Abstract
Smith-Lemli-Opitz syndrome (SLOS), also known as RSH syndrome, is an inborn error of cholesterol biosynthesis first described in 1964. Since then, significant advances have been made in understanding its pathophysiology, both during fetal development and postnatally. Cholesterol is a crucial lipid in the body, especially in the central nervous system, which accounts for nearly 25% of the body's total cholesterol. Cholesterol deficiency in SLOS can lead to congenital malformations and severe neurodevelopmental disabilities. The biochemical and genetic bases of SLOS have been elucidated. Reduced or absent 7-dehydrocholesterol reductase (DHCR7) enzymatic activity results not only in cholesterol deficiency but also in accumulation of 7-dehydrocholesterol, 8-dehydrocholesterol, and toxic oxysterol metabolites, which contribute to the pathophysiology of SLOS and correlate variably with the severity of its clinical symptoms. Despite decades of research, the clinical recognition of SLOS remains challenging due to the condition's multisystemic nature and noteworthy phenotypic variability. This review provides an up-to-date summary of major research advances in the study of SLOS with a focus on clinical manifestations and biochemical and genetic findings, which taken together facilitate recognition and diagnostic confirmation. Additionally, we recap past and current efforts in therapeutic development and offer guidance for disease management.
Korade Z, Anderson AC, Balog M, Tallman KA, Porter NA, Mirnics K. Hydroxyzine Effects on Post-Lanosterol Biosynthesis in Smith-Lemli-Opitz Syndrome (SLOS) Models. Biomolecules. 2025 Apr 10;15(4):562. doi: 10.3390/biom15040562. PMID: 40305315; PMCID: PMC12024545.
Abstract
Smith-Lemli-Opitz syndrome (SLOS) is a developmental disability arising from bi-allelic pathogenic variants in the 7-dehydrocholestrol reductase (DHCR7) enzyme and the accumulation of 7-dehydrocholesterol (7-DHC). 7-DHC spontaneously oxidizes and gives rise to cytotoxic oxysterols. Our recent high-throughput screening on Dhcr7-deficient Neuro2a cells identified hydroxyzine (HYZ) as a medication that could counteract the high levels of 7-DHC. We assessed the effects of HYZ in Dhcr7-deficient Neuro2a cells, neuronal cultures and glial cultures from Dhcr7T93M/T93M transgenic mice, and human dermal fibroblasts from patients with SLOS. LC-MS/MS biochemical analyses revealed a strong modulatory effect of HYZ on post-lanosterol biosynthesis across all four SLOS models. However, the HYZ-induced biochemical changes were complex, dose-dependent, and variable across the four SLOS models. Dhcr7-deficient Neuro2a cells showed decreased 7-DHC, 8-dehydrocholesterol (8-DHC), and desmosterol (DES) levels (all p < 0.01), while neuronal and glial cultures from Dhcr7T93M/T93M transgenic mice reported 8 significantly altered analytes (all p < 0.001). Human dermal fibroblast from patients with SLOS reacted to HYZ exposure with significantly decreased 7-DHC, 7-dehydrodesmosterol (7-DHD), and dihydrolanosterol (DHL) levels (p < 0.001), coupled with elevation in zymosterol (ZYM), zymostenol (ZYME), and 8-DHC (p < 0.001). Further evaluations are required to determine if the potentially beneficial effects of decreased 7-DHC, 7-DHD and DHL levels in SLOS models and patient biomaterials are counteracted by the rise in other post-lanosterol intermediates.
Westbye AB, Dizdarevic LL, Dahl SR, Asprusten EA, Bliksrud YT, Sandblom AL, Diczfalusy U, Thorsby PM, Retterstøl K. A sterol panel for rare lipid disorders: sitosterolemia, cerebrotendinous xanthomatosis and Smith-Lemli-Opitz syndrome. J Lipid Res. 2025 Jan;66(1):100698. doi: 10.1016/j.jlr.2024.100698. Epub 2024 Nov 19. PMID: 39566847; PMCID: PMC11714705.
Abstract
Disease-specific sterols accumulate in the blood of patients with several rare lipid disorders. Biochemical measurement of these sterols is important for correct diagnosis and sometimes monitoring of treatment. Existing methods to measure sterols in blood, particularly plant sterols, are often laborious and time consuming. Partly as a result, clinical access to sterol measurements is limited in many parts of the world. A simple and rapid method to extract free sterols from human serum and quantitate their concentration using isotope-dilution liquid chromatography-tandem mass spectrometry (LC-MS/MS) without derivatization was developed. The method was designed to be compatible with routine workflows (e.g., 96-well format) in a clinical lab and extensively validated. Serum from at least 125 controls were analyzed and used to estimate the upper reference limits for sitosterol, campesterol, stigmasterol, desmosterol, 7-dehydrocholesterol (7DHC), lathosterol, and cholestanol. Serum from patients with the rare lipid disorders sitosterolemia (n = 7), Smith-Lemli-Opitz syndrome (SLOS; n = 1), and cerebrotendinous xanthomatosis (CTX; n = 1) were analyzed. All seven sitosterolemia patients had greatly elevated levels of free plant sterols (sitosterol, campesterol, and stigmasterol) compared to the controls. The SLOS serum contained massively increased concentrations of 7DHC. CTX serum contained greatly increased concentrations of cholestanol, as well as 7DHC and lathosterol. Spiking experiments indicated that the method is likely also useful for the diagnosis of desmosterolosis and lathosterolosis. The reported method is a relatively simple and fast LC-MS/MS method capable of quantitating diagnostically important sterols and differentiated patients with three rare lipid disorders from controls.
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