapphahn, R. J. et al. (2019). Lipid-derived and other oxidative modifications of retinal proteins in a rat model of Smith-Lemli-Opitz syndrome. Exp Eye Res, 178, pp. 247-254. DOI: https://doi.org/10.1016/j.exer.2018.08.006

Kaushal, J. B., Batra, S. K. e Rachagani, S. (2022). Hedgehog signaling and its molecular perspective with cholesterol: a comprehensive review. Cell Mol Life Sci, 79(5), pp. 266. DOI: https://doi.org/10.1007/s00018-022-04233-1

Koczok, K. et al. (2019). Subcellular localization of sterol biosynthesis enzymes. J Mol Histol, 50(1), pp. 63-73. DOI: https://doi.org/10.1007/s10735-018-9807-y

Koczok, K. et al. (2021). Biochemical and Clinical Effects of Vitamin E Supplementation in Hungarian Smith-Lemli-Opitz Syndrome Patients. Biomolecules, 11(8), pp. 1-11. DOI: https://doi.org/10.3390/biom11081228

Korade, Z., Heffer, M. e Mirnics, K. (2022). Medication effects on developmental sterol biosynthesis. Mol Psychiatry, 27(1), pp. 490-501. DOI: https://doi.org/10.1038/s41380-021-01074-5

Kruszka, P. e Muenke, M. (2018). Syndromes associated with holoprosencephaly. Am J Med Genet C Semin Med Genet, 178(2), pp. 229-237. DOI: https://doi.org/10.1002/ajmg.c.31620

Lai, L. M., Gropman, A. L. e Whitehead, M. T. (2022). MR Neuroimaging in Pediatric Inborn Errors of Metabolism. Diagnostics (Basel), 12(4), pp. 1-25. DOI: https://doi.org/10.3390/diagnostics12040861

Lee, S. H. et al. (2018). Severe persistent hypocholesterolemia after emergency gastrointestinal surgery predicts in-hospital mortality in critically ill patients with diffuse peritonitis. PLoS One, 13(7), pp. e0200187. DOI: https://doi.org/10.1371/journal.pone.0200187

Liu, J. et al. (2020). 7-dehydrocholesterol suppresses melanoma cell proliferation and invasion via Akt1/NF-kappaB signaling. Oncol Lett, 20(6), pp. 398. DOI: https://doi.org/10.3892/ol.2020.12261

Lubert, A. M. et al. (2021). Fontan-Associated Dyslipidemia. J Am Heart Assoc, 10(7), pp. e019578. DOI: https://doi.org/10.1161/JAHA.120.019578

Luo, Y. et al. (2022). Measurement of 7-dehydrocholesterol and cholesterol in hair can be used in the diagnosis of Smith-Lemli-Opitz syndrome. J Lipid Res, 63(6), pp. 100228. DOI: https://doi.org/10.1016/j.jlr.2022.100228

Malhotra, P. et al. (2020). Disturbances in Cholesterol Homeostasis and Non-alcoholic Fatty Liver Diseases. Front Med (Lausanne), 7, pp. 467. DOI: https://doi.org/10.3389/fmed.2020.00467

Marcuzzi, A. et al. (2018). Neuronal Dysfunction Associated with Cholesterol Deregulation. Int J Mol Sci, 19(5), pp. 1-12. DOI: https://doi.org/10.3390/ijms19051523

Meienberg, J. et al. (2016). Clinical sequencing: is WGS the better WES? Hum Genet, 135(3), pp. 359-362. DOI: https://doi.org/10.1007/s00439-015-1631-9

Mitra, A. et al. (2020). Smith-Lemli-Opitz's Syndrome as a Possible Cause of Recurrent Pregnancy Loss: A Case Report. AJP Rep, 10(1), pp. e118-e120. DOI: https://doi.org/10.1055/s-0040-1705131

Moutzouri, Moisés Elisaf e Liberopoulos, E. N. (2011). Hypocholesterolemia Current Vascular Pharmacology, 9, pp. 200-212. DOI: https://doi.org/10.2174/157016111794519354

Nakano, T., Inoue, I. e Murakoshi, T. (2019). A Newly Integrated Model for Intestinal Cholesterol Absorption and Efflux Reappraises How Plant Sterol Intake Reduces Circulating Cholesterol Levels. Nutrients, 11(2), pp. 1-18. DOI: https://doi.org/10.3390/nu11020310

Nowaczyk et al. (2020). Smith-Lemli-Opitz Syndrome. Gene Reviews, pp. 1-25.

Nowak, J. K. et al. (2019). Cystic fibrosis dyslipidaemia: A cross-sectional study. J Cyst Fibros, 18(4), pp. 566-571. DOI: https://doi.org/10.1016/j.jcf.2019.04.001

Ozturk, E. (2021). The Relationship Between Hematological Malignancy and Lipid Profile. Medeni Med J, 36(2), pp. 146-151. DOI: https://doi.org/10.5222/MMJ.2021.91145

Park, J. E. et al. (2021). Carrier frequency and incidence estimation of Smith-Lemli-Opitz syndrome in East Asian populations by Genome Aggregation Database (gnomAD) based analysis. Orphanet J Rare Dis, 16(1), pp. 166. DOI: https://doi.org/10.1186/s13023-021-01789-2

Pfeffer, B. A., Xu, L. e Fliesler, S. J. (2021). Transcriptomic Changes Associated with Loss of Cell Viability Induced by Oxysterol Treatment of a Retinal Photoreceptor-Derived Cell Line: An In Vitro Model of Smith-Lemli-Opitz Syndrome. Int J Mol Sci, 22(5), pp. 1-48. DOI: https://doi.org/10.3390/ijms22052339

Piscianz, E. et al. (2019). Is autophagy an elective strategy to protect neurons from dysregulated cholesterol metabolism? Neural Regen Res, 14(4), pp. 582-587. DOI: https://doi.org/10.4103/1673-5374.247441

Rhea, E. M. e Banks, W. A. (2021). Interactions of Lipids, Lipoproteins, and Apolipoproteins with the Blood-Brain Barrier. Pharm Res, 38(9), pp. 1469-1475. DOI: https://doi.org/10.1007/s11095-021-03098-6

Schoner, K. et al. (2020). Smith-Lemli-Opitz syndrome - Fetal phenotypes with special reference to the syndrome-specific internal malformation pattern. Birth Defects Res, 112(2), pp. 175-185. DOI: https://doi.org/10.1002/bdr2.1620

Schroor, M. M. et al. (2021). Associations between SNPs in Intestinal Cholesterol Absorption and Endogenous Cholesterol Synthesis Genes with Cholesterol Metabolism. Biomedicines, 9(10), pp. 1-14. DOI: https://doi.org/10.3390/biomedicines9101475

Sharma, A., Kumar, G. A. e Chattopadhyay, A. (2021). Late endosomal/lysosomal accumulation of a neurotransmitter receptor in a cellular model of Smith-Lemli-Opitz syndrome. Traffic, 22(10), pp. 332-344. DOI: https://doi.org/10.1111/tra.12811

Shengir, M., Elgara, M. e Sebastiani, G. (2021). Metabolic and cardiovascular complications after virological cure in hepatitis C: What awaits beyond. World J Gastroenterol, 27(17), pp. 1959-1972. DOI: https://doi.org/10.3748/wjg.v27.i17.1959

Shi, H. et al. (2018). Effects of a wide range of dietary forage-to-concentrate ratios on nutrient utilization and hepatic transcriptional profiles in limit-fed Holstein heifers. BMC Genomics, 19(1), pp. 148. DOI: https://doi.org/10.1186/s12864-018-4529-9

Shin, H. J. et al. (2021). Prognostic value of hypocholesterolemia in patients with gastric cancer. Asian J Surg, 44(1), pp. 72-79. DOI: https://doi.org/10.1016/j.asjsur.2020.08.014

Shyamali, N. L. A. e Ponnamperuma, C. (2020). Pulmonary Hypertension and Hypocholesterolemia Secondary to Thyrotoxicosis. Case Rep Endocrinol, 2020, pp. 8884061. DOI: https://doi.org/10.1155/2020/8884061

Simonen, P. et al. (2023). High cholesterol absorption: A risk factor of atherosclerotic cardiovascular diseases? Atherosclerosis, 376, pp. 53-62. DOI: https://doi.org/10.1016/j.atherosclerosis.2023.06.003

Soliman, G. A. (2018). Dietary Cholesterol and the Lack of Evidence in Cardiovascular Disease. Nutrients, 10(6), pp. 1-14. DOI: https://doi.org/10.3390/nu10060780

Strahlhofer-Augsten, M. et al. (2022). The Distinct Role of the HDL Receptor SR-BI in Cholesterol Homeostasis of Human Placental Arterial and Venous Endothelial Cells. Int J Mol Sci, 23(10), pp. 1-16. DOI: https://doi.org/10.3390/ijms23105364

Temple, S. E. L., Sachdev, R. e Ellaway, C. (2020). Familial DHCR7 genotype presenting as a very mild form of Smith-Lemli-Opitz syndrome and lethal holoprosencephaly. JIMD Rep, 56(1), pp. 3-8. DOI: https://doi.org/10.1002/jmd2.12155

Tomita, H. et al. (2022). 7-Dehydrocholesterol-derived oxysterols cause neurogenic defects in Smith-Lemli-Opitz syndrome. Elife, 11, pp. 1-27. DOI: https://doi.org/10.7554/eLife.67141

Tuckey, R. C. et al. (2021). Selective ability of rat 7-Dehydrocholesterol reductase (DHCR7) to act on some 7-Dehydrocholesterol metabolites but not on lumisterol metabolites. J Steroid Biochem Mol Biol, 212, pp. 105929. DOI: https://doi.org/10.1016/j.jsbmb.2021.105929

Wassif, C. A. et al. (2017). A placebo-controlled trial of simvastatin therapy in Smith-Lemli-Opitz syndrome. Genet Med, 19(3), pp. 297-305. DOI: https://doi.org/10.1038/gim.2016.102

Waterham e Wanders, R. J. A. (2000). Biochemical and gebetic aspects of 7-dehydrocholesterol redutase and Smith-Lemli-Opitz syndrome. Biochimica et Biophysica Acta, 1529, pp. 340-356. DOI: https://doi.org/10.1016/S1388-1981(00)00159-1

Woollett, L. A. (2005). Maternal cholesterol in fetal development: transport of cholesterol from the maternal to the fetal circulation. Am J Clin Nutr, 82(6), pp. 1155-1161. DOI: https://doi.org/10.1093/ajcn/82.6.1155

Xiao, J. et al. (2020). Targeting 7-Dehydrocholesterol Reductase Integrates Cholesterol Metabolism and IRF3 Activation to Eliminate Infection. Immunity, 52(1), pp. 109-122 e106. DOI: https://doi.org/10.1016/j.immuni.2019.11.015

Yan, H. et al. (2019). Targeted next generation sequencing in 112 Chinese patients with intellectual disability/developmental delay: novel mutations and candidate gene. BMC Med Genet, 20(1), pp. 80. DOI: https://doi.org/10.1186/s12881-019-0794-y

Yanagisawa, R. et al. (2022). The Impacts of Cholesterol, Oxysterols, and Cholesterol Lowering Dietary Compounds on the Immune System. Int J Mol Sci, 23(20), pp. 1-25. DOI: https://doi.org/10.3390/ijms232012236

Yanez, M. J. e Leiva, A. (2022). Human Placental Intracellular Cholesterol Transport: A Focus on Lysosomal and Mitochondrial Dysfunction and Oxidative Stress. Antioxidants (Basel), 11(3), pp. 1-15. DOI: https://doi.org/10.3390/antiox11030500

Zalewski, C. K. et al. (2021). Auditory phenotype of Smith-Lemli-Opitz syndrome. Am J Med Genet A, 185(4), pp. 1131-1141. DOI: https://doi.org/10.1002/ajmg.a.62087

Zigman, T. et al. (2021). Inborn Errors of Metabolism Associated With Autism Spectrum Disorders: Approaches to Intervention. Front Neurosci, 15, pp. 673600. DOI: https://doi.org/10.3389/fnins.2021.673600