Explore the vast range of titles available.

Smith-Lemli-Opitz syndrome (SLOS) is a multiple malformation/cognitive impairment syndrome characterized by the accumulation of 7-dehydrocholesterol, a precursor sterol of cholesterol. Simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor that crosses the blood–brain barrier, has been proposed for the treatment of SLOS based on in vitro and in vivo studies suggesting that simvastatin increases the expression of hypomorphic DHCR7 alleles. Safety and efficacy of simvastatin therapy in 23 patients with mild to typical SLOS were evaluated in a randomized, double-blind, placebo-controlled trial. The crossover trial consisted of two 12-month treatment phases separated by a 2-month washout period. No safety issues were identified in this study. Plasma dehydrocholesterol concentrations decreased significantly: 8.9 ± 8.4% on placebo to 6.1 ± 5.5% on simvastatin (P < 0.005); we observed a trend toward decreased cerebrospinal fluid dehydrocholesterol concentrations. A significant improvement (P = 0.017, paired t-test) was observed on the irritability subscale of the Aberrant Behavior Checklist–C when subjects were taking simvastatin. This article reports what is, to our knowledge, the first randomized, placebo-controlled trial designed to test the safety and efficacy of simvastatin therapy in SLOS. Simvastatin seems to be relatively safe in patients with SLOS, improves the serum dehydrocholesterol–to–total sterol ratio, and significantly improves irritability symptoms in patients with mild to classic SLOS. Genet Med19 3, 297–305.

Background: Smith–Lemli–Opitz syndrome (SLOS) is an inborn error of cholesterol biosynthesis, caused by biallelic mutations in the DHCR7 gene. Genotype–phenotype correlations regarding DHCR7 variants could explain the variation in severity, ranging from in utero demise or severe SLOS to a mild phenotype. Clinical recognition can be challenging. This study aimed to determine the frequency of SLOS carriers in the Central European population, as well as the mutational spectrum of DHCR7 in these carriers. Methods: A retrospective analysis of DHCR7 variants was conducted using next-generation sequencing data from 55,289 individuals in Czech and Hungarian genetic laboratories. Results: The SLOS carrier frequency and the mutational spectrum of the DHCR7 gene in its carriers were established in the Czech and Hungarian sub-cohorts. In the combined dataset, we identified causative DHCR7 variants on 1567 alleles among 55,289 tested individuals, contributing to an SLOS carrier frequency of 2.83%. Of the 31 DHCR7 variants detected, the c.452G>A variant was the most prevalent, accounting for 1.8% of all detected alleles in our cohorts. In contrast, the c.964-1G>C variant was more frequent in non-Finnish Europeans, as indicated by the gnomAD 4.1.0 database. The DHCR7 mutational spectra of patients and carriers were comparable in terms of the most common variants. Conclusions: The high SLOS carrier frequency (2.83%) underscores the importance of SLOS carrier screening in Central European populations. The prevalent DHCR7 null mutations and their potential combinations may explain the lower-than-expected prevalence of SLOS, whilst Central and Eastern European populations remain likely underrepresented in the current gnomAD database.

Defective 3β-hydroxysterol-Δ 7 -reductase (DHCR7) in the developmental disorder, Smith-Lemli-Opitz syndrome (SLOS), results in a deficiency in cholesterol and accumulation of its precursor, 7-dehydrocholesterol (7-DHC). Here, we show that loss of DHCR7 causes accumulation of 7-DHC-derived oxysterol metabolites, premature neurogenesis from murine or human cortical neural precursors, and depletion of the cortical precursor pool, both in vitro and in vivo. We found that a major oxysterol, 3β,5α-dihydroxycholest-7-en-6-one (DHCEO), mediates these effects by initiating crosstalk between glucocorticoid receptor (GR) and neurotrophin receptor kinase TrkB. Either loss of DHCR7 or direct exposure to DHCEO causes hyperactivation of GR and TrkB and their downstream MEK-ERK-C/EBP signaling pathway in cortical neural precursors. Moreover, direct inhibition of GR activation with an antagonist or inhibition of DHCEO accumulation with antioxidants rescues the premature neurogenesis phenotype caused by the loss of DHCR7 . These results suggest that GR could be a new therapeutic target against the neurological defects observed in SLOS.

Owing to the need for de novo cholesterol synthesis and cholesterol-enriched structures within the nervous system, cholesterol homeostasis is critical to neurodevelopment. Diseases caused by genetic disruption of cholesterol biosynthesis, such as Smith–Lemli–Opitz syndrome, which is caused by mutations in 7-dehydrocholesterol reductase (DHCR7), frequently result in broad neurological deficits. Although astrocytes regulate multiple neural processes ranging from cell migration to network-level communication, immunological activation of astrocytes is a hallmark pathology in many diseases. However, the impact of DHCR7 on astrocyte function and immune activation remains unknown. We demonstrate that astrocytes from Dhcr7 mutant mice display hallmark signs of reactivity, including increased expression of glial fibrillary acidic protein (GFAP) and cellular hypertrophy. Transcript analyses demonstrate extensive Dhcr7 astrocyte immune activation, hyper-responsiveness to glutamate stimulation and altered calcium flux. We further determine that the impacts of Dhcr7 are not astrocyte intrinsic but result from non-cell-autonomous effects of microglia. Our data suggest that astrocyte–microglia crosstalk likely contributes to the neurological phenotypes observed in disorders of cholesterol biosynthesis. Additionally, these data further elucidate a role for cholesterol metabolism within the astrocyte–microglia immune axis, with possible implications in other neurological diseases.

Background Smith‐Lemli‐Opitz syndrome (SLOS) is a common autosomal recessive disorder caused by pathogenic variants in the DHCR7 gene, resulting in a deficiency of the enzyme 7‐dehydrocholesterol reductase. Two forms of SLOS are recognized based on the severity of associated symptoms. Type I is characterized by a milder phenotype, whereas type II is more severe and frequently results in fetal loss or early neonatal death. We observed two unrelated patients: a 5‐year‐old boy and a 3.5‐year‐old girl, with elevated 7‐DHC levels, a milder phenotype, and an identical genotype. Methods Variants were confirmed by Sanger sequencing. Results A rare heterozygous likely pathogenic variant, c.89G>C p.(Gly30Ala), and a pathogenic variant, c.964‐1G>C, in the trans position in the DHCR7 gene were identified in both patients. Conclusion The two unique patients presented here suggest that the c.89G>C p.(Gly30Ala) variant is associated with a mild SLOS phenotype, which may be overlooked and unrecognized in clinical practice. Information about this rare DHCR7 variant is important for diagnostic awareness of SLOS, especially within the Central European population. We present clinical data and a literature review of the DHCR7 variants associated with the mild SLOS phenotype. Smith‐Lemli‐Opitz syndrome (SLOS) is an autosomal recessive disorder caused by pathogenic variants in the DHCR7 gene. Based on our observations and a review of the literature, we demonstrate that the NM₀01360.2(DHCR7):c.89G>C p.(Gly30Ala) variant is associated with a mild SLOS phenotype.

Cholesterol biosynthesis is indispensable for CNS development and function. The developing brain relies almost entirely on intrinsic sterol synthesis to support membrane biogenesis, axonal outgrowth, synaptogenesis, and myelination. Pathogenic variants in sterol biosynthetic enzymes, including DHCR7 and DHCR24, result in complex neurodevelopmental disorders such as Smith-Lemli-Opitz syndrome and desmosterolosis. In addition to cholesterol-lowering drugs (statins), some other pharmacological agents such as antipsychotics, antidepressants, and beta blockers can also inhibit cholesterol biosynthesis due to off-target effects. This inhibition produces dual pathophysiological effects: cholesterol depletion and accumulation of its precursor, 7-dehydrocholesterol, an exceptionally oxidizable molecule that spontaneously generates toxic oxysterols. Given the intense demand for cholesterol synthesis in the developing brain, prenatal exposure to sterol biosynthesis–inhibiting medications may have far-reaching effects. In this Review, we describe convergent biochemical, genetic, and epidemiologic data that implicate developmental sterol dysregulation as a modifiable risk factor for neurodevelopmental pathology and underscore the urgent need for routine sterol pathway safety assessment in drug development and prenatal pharmacotherapy.

Background Smith-Lemli-Opitz Syndrome (SLOS) is an autosomal recessive disorder of cholesterol biosynthesis caused by biallelic pathogenic variants in DHCR7 , which encodes the enzyme 7-dehydrocholesterol reductase (DHCR7). SLOS is a multisystemic disorder affecting various aspects of health, including growth, development, behavior, and quality of life, underscoring the need for safe, efficacious interventions that limit disease burden. DHCR7 enzyme deficiency leads to a “metabolic block” resulting in decreased cholesterol production and accumulation of its precursor 7-dehydrocholesterol and the secondary isomer 8-dehydrocholesterol. Reduced cholesterol synthesis, in turn, leads to decreased levels of cholic acid (CA), an endogenous bile acid synthesized from cholesterol and essential for cholesterol absorption. Dietary cholesterol supplementation is standard therapy. Bile acid supplementation with CA has been shown to improve dietary cholesterol absorption and raise plasma cholesterol levels. However, there is a paucity of patient-level data regarding the utility of CA as a treatment for SLOS. The purpose of this case series is to address the lack of comprehensive patient data through documentation of the outcomes of a company-sponsored CA patient experience program. A retrospective chart review was conducted for these individuals while on CA plus cholesterol supplementation. Data for demographics and key clinical/laboratory parameters were captured with a standardized data collection tool. Results Eight genetically confirmed individuals with SLOS (age range 1 to 20 years) with median plasma cholesterol levels at baseline ≤ 125 mg/dL were treated with CA at 10–15 mg/kg/d for 30 to 450 days. Exogenous CA administration improved cholesterol levels in the majority of patients. Growth improved after CA initiation and trended toward age-appropriate growth percentiles. Reports from the patient, parent/caregiver, and/or healthcare professional noted positive behavioral changes leading to increased social interaction, cognitive engagement, and improved communication skills. Improvements in biochemical parameters and quality of life were also observed in several patients after CA treatment. CA supplementation was well tolerated with minimal adverse events. Conclusions The cumulative experiences of eight patients provide a compelling narrative supporting the potential utility of CA treatment in SLOS while underscoring the safety of CA in this patient population. Larger longitudinal studies of CA in patients with SLOS are warranted.

Smith–Lemli–Opitz syndrome (SLOS) is a malformation syndrome due to a deficiency of 7-dehydrocholesterol reductase (DHCR7). DHCR7 primarily catalyzes the reduction of 7-dehydrocholesterol (7DHC) to cholesterol. In SLOS, this results in decreased cholesterol and increased 7DHC levels, both during embryonic development and after birth. The malformations found in SLOS may result from decreased cholesterol, increased 7DHC or a combination of these two factors. This review discusses the clinical aspects and diagnosis of SLOS, therapeutic interventions and the current understanding of pathophysiological processes involved in SLOS.

Biallelic pathogenic variants in DHCR7 result in decreased activity of 7-dehydrocholesterol (7-DHC) reductase, which converts 7-DHC to cholesterol, and causes Smith–Lemli–Opitz syndrome (SLOS). Elevated serum 7-DHC levels are indicative of SLOS as are intellectual disability (ID), growth retardation, microcephaly, craniofacial anomalies, and 2–3 toe syndactyly. Additional congenital malformations may be present in SLOS, and broad clinical variability has been recognized in SLOS. Rarely, biallelic pathogenic DHCR7 variants were reported with low-normal and normal intelligence quotient (IQ) and development. We report here a pair of siblings with mild global developmental delay, infrequent epileptic seizures, and elevated serum 7-DHC levels, associated with the homozygous DHCR7 variant c.988G>A (p.Val330Met). Remarkably, neither sibling displayed congenital anomalies nor dysmorphisms. Quattro-exome sequencing performed for global delay and mild ID in both siblings did not identify other ID causes. c.988G>A affects a highly conserved amino acid and displays a relatively high global population allele frequency of 0.04%, with absence of homozygotes from the population database gnomADv4.1.0. Our observation leads us to suggest that DHCR7 variant c.988G>A and other DHCR7 variants might be generally considered as underlying non-syndromic ID.