The Smith-Lemli-Opitz syndrome.
Ontology highlight
ABSTRACT:
SUBMITTER: Kelley RI
PROVIDER: S-EPMC1734573 | biostudies-other | 2000 May
REPOSITORIES: biostudies-other
Publications
The Smith-Lemli-Opitz syndrome.
Journal of medical genetics 20000501 5
The Smith-Lemli-Opitz syndrome (SLOS) is one of the archetypical multiple congenital malformation syndromes. The recent discovery of the biochemical cause of SLOS and the subsequent redefinition of SLOS as an inborn error of cholesterol metabolism have led to important new treatment possibilities for affected patients. Moreover, the recent recognition of the important role of cholesterol in vertebrate embryogenesis, especially with regard to the hedgehog embryonic signalling pathway and its effe ...[more]
Similar Datasets
Project description:Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive, multiple congenital malformation and intellectual disability syndrome, with clinical characteristics that encompass a wide spectrum and great variability. Elucidation of the biochemical and genetic basis for SLOS, specifically understanding SLOS as a cholesterol deficiency syndrome caused by mutation in DHCR7, opened up enormous possibilities for therapeutic intervention. When cholesterol was discovered to be the activator of sonic hedgehog, cholesterol deficiency with inactivation of this developmental patterning gene was thought to be the cause of SLOS malformations, yet this explanation is overly simplistic. Despite these important research breakthroughs, there is no proven treatment for SLOS. Better animal models are needed to allow potential treatment testing and the study of disease pathophysiology, which is incompletely understood. Creation of human cellular models, especially models of brain cells, would be useful, and in vivo human studies are also essential. Biomarker development will be crucial in facilitating clinical trials in this rare condition, because the clinical phenotype can change over many years. Additional research in these and other areas is critical if we are to make headway towards ameliorating the effects of this devastating condition.
| S-EPMC3366105 | biostudies-literature
Project description:This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: 1. To evaluate the efficacy of statin therapy in reducing the frequency or severity of the neurobehavioral abnormalities seen in people with SLOS (e.g. aggression, anxiety, irritability, self-mutilation, autistic behaviors, sleep disturbances, etc.) (Wassif 2017). 2. To evaluate the potential effects of statin therapy on survival.
| S-EPMC7055734 | biostudies-literature
Project description:Smith-Lemli-Opitz syndrome (SLOS) is a multiple malformation syndrome due to mutations of the 7-dehydrocholesterol reductase gene (DHCR7), which leads to a deficiency of cholesterol synthesis and an accumulation of 7-dehydrocholesterol. The SLOS clinical spectrum ranges from multiple major malformations to a mild phenotype with minor anomalies and intellectual disability. Several children with SLOS and adrenal insufficiency have been described. We performed ovine corticotropin (oCRH) testing in 35 SLOS patients and 16 age- and gender-matched controls. We reviewed prior adrenocorticotropin (ACTH) stimulation tests of our SLOS patients (19 of 35 available) and reviewed results of ACTH stimulation tests from 10 additional SLOS patients. Results from oCRH testing showed that patients with SLOS had significantly higher ACTH baseline values than healthy controls (24.8 ± 15.3 pg/ml vs. 17.8 ± 7.5 pg/ml, P = 0.034). However, no statistically significant differences were noted for peak ACTH values (74.4 ± 35.0 pg/ml vs. 64.0 ± 24.9 pg/ml, P = 0.303) and for baseline (14.2 ± 7.8 mcg/dl vs. 14.2 ± 6.3 mcg/dl, P = 0.992) and peak cortisol values (28.2 ± 7.9 mcg/dl vs. 24.8 ± 8.1 mcg/dl, P = 0.156). The area-under-the-curve (AUC) was not significantly different in SLOS patients compared to controls for both ACTH (250.1 ± 118.7 pg/ml vs. 195.3 ± 96.6 pg/ml, P = 0.121) as well as cortisol secretion (83.1 ± 26.1 mcg/dl vs. 77.8 ± 25.9 mcg/dl, P = 0.499). ACTH stimulation test results were normal in 28 of 29 tests. The individual with the abnormal test results had subsequent normal oCRH tests. The slightly increased baseline ACTH level seen during oCRH testing may be due to compensated adrenocortical insufficiency. However, we were able to show that our patients with SLOS had an adequate glucocorticoid response, and thus, in mild to moderate cases of SLOS stress steroid coverage may not be warranted.
| S-EPMC3488380 | biostudies-literature
Project description:Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive multiple congenital malformation and intellectual disability syndrome resulting from variants in DHCR7. Auditory characteristics of persons with SLOS have been described in limited case reports but have not been systematically evaluated. The objective of this study is to describe the auditory phenotype in SLOS. Age- and ability-appropriate hearing evaluations were conducted on 32 patients with SLOS. A subset of 21 had auditory brainstem response testing, from which an auditory neural phenotype is described. Peripheral or retrocochlear auditory dysfunction was observed in at least one ear of 65.6% (21) of the patients in our SLOS cohort. The audiometric phenotype was heterogeneous and included conductive, mixed, and sensorineural hearing loss. The most common presentation was a slight to mild conductive hearing loss, although profound sensorineural hearing loss was also observed. Abnormal auditory brainstem responses indicative of retrocochlear dysfunction were identified in 21.9% of the patients. Many were difficult to test behaviorally and required objective assessment methods to estimate hearing sensitivity. Individuals with SLOS are likely to have hearing loss that may impact communication, including speech and language development. Routine audiologic surveillance should be conducted to ensure prompt management of hearing loss.
| S-EPMC7994936 | biostudies-literature
Project description:Recent insights into the Smith-Lemli-Opitz syndrome. The Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive multiple congenital anomaly/mental retardation disorder caused by an inborn error of post-squalene cholesterol biosynthesis. Deficient cholesterol synthesis in SLOS is caused by inherited mutations of 3beta-hydroxysterol-Delta7 reductase gene (DHCR7). DHCR7 deficiency impairs both cholesterol and desmosterol production, resulting in elevated 7DHC/8DHC levels, typically decreased cholesterol levels and, importantly, developmental dysmorphology. The discovery of SLOS has led to new questions regarding the role of the cholesterol biosynthesis pathway in human development. To date, a total of 121 different mutations have been identified in over 250 patients with SLOS who represent a continuum of clinical severity. Two genetic mouse models have been generated which recapitulate some of the developmental abnormalities of SLOS and have been useful in elucidating the pathogenesis. This mini review summarizes the recent insights into SLOS genetics, pathophysiology and potential therapeutic approaches for the treatment of SLOS.
| S-EPMC1350989 | biostudies-literature
Project description:Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive congenital malformation syndrome caused by mutations in the 7-dehydrocholesterol reductase gene. This inborn error of cholesterol synthesis leads to elevated concentrations of 7-dehydrocholesterol (7-DHC). 7-DHC also serves as the precursor for vitamin D synthesis. Limited data is available on vitamin D levels in individuals with SLOS. Due to elevated concentrations of 7-DHC, we hypothesized that vitamin D status would be abnormal and possibly reach toxic levels in patients with SLOS. Through a retrospective analysis of medical records between 1998 and 2006, we assessed markers of vitamin D and calcium metabolism from 53 pediatric SLOS patients and 867 pediatric patients who were admitted to the NIH Clinical Center (NIHCC) during the same time period. SLOS patients had significantly higher levels of 25(OH)D (48.06 ± 19.53 ng/ml, p < 0.01) across all seasons in comparison to the NIHCC pediatric patients (30.51 ± 16.14 ng/ml). Controlling for season and age of blood draw, 25(OH)D levels were, on average, 15.96 ng/ml (95%CI 13.95-17.90) higher in SLOS patients. Although, mean calcium values for both patient cohorts never exceeded the normal clinical reference range (8.6-10.2 mg/dl), the levels were higher in the SLOS cohort (9.49 ± 0.56 mg/dl, p < 0.01) compared to the NIHCC patients (9.25 ± 0.68 mg/dl). Overall, in comparison to the control cohort, individuals with SLOS have significantly higher concentrations of 25(OH)D that may be explained by elevated concentrations of serum 7-DHC. Despite the elevated vitamin D levels, there was no laboratory or clinical evidence of vitamin D toxicity.
| S-EPMC5603413 | biostudies-literature
Project description:Smith-Lemli-Opitz syndrome (SLOS) is a rare multiple congenital anomaly neurodevelopmental syndrome of impaired cholesterol synthesis. Growth restriction and developmental delay are very common clinical manifestations of SLOS. The degree, etiology, and consequences of growth restriction in SLOS remain an area of limited knowledge to the scientific community. There have been no studies describing the growth parameters and providing reference growth charts for individuals with SLOS. Our longitudinal data from 78 patients between the ages of 0.1 and 16 years with SLOS show a growth restriction of about two standard deviations below the Centers for Disease Control (CDC) norms for age. This study represents comprehensive anthropometric data from the largest cohort available, and proposes growth charts for widespread use in the management and study of individuals with SLOS.
| S-EPMC3427420 | biostudies-literature
Project description:Smith-Lemli-Opitz syndrome (SLOS) is a metabolic disorder caused by an inborn error of cholesterol synthesis that affects the development of many organ systems. Malformations in the central nervous system typically involve midline structures and reflect abnormal growth and differentiation of neurons and supporting cells. Despite these defects in central nervous system development, brain tumor formation has only rarely been reported in association with SLOS. We present three individuals with SLOS and lesions in the basal ganglia or brainstem detected by MRI that were concerning for tumor formation. However, the individuals' clinical and neurological course remained stable, and the lesions regressed after several years. These lesions have similarities to spongiotic changes observed in individuals with neurofibromatosis type 1 (NF1). Notably, impaired activity of small GTPases is present in both SLOS and NF1, perhaps giving mechanistic insight into the formation of these lesions.
| S-EPMC6309987 | biostudies-literature
Project description:Children with Smith-Lemli-Opitz syndrome (SLOS) are typically reported to have moderate to severe intellectual disability. This study aims to determine whether normal cognitive function is possible in this population and to describe clinical, biochemical and molecular characteristics of children with SLOS and normal intelligent quotient (IQ). The study included children with SLOS who underwent cognitive testing in four centers. All children with at least one IQ composite score above 80 were included in the study. Six girls, three boys with SLOS were found to have normal or low-normal IQ in a cohort of 145 children with SLOS. Major/multiple organ anomalies and low serum cholesterol levels were uncommon. No correlation with IQ and genotype was evident and no specific developmental profile were observed. Thus, normal or low-normal cognitive function is possible in SLOS. Further studies are needed to elucidate factors contributing to normal or low-normal cognitive function in children with SLOS.
| S-EPMC6016830 | biostudies-literature
Project description:BACKGROUND:Smith-Lemli-Opitz syndrome (SLOS) is an inborn error of cholesterol biosynthesis characterized by diminished cholesterol and increased 7-dehydrocholesterol (7-DHC) levels. 7-Dehydrocholesterol is highly reactive, giving rise to biologically active oxysterols. METHODS:7-DHC-derived oxysterols were measured in fibroblasts from SLOS patients and an in vivo SLOS rodent model using high-performance liquid chromatography tandem mass spectrometry. Expression of lipid biosynthesis genes was ascertained by quantitative polymerase chain reaction and Western blot. The effects of an antioxidant mixture of vitamin A, coenzyme Q10, vitamin C, and vitamin E were evaluated for their potential to reduce formation of 7-DHC oxysterols in fibroblast from SLOS patients. Finally, the effect of maternal feeding of vitamin E enriched diet was ascertained in the brain and liver of newborn SLOS mice. RESULTS:In cultured human SLOS fibroblasts, the antioxidant mixture led to decreased levels of the 7-DHC-derived oxysterol, 3?,5?-dihydroxycholest-7-en-6-one. Furthermore, gene expression changes in SLOS human fibroblasts were normalized with antioxidant treatment. The active ingredient appeared to be vitamin E, as even at low concentrations, it significantly decreased 3?,5?-dihydroxycholest-7-en-6-one levels. In addition, analyzing a mouse SLOS model revealed that feeding a vitamin E enriched diet to pregnant female mice led to a decrease in oxysterol formation in brain and liver tissues of the newborn Dhcr7-knockout pups. CONCLUSIONS:Considering the adverse effects of 7-DHC-derived oxysterols in neuronal and glial cultures and the positive effects of antioxidants in patient cell cultures and the transgenic mouse model, we believe that preventing formation of 7-DHC oxysterols is critical for countering the detrimental effects of DHCR7 mutations.
| S-EPMC3874268 | biostudies-literature