RARE DISEASE
Smith-Lemli-Opitz syndrome
Smith-Lemli-Opitz syndrome
Smith-Lemli-Opitz syndrome
Synonyms: 7-dehydrocholesterol reductase deficiency, RSH syndrome, SLOS
Synonyms: 7-dehydrocholesterol reductase deficiency, RSH syndrome, SLOS
Synonyms: 7-dehydrocholesterol reductase deficiency, RSH syndrome, SLOS
Drug discovery
0
drugs
With orphan designations
Overview
Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder caused by DHCR7 gene mutations, impairing cholesterol synthesis. It manifests with developmental delays, intellectual disability, microcephaly, facial dysmorphism (broad nasal tip, ptosis), syndactyly, congenital anomalies (cardiac, genital), and autism spectrum behaviors [1][7][11]. Diagnosis relies on elevated 7-/8-dehydrocholesterol and low cholesterol levels, confirmed by genetic testing [1][6]. Current management includes cholesterol supplementation and statins (e.g., simvastatin) to modulate sterol levels, though neurological benefits remain uncertain [3][8][10].
Burden
Mortality: Up to 88% prenatal demise in severe cases; postnatal mortality linked to organ malformations (e.g., cardiac, pulmonary) [2][4].
Morbidity: Intellectual disability (90%), autism (75%), chronic growth failure, recurrent infections, and self-injurious behavior [1][6][11].
Lifelong care: Requires multidisciplinary management, burdening families with complex medical and behavioral needs [6][10].
Therapies
Cholesterol supplementation: Primary approach to address deficiency, though limited blood-brain barrier penetration [6][10].
Statins (simvastatin): May reduce toxic 7-dehydrocholesterol accumulation but lack robust evidence for neurobehavioral improvement [3][8].
Supportive care: Surgical correction of malformations, behavioral therapies, and infection management [6][10][11].
Categories: rare bone diseases, rare developmental anomalies during embryogenesis, rare endocrine diseases, rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases, rare ophthalmic disorders, rare renal diseases, rare transplant-related disorders, rare urogenital diseases
Research Papers
141 drug discovery papers about Smith-Lemli-Opitz syndrome, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
141 drug discovery papers about Smith-Lemli-Opitz syndrome, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-05-25 | Loss of 7-Dehydrocholesterol Reductase mediated cholesterol biosynthesis activates IRF3 and inhibits control of Mycobacterium marinum infection.
Cholesterol immunometabolism is a critical controller of immunopathology in respiratory infections such as tuberculosis. Smith-Lemli-Opitz syndrome (SLOS) patients are affected by a loss of 7-dehydrocholesterol reductase (DHCR7) function and have elevated 7-dehydrocholesterol (7DHC) and reduced cholesterol. Increased 7DHC has been found to be protective against viral infections in a range of infection models however SLOS patients have a higher susceptibility to respiratory infection. Here we use the zebrafish-Mycobacterium marinum infection model to demonstrate a compromised innate immune response to bacterial infection in the absence of dhcr7. We correlate increased 7DHC with increased activation of the IRF3/type I interferon axis and demonstrate Irf3 is a targetable signaling node to restore anti-bacterial immunity in a dhcr7-depleted background.
2026-05-04 | Pathophysiological significance of cholesterol in ciliopathies.
Primary cilia are sensory organelles essential for cellular signaling, the dysfunction of which causes ciliopathies, characterized by polycystic kidney disease, retinopathy, and developmental anomalies. Here, we review recent studies which have shown that cholesterol is a critical mediator of ciliary function and the pathogenesis of ciliopathies. Ciliary membranes show distinct cholesterol enrichment that is essential for the physiological function of various G-protein-coupled receptors and ion channels. Defects in de novo cholesterol synthesis (Smith-Lemli-Opitz syndrome) and peroxisome-facilitated cholesterol trafficking to ciliary membranes (Zellweger syndrome) result in ciliopathy-like phenotypes, establishing ciliary cholesterol insufficiency as a novel pathological mechanism. The polycystin complex associated autosomal dominant polycystic kidney disease localizes into ciliary membranes in a cholesterol-dependent manner. Specific cholesterol-binding sites in polycystin-2 are crucial for the distribution of cholesterol to cilia, while pathogenic mutations at these sites disrupt these interactions. We also discuss the previously underappreciated connections between ciliopathies, cholesterol, and other disorders such as cancer and neurodegenerative diseases, and opportunities for manipulating cholesterol for novel therapeutic strategies.
2025-12-11 | Smith-Lemli-Opitz Syndrome (SLOS)-Case Description and the Impact of Therapeutic Interventions on Psychomotor Development.
Background/Objectives: Smith-Lemli-Opitz syndrome (SLOS) is a genetic metabolic disorder characterized by impaired cholesterol synthesis and a wide range of developmental anomalies. This article presents a case of a girl with SLOS, diagnosed with two pathogenic variants of the DHCR7 gene. The objective is to evaluate the impact of early, multidisciplinary therapeutic interventions on the patient's development. Methods: Following diagnosis, a comprehensive metabolic therapy was initiated, including cholesterol and cholic acid supplementation. An interdisciplinary therapeutic approach was employed, involving physical therapy, speech therapy, and sensory integration, aimed at addressing various developmental challenges faced by the patient. Results: The therapy led to gradual improvements in the patient's psychomotor development, although the cholesterol levels were only partially improved and the accumulation of sterol precursors (7-DHC and 8-DHC) persisted. The coordinated care model facilitated better outcomes compared to less integrated efforts. Conclusions: The results highlight the importance of early diagnosis and integrated care in optimizing developmental outcomes for children with SLOS. A multidisciplinary approach is essential for addressing the complexities of the syndrome and promoting overall development.
2025-10-23 | Use of a cholesterol emulsion in Smith-Lemli-Opitz syndrome (SLOS): A single-center observational study, retrospective analysis and structured caregiver interview.
Smith-Lemli-Opitz syndrome (SLOS) is a rare autosomal recessive disorder of cholesterol biosynthesis. SLOS leads to increased levels of 7-dehydrocholesterol (7-DHC) and decreased levels of total cholesterol (TC). Dietary therapy usually involves supplementation with cholesterol in an oil-based or, less commonly, an aqueous cholesterol suspension. The limited solubility of cholesterol can result in uneven distribution, sedimentation and clumping. In seven patients (6 m, 1 f, 1-12 years) the previously administered dose of cholesterol was replaced by a newly developed emulsion and primary parameters TC, 7-DHC, HDL, LDL, vitamin D (25; 1-25), height and weight were determined. In addition, a personal structured interview was conducted with the caregivers of five participants to determine their satisfaction with the product, the care, and the effects on behaviour and health. One patient was excluded due to non-compliance (N = 6). Before the intervention, the mean TC level was 42 ± 9 mg/dl (min = 29, max = 52; n = 5) and increased by at least 95% and at most 299% (163 ± 93%). 7-DHC levels showed a decrease of -28% to -96% (-63 ± 29%). No effect on anthropometric parameters was observed. Overall, the families were satisfied with the care and the effect of the emulsion was predominantly described as successful. The emulsion and its application were well tolerated with few side effects. Overall, there was an improved effect on TC and 7-DHC levels compared to standard therapy, with high patient satisfaction and low side effects.
2025-09-22 | Cross-sectional analysis of expressive and receptive language skills in Smith-Lemli-Opitz syndrome (SLOS).
This study investigates receptive and expressive language abilities in individuals with Smith-Lemli-Opitz syndrome (SLOS) and examines how these are associated with intellectual functioning, sex, autism spectrum disorder (ASD) diagnosis, and biochemical markers of cholesterol metabolism. Participants (ages 4-18) with mild to classic SLOS were enrolled from a double-blind, placebo-controlled simvastatin trial. Receptive and expressive language scores were assessed using the Peabody Picture Vocabulary Test, Third Edition (PPVT-3), the Expressive One-Word Picture Vocabulary Test, 2000 Edition (EOWPVT-2000), and the MacArthur Communicative Developmental Inventories (MCDI). Intellectual ability and adaptive functioning were measured using the Stanford-Binet Intelligence Scales, Fifth Edition (SB-5) and Vineland Adaptive Behavior Scales, Third Edition (VABS-3). The SLOS Severity Scale (SSS) quantified disease severity. Associations with plasma and CSF sterol biomarkers (cholesterol, 7-dehydrocholesterol [7-DHC], 8-dehydrocholesterol [8-DHC]) were examined using nonparametric statistics with correction for multiple comparisons. Twenty-one participants (mean age 7.85 years) had complete data; 71.4% had a diagnosis of ASD. Receptive and expressive language scores correlated with IQ and adaptive functioning. Receptive vocabulary scores were significantly negatively associated with disease severity, plasma 7-DHC and 8-DHC, and CSF 7-DHC. Expressive vocabulary scores also declined with increasing disease severity, but associations with sterol biomarkers were not significant. ASD was linked to higher rates of non-scorable assessments, though did not fully explain floor effects. No sex differences were found. Language impairment in SLOS reflects contributions from disease severity, disrupted cholesterol metabolism, and ASD. Receptive language showed stronger biomarker associations, while expressive impairments were more pervasive. Integrating clinical, biochemical, and caregiver-report tools is critical for comprehensive assessment of individuals with SLOS.
cell therapies
2022-04-20 | Liver Transplant and Improvements in Cholesterol Biosynthesis Defects: A Case Report of Smith-Lemli-Opitz Syndrome.
Smith-Lemli-Opitz syndrome is an autosomal recessive metabolic disease characterized by mental retardation and multiple congenital anomalies. The main pathology is the lack of the enzyme 3β-hydroxysterol Δ7-reductase, which is the last enzymatic step in cholesterol synthesis, ending with a low cholesterol level. Cholesterol is vitally important in cell membranes and myelination of the nervous system. The cholesterol level affects many systems of the body, especially the nervous system. The cause of liver involvement in Smith-Lemli-Opitz syndrome is unclear, and many hypotheses have been suggested. Here, we present the early results of a patient with Smith-Lemli-Opitz syndrome who underwent living-donor liver transplant due to cirrhosis. As a result of liver transplant, normal cholesterol levels were shown, as well as improvements in the patient's neurodevelopment and behavior. Early liver transplant may be considered for patients with a defect of cholesterol biosynthesis, even in the absence of cirrhosis, and may be a future treatment option to prevent risks of neurologic deterioration.
proteins
2023-11-07 | Abstract 17196: Genetic and Acquired DHCR7 Deficiency Upregulates 7β-hydroxycholesterol to Drive Endothelial Apoptosis and Pulmonary Hypertension
Introduction: Pulmonary hypertension (PH) is a fatal disease without a cure, in which endothelial dysfunction drives pathologic remodeling of the pulmonary vasculature. Individuals with Smith-Lemli-Opitz syndrome (SLOS) develop PH, but the underlying mechanisms remain undefined. SLOS is an autosomal recessive disorder of cholesterol synthesis, resulting from loss-of-function mutations in 7-dehydrocholesterol reductase (DHCR7)-the terminal enzyme in the de novo synthesis of cholesterol- that leads to accumulation of 7-dehydrocholesterol (7-DHC) and cytotoxic oxysterol species. The role of DHCR7 in PH, however, is unknown. Hypothesis: Elevated cytotoxic oxysterols resulting from genetic or acquired DHCR7 deficiency promotes endothelial dysfunction and the development of PH. Methods & Results: DHCR7 mRNA and protein expression was decreased in pulmonary artery endothelial cells (ECs) in cellular (P=0.0089), rodent, and human PH models, mirroring DHCR7 reduction in SLOS. Both genetic loss of DHCR7 and hypoxia promoted a global shutdown of de novo cholesterol synthesis, resulting in an accumulation of cholesterol intermediates and increased derivative oxysterols. Specifically, 7β-hydroxycholesterol (7β-HC) was elevated in DHCR7-deficient ECs (P<0.0001), and 7β-HC drove endothelial apoptosis (P<0.0001) via downregulation of insulin-like growth factor 1 (IGF1) in ECs (fold change=0.101 ± 0.034, FDR=6.65E-11). Conversely, overexpression of DHCR7 upregulated IGF1 expression (P<0.0007), and IGF1 delivery reversed apoptosis (P<0.0001). Correspondingly, ECs derived from SLOS patient stem cells with DHCR7 mutations (p.T93M/c.964-1G>C) exhibited IGF1-dependent apoptosis. Finally, EC-specific DHCR7 deletion in chronically hypoxic mice induced more severe PH in vivo (right ventricular systolic pressure 36.4 mmHg vs. 30.8 mmHg, P<0.0130). Conclusions: Resulting either from hypoxic or genetic causes, DHCR7 deficiency promoted EC apoptosis and PH via 7β-HC accumulation and subsequent IGF1 downregulation. Our work is the first to define an oxysterol-dependent mechanism underlying the link between genetic and acquired DHCR7 deficiency and PH.
small molecules
2026-05-25 | Loss of 7-Dehydrocholesterol Reductase mediated cholesterol biosynthesis activates IRF3 and inhibits control of Mycobacterium marinum infection.
Cholesterol immunometabolism is a critical controller of immunopathology in respiratory infections such as tuberculosis. Smith-Lemli-Opitz syndrome (SLOS) patients are affected by a loss of 7-dehydrocholesterol reductase (DHCR7) function and have elevated 7-dehydrocholesterol (7DHC) and reduced cholesterol. Increased 7DHC has been found to be protective against viral infections in a range of infection models however SLOS patients have a higher susceptibility to respiratory infection. Here we use the zebrafish-Mycobacterium marinum infection model to demonstrate a compromised innate immune response to bacterial infection in the absence of dhcr7. We correlate increased 7DHC with increased activation of the IRF3/type I interferon axis and demonstrate Irf3 is a targetable signaling node to restore anti-bacterial immunity in a dhcr7-depleted background.
2026-05-04 | Pathophysiological significance of cholesterol in ciliopathies.
Primary cilia are sensory organelles essential for cellular signaling, the dysfunction of which causes ciliopathies, characterized by polycystic kidney disease, retinopathy, and developmental anomalies. Here, we review recent studies which have shown that cholesterol is a critical mediator of ciliary function and the pathogenesis of ciliopathies. Ciliary membranes show distinct cholesterol enrichment that is essential for the physiological function of various G-protein-coupled receptors and ion channels. Defects in de novo cholesterol synthesis (Smith-Lemli-Opitz syndrome) and peroxisome-facilitated cholesterol trafficking to ciliary membranes (Zellweger syndrome) result in ciliopathy-like phenotypes, establishing ciliary cholesterol insufficiency as a novel pathological mechanism. The polycystin complex associated autosomal dominant polycystic kidney disease localizes into ciliary membranes in a cholesterol-dependent manner. Specific cholesterol-binding sites in polycystin-2 are crucial for the distribution of cholesterol to cilia, while pathogenic mutations at these sites disrupt these interactions. We also discuss the previously underappreciated connections between ciliopathies, cholesterol, and other disorders such as cancer and neurodegenerative diseases, and opportunities for manipulating cholesterol for novel therapeutic strategies.
2025-12-11 | Smith-Lemli-Opitz Syndrome (SLOS)-Case Description and the Impact of Therapeutic Interventions on Psychomotor Development.
Background/Objectives: Smith-Lemli-Opitz syndrome (SLOS) is a genetic metabolic disorder characterized by impaired cholesterol synthesis and a wide range of developmental anomalies. This article presents a case of a girl with SLOS, diagnosed with two pathogenic variants of the DHCR7 gene. The objective is to evaluate the impact of early, multidisciplinary therapeutic interventions on the patient's development. Methods: Following diagnosis, a comprehensive metabolic therapy was initiated, including cholesterol and cholic acid supplementation. An interdisciplinary therapeutic approach was employed, involving physical therapy, speech therapy, and sensory integration, aimed at addressing various developmental challenges faced by the patient. Results: The therapy led to gradual improvements in the patient's psychomotor development, although the cholesterol levels were only partially improved and the accumulation of sterol precursors (7-DHC and 8-DHC) persisted. The coordinated care model facilitated better outcomes compared to less integrated efforts. Conclusions: The results highlight the importance of early diagnosis and integrated care in optimizing developmental outcomes for children with SLOS. A multidisciplinary approach is essential for addressing the complexities of the syndrome and promoting overall development.
2025-10-23 | Use of a cholesterol emulsion in Smith-Lemli-Opitz syndrome (SLOS): A single-center observational study, retrospective analysis and structured caregiver interview.
Smith-Lemli-Opitz syndrome (SLOS) is a rare autosomal recessive disorder of cholesterol biosynthesis. SLOS leads to increased levels of 7-dehydrocholesterol (7-DHC) and decreased levels of total cholesterol (TC). Dietary therapy usually involves supplementation with cholesterol in an oil-based or, less commonly, an aqueous cholesterol suspension. The limited solubility of cholesterol can result in uneven distribution, sedimentation and clumping. In seven patients (6 m, 1 f, 1-12 years) the previously administered dose of cholesterol was replaced by a newly developed emulsion and primary parameters TC, 7-DHC, HDL, LDL, vitamin D (25; 1-25), height and weight were determined. In addition, a personal structured interview was conducted with the caregivers of five participants to determine their satisfaction with the product, the care, and the effects on behaviour and health. One patient was excluded due to non-compliance (N = 6). Before the intervention, the mean TC level was 42 ± 9 mg/dl (min = 29, max = 52; n = 5) and increased by at least 95% and at most 299% (163 ± 93%). 7-DHC levels showed a decrease of -28% to -96% (-63 ± 29%). No effect on anthropometric parameters was observed. Overall, the families were satisfied with the care and the effect of the emulsion was predominantly described as successful. The emulsion and its application were well tolerated with few side effects. Overall, there was an improved effect on TC and 7-DHC levels compared to standard therapy, with high patient satisfaction and low side effects.
2025-09-22 | Cross-sectional analysis of expressive and receptive language skills in Smith-Lemli-Opitz syndrome (SLOS).
This study investigates receptive and expressive language abilities in individuals with Smith-Lemli-Opitz syndrome (SLOS) and examines how these are associated with intellectual functioning, sex, autism spectrum disorder (ASD) diagnosis, and biochemical markers of cholesterol metabolism. Participants (ages 4-18) with mild to classic SLOS were enrolled from a double-blind, placebo-controlled simvastatin trial. Receptive and expressive language scores were assessed using the Peabody Picture Vocabulary Test, Third Edition (PPVT-3), the Expressive One-Word Picture Vocabulary Test, 2000 Edition (EOWPVT-2000), and the MacArthur Communicative Developmental Inventories (MCDI). Intellectual ability and adaptive functioning were measured using the Stanford-Binet Intelligence Scales, Fifth Edition (SB-5) and Vineland Adaptive Behavior Scales, Third Edition (VABS-3). The SLOS Severity Scale (SSS) quantified disease severity. Associations with plasma and CSF sterol biomarkers (cholesterol, 7-dehydrocholesterol [7-DHC], 8-dehydrocholesterol [8-DHC]) were examined using nonparametric statistics with correction for multiple comparisons. Twenty-one participants (mean age 7.85 years) had complete data; 71.4% had a diagnosis of ASD. Receptive and expressive language scores correlated with IQ and adaptive functioning. Receptive vocabulary scores were significantly negatively associated with disease severity, plasma 7-DHC and 8-DHC, and CSF 7-DHC. Expressive vocabulary scores also declined with increasing disease severity, but associations with sterol biomarkers were not significant. ASD was linked to higher rates of non-scorable assessments, though did not fully explain floor effects. No sex differences were found. Language impairment in SLOS reflects contributions from disease severity, disrupted cholesterol metabolism, and ASD. Receptive language showed stronger biomarker associations, while expressive impairments were more pervasive. Integrating clinical, biochemical, and caregiver-report tools is critical for comprehensive assessment of individuals with SLOS.
cell therapies
2022-04-20 | Liver Transplant and Improvements in Cholesterol Biosynthesis Defects: A Case Report of Smith-Lemli-Opitz Syndrome.
Smith-Lemli-Opitz syndrome is an autosomal recessive metabolic disease characterized by mental retardation and multiple congenital anomalies. The main pathology is the lack of the enzyme 3β-hydroxysterol Δ7-reductase, which is the last enzymatic step in cholesterol synthesis, ending with a low cholesterol level. Cholesterol is vitally important in cell membranes and myelination of the nervous system. The cholesterol level affects many systems of the body, especially the nervous system. The cause of liver involvement in Smith-Lemli-Opitz syndrome is unclear, and many hypotheses have been suggested. Here, we present the early results of a patient with Smith-Lemli-Opitz syndrome who underwent living-donor liver transplant due to cirrhosis. As a result of liver transplant, normal cholesterol levels were shown, as well as improvements in the patient's neurodevelopment and behavior. Early liver transplant may be considered for patients with a defect of cholesterol biosynthesis, even in the absence of cirrhosis, and may be a future treatment option to prevent risks of neurologic deterioration.
proteins
2023-11-07 | Abstract 17196: Genetic and Acquired DHCR7 Deficiency Upregulates 7β-hydroxycholesterol to Drive Endothelial Apoptosis and Pulmonary Hypertension
Introduction: Pulmonary hypertension (PH) is a fatal disease without a cure, in which endothelial dysfunction drives pathologic remodeling of the pulmonary vasculature. Individuals with Smith-Lemli-Opitz syndrome (SLOS) develop PH, but the underlying mechanisms remain undefined. SLOS is an autosomal recessive disorder of cholesterol synthesis, resulting from loss-of-function mutations in 7-dehydrocholesterol reductase (DHCR7)-the terminal enzyme in the de novo synthesis of cholesterol- that leads to accumulation of 7-dehydrocholesterol (7-DHC) and cytotoxic oxysterol species. The role of DHCR7 in PH, however, is unknown. Hypothesis: Elevated cytotoxic oxysterols resulting from genetic or acquired DHCR7 deficiency promotes endothelial dysfunction and the development of PH. Methods & Results: DHCR7 mRNA and protein expression was decreased in pulmonary artery endothelial cells (ECs) in cellular (P=0.0089), rodent, and human PH models, mirroring DHCR7 reduction in SLOS. Both genetic loss of DHCR7 and hypoxia promoted a global shutdown of de novo cholesterol synthesis, resulting in an accumulation of cholesterol intermediates and increased derivative oxysterols. Specifically, 7β-hydroxycholesterol (7β-HC) was elevated in DHCR7-deficient ECs (P<0.0001), and 7β-HC drove endothelial apoptosis (P<0.0001) via downregulation of insulin-like growth factor 1 (IGF1) in ECs (fold change=0.101 ± 0.034, FDR=6.65E-11). Conversely, overexpression of DHCR7 upregulated IGF1 expression (P<0.0007), and IGF1 delivery reversed apoptosis (P<0.0001). Correspondingly, ECs derived from SLOS patient stem cells with DHCR7 mutations (p.T93M/c.964-1G>C) exhibited IGF1-dependent apoptosis. Finally, EC-specific DHCR7 deletion in chronically hypoxic mice induced more severe PH in vivo (right ventricular systolic pressure 36.4 mmHg vs. 30.8 mmHg, P<0.0130). Conclusions: Resulting either from hypoxic or genetic causes, DHCR7 deficiency promoted EC apoptosis and PH via 7β-HC accumulation and subsequent IGF1 downregulation. Our work is the first to define an oxysterol-dependent mechanism underlying the link between genetic and acquired DHCR7 deficiency and PH.
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