Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder of cholesterol biosynthesis characterised by facial dysmorphisms, mental retardation and multiple congenital anomalies. SLOS is caused by mutations of the human Delta7-sterol reductase (DHCR7) gene and, so far, 19 different mutations have been described. Among these, mutations impairing the activity of the C-terminus appear to be the most severe. Here we report the mutational analysis of the DHCR7 gene in nine Italian SLOS patients. The T93M mutation, previously reported in one patient, results the most frequent one (7/18 alleles) in our survey. Furthermore, we identified three novel mutations, two missense mutations (N407Y and E448K), and a 33 bp deletion spanning part of exon 5 and the donor splice site of intron 5.
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PMID:Smith-Lemli-Opitz syndrome: evidence of T93M as a common mutation of delta7-sterol reductase in Italy and report of three novel mutations. 1060 71

Smith-Lemli-Opitz syndrome (SLOS), an autosomal recessive condition with multiple malformations, mental retardation, and growth failure, results from markedly reduced activity of the final enzyme in the cholesterol biosynthetic pathway, 7-dehydrocholesterol Delta(7)-reductase (DHCR7). We diagnosed SLOS in a fetus following intrauterine demise at 32 weeks' gestation. Chorionic villus (CV) sampling had been performed at 30 weeks because oligohydramnios and atrioventricular septal defect were noted on fetal ultrasound. On fetal post-mortem examination, a midline U-shaped soft palate cleft, micrognathia, postaxial polydactyly of the fingers with single transverse palmar creases bilaterally, and cutaneous syndactyly of toes two-three bilaterally suggested SLOS. We hypothesized that SLOS could be confirmed by analysis of tissue sterols despite extensive autolysis, and by measurement of enzyme activity in CV cells. Measurement of DHCR7 activity in CV cells was undertaken using ergosterol as a substrate. CV cells were unable to convert any ergosterol to brassicasterol after a 72 h incubation period while control CV cells reduced 12.6-71.8% of ergosterol to brassciasterol in a 72 h period. SLOS was confirmed by measurement of elevated 7-dehydrocholesterol (7-DHC) in the CV cells. Measurements of sterols were made in multiple fetal tissues. All tissues analysed showed elevated 7-DHC with markedly increased 7-DHC/cholesterol ratios.
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PMID:Fetal demise with Smith-Lemli-Opitz syndrome confirmed by tissue sterol analysis and the absence of measurable 7-dehydrocholesterol Delta(7)-reductase activity in chorionic villi. 1071 29

Smith-Lemli-Opitz syndrome (SLOS) is an autosomal recessive disorder characterized by minor facial anomalies, mental retardation, and multiple congenital abnormalities. Biochemically, the disorder is caused by deficient activity of 7-dehydrocholesterol reductase, which catalyzes the reduction of the Delta7 double bond of 7-dehydrocholesterol to produce cholesterol. Recently, mutations in the gene encoding 7-dehydrocholesterol reductase (7DHCR) were found to cause SLOS. We report the first molecular characterization of an Italian SLOS patient. Interestingly, his paternal 7DHCR allele, of Arab origin, harbored a novel P329L mutation which in combination with a maternal splice-site (IVS8-1 G>C) mutation resulted in a relatively milder phenotype.
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PMID:Novel 7-DHCR mutation in a child with Smith-Lemli-Opitz syndrome. 1074 14

We showed previously that 3 distal inhibitors of cholesterol synthesis are highly teratogenic in rats. AY 9944 and BM 15766 inhibit 7-dehydrocholesterol reductase, which catalyzes the last step of cholesterol synthesis, and triparanol inhibits Delta(24)-dehydrocholesterol reductase, which catalyzes the last step in another pathway. These molecules cause holoprosencephalic brain anomalies. Under certain experimental conditions, other anomalies (of the limbs and male genitalia) are also observed. Assays performed by gas chromatography-mass spectrometry (GC-MS) show hypocholesterolemia and an accumulation of precursors. These data indicate that this animal model can be considered a model of Smith-Lemli-Opitz syndrome. Smith-Lemli-Opitz syndrome is a recessive autosomal genetic disease characterized by malformations (microcephaly, corpus callosum agenesis, holoprosencephaly, and mental retardation), male pseudohermaphroditism, finger anomalies, and failure to thrive. The syndrome has been attributed to a deficit in 7-dehydrocholesterol reductase. As assayed by GC-MS, the sterol status of these patients indicates severe hypocholesterolemia and an accumulation of precursors: 7-dehydrocholesterol, 8-dehydrocholesterol, and oxidized derivatives. The presence of 7-dehydrocholesterol in the serum of patients is pathognomonic of the disease. The developmental gene Shh (sonic hedgehog) plays a key role in brain, limb, and genital development; it was shown recently that the Shh protein has to be covalently linked to cholesterol to be active. This is the first time that a posttranslational function has been attributed to cholesterol. There is an obvious relation between Shh dysfunction and the malformations observed in our experiments and in patients with Smith-Lemli-Opitz syndrome. However, the exact relation remains to be clarified. It is clear, however, that the role of cholesterol in embryonic development must be taken into account.
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PMID:Role of cholesterol in embryonic development. 1079 1

The Smith-Lemli-Opitz syndrome (SLOS; also known as the RSH syndrome) is an autosomal recessive genetic disorder, leading to characteristic multi-organ developmental abnormalities, dysmorphic facies, limb malformations and mental retardation. Mutations in the gene for Delta(7)-dehydrocholesterol reductase (Delta(7)-reductase), which catalyzes the last step in cholesterol biosynthesis, cause the disease. We screened 32 patients with SLOS, 28 from the USA and four from Sweden. Twenty-two different nucleotide changes, predicted to be disease-causing mutations, were identified; 20 missense mutations, one nonsense mutation and one splice-site mutation involving the exon 9 acceptor site (IVS8 -1G-->C) were detected. All probands were heterozygous for mutations. Twelve of these mutations have not been reported previously, including missense mutations L148R, F168I, D175H, P179L, P243R, F284L, N287K, F302L, R404S, Y462H, R469P and one nonsense mutation W37X [corrected]. Coupled with previously reported mutations, these findings bring the total of different Delta(7)-reductase mutations to 36. These are distributed throughout the coding sequence of the Delta(7)-reductase gene except exons 3 and 5, with a clustering in exon 9. Three mutations account for 54% of those observed in our cohort, the splice acceptor site mutation IVS8 -1G-->C (22/64 alleles, 34%), T93M (8/64, 12.5%) and V326L (5/64, 7.8%). Severity of SLOS was negatively correlated with both plasma cholesterol and relative plasma cholesterol, but not with 7-dehydrocholesterol, the immediate precursor, confirming previous observations. However, no correlation was observed between mutations and phenotype, suggesting that the degree of severity may be affected by other factors. We estimate that between 33 and 42% of the variation in the SLOS severity score is accounted for by variation in plasma cholesterol. Thus, factors other than plasma cholesterol are additionally involved in determining severity.
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PMID:Spectrum of Delta(7)-dehydrocholesterol reductase mutations in patients with the Smith-Lemli-Opitz (RSH) syndrome. 1081 20

Smith-Lemli-Opitz syndrome (SLOS, RSH/SLO syndrome, MIM 270400) is an autosomal recessive multiple malformation/mental retardation syndrome initially described by Smith et al. [1964] that is due to a defect in cholesterol biosynthesis. The behavioral phenotype of Smith-Lemli-Opitz syndrome demonstrates cognitive abilities from borderline intellectual functioning to profound mental retardation, sensory hyperreactivity, irritability, language impairment, sleep cycle disturbance, self-injurious behavior, and autism spectrum behaviors. In a recent study of 28 subjects, 14 subjects (50%) with SLOS also exhibited the behavior of throwing themselves backward in a characteristic upper body movement ("opisthokinesis") and 2 adolescents had a stretching motion of the upper body accompanied by hand flicking [Tierney et al., 1999]. In that same study, 6 of 13 subjects (46%) met the Autism Diagnostic Interview-Revised (ADI-R) algorithm criteria (Lord et al. [1993] Infant Mental Health 14:234-252; Lord et al. [1994] J Autism Dev Disord 24:659-685) and the Diagnostic and Statistical Manual (APA [1994] DSM-IV) diagnostic criteria for autistic disorder. Smith-Lemli-Opitz syndrome is a metabolic disorder that is associated with autism. MRDD Research Reviews 2000;6:131-134.
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PMID:Behavioral phenotype of RSH/Smith-Lemli-Opitz syndrome. 1089 6

Smith-Lemli-Opitz syndrome (SLOS), an autosomal recessive condition comprising multiple malformations, mental retardation, and growth failure, results from reduced activity of the final enzyme in cholesterol biosynthesis, 7-dehydrocholesterol Delta(7)-reductase (DHCR7). Reduced plasma and tissue cholesterol concentrations and accumulation of cholesterol precursors including 7-dehydrocholesterol (7-DHC) are characteristic biochemical abnormalities. While it is still unclear what role these potentially toxic precursors have in the pathogenesis of this disorder, the accumulation of 7-DHC in the brain has been associated with impaired learning in rats and oxidized 7-DHC has been shown to induce growth retardation in cultured rat embryos. We hypothesized that supplemental dietary cholesterol would increase plasma cholesterol levels and suppress synthesis of 7-DHC and other abnormal sterols in individuals with SLOS. After baseline sterol levels were obtained, patients were provided supplemental cholesterol as egg yolk. Plasma sterols were analyzed by capillary-column gas chromatography over time in four children with SLOS. When evaluated at 4-8 weeks after the initiation of cholesterol supplementation, there was a marked increase in mean plasma cholesterol, from 53 mg/dl to 82 mg/dl. While the percent of total sterols as 7-DHC decreased from 15% to 10%, there was no change in total plasma 7-DHC levels. However, when evaluated 35-90 weeks after the institution of cholesterol supplementation, mean plasma 7-DHC decreased, from 11.3 mg/dl to 3.5 mg/dl (-67%, P < 0.05), along with an increase in mean plasma cholesterol from 53 mg/dl to 114 mg/dl (+116%, P < 0.05). These results support the hypothesis that over time dietary cholesterol supplementation from egg yolk increases the plasma cholesterol levels and decreases levels of 7-DHC which may be toxic. These data have important therapeutic implications in the management of SLOS.
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PMID:Cholesterol supplementation with egg yolk increases plasma cholesterol and decreases plasma 7-dehydrocholesterol in Smith-Lemli-Opitz syndrome. 1095 58

The Smith-Lemli-Opitz syndrome (SLOS) is a multiple malformation/mental retardation syndrome caused by a deficiency of the enzyme 7-dehydrocholesterol Delta(7)-reductase. This enzyme converts 7-dehydrocholesterol (7-DHC) to cholesterol in the last step in cholesterol biosynthesis. The pathology of this condition may result from two different factors: the deficiency of cholesterol itself and/or the accumulation of precursor sterols such as 7-DHC. Although cholesterol synthesis is defective in cultured SLOS cells, to date there has been no evidence of decreased whole body cholesterol synthesis in SLOS and only incomplete information on the synthesis of 7-DHC and bile acids. In this first report of the sterol balance in SLOS, we measured the synthesis of cholesterol, other sterols, and bile acids in eight SLOS subjects and six normal children. The diets were very low in cholesterol content and precisely controlled. Cholesterol synthesis in SLOS subjects was significantly reduced when compared with control subjects (8.6 vs. 19.6 mg/kg per day, respectively, P < 0.002). Cholesterol precursors 7-DHC, 8-DHC, and 19-nor-cholestatrienol were synthesized in SLOS subjects (7-DHC synthesis was 1.66 +/- 1.15 mg/kg per day), but not in control subjects. Total sterol synthesis was also reduced in SLOS subjects (12 vs. 20 mg/kg per day, P < 0.022). Bile acid synthesis in SLOS subjects (3.5 mg/kg per day) did not differ significantly from control subjects (4.6 mg/kg per day) and was within the range reported previously in normals. Normal primary and secondary bile acids were identified. This study provides direct evidence that whole body cholesterol synthesis is reduced in patients with SLOS and that the synthesis of 7-DHC and other cholesterol precursors is profoundly increased. It is also the first reported measure of daily bile acid synthesis in SLOS and provides evidence that bile acid supplementation is not likely to be necessary for treatment. These sterol balance studies provide basic information about the biochemical defect in SLOS and strengthen the rationale for the use of dietary cholesterol in its treatment.
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PMID:Sterol balance in the Smith-Lemli-Opitz syndrome. Reduction in whole body cholesterol synthesis and normal bile acid production. 1097 51

Smith-Lemli-Opitz syndrome (SLOS), an autosomal recessive condition with multiple malformations, mental retardation, and growth failure, results from markedly reduced activity of the final enzyme in the cholesterol biosynthetic pathway, 7-dehydrocholesterol reductase (DHCR7). Clinical signs vary in severity, ranging from fetal loss to holoprosencephaly with multiple malformations to isolated syndactyly. The biochemical defect in SLOS is a deficiency of DHCR7, which results in an abnormally low cholesterol level, and increased amounts of intermediates of sterol biosynthesis. Animal models currently exist through the use of cholesterol biosynthesis inhibitors, from which a great deal has been learned. Pregnant rats treated with inhibitors of DHCR7 yield pups that have abnormal sterol profiles and craniofacial abnormalities characteristic of severe SLOS. Biochemical testing of human patients can be performed using gas chromatography/mass spectroscopy (GC/MS) to analyze the sterol content of tissues, amniotic fluid, or cell culture lysate. Numerous mutations have been identified in DHCR7 but seven individual mutations account for 67% of the total mutations reported in the literature. Clinical trials with SLOS are underway, with the goal of increasing the cholesterol concentration in the plasma and tissues through the administration of dietary cholesterol. Thus far, this approach has shown limited efficacy. Nevertheless, the recent identification of the biochemical and molecular genetic basis for SLOS is reason for optimism that the condition may one day yield to treatment.
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PMID:Smith-Lemli-Opitz syndrome: the first malformation syndrome associated with defective cholesterol synthesis. 1100 6

The RSH/Smith-Lemli-Opitz syndrome (RSH/SLOS) is an autosomal recessive multiple congenital anomaly/mental retardation syndrome caused by an inborn error of cholesterol biosynthesis. The RSH/SLOS phenotypic spectrum is broad; however, typical features include microcephaly, ptosis, a small upturned nose, micrognathia, postaxial polydactaly, second and third toe syndactaly, genital anomalies, growth failure, and mental retardation. RSH/SLOS is due to a deficiency of the 3beta-hydroxysterol Delta(7)-reductase, which catalyzes the reduction of 7-dehydrocholesterol (7-DHC) to cholesterol. This inborn error of cholesterol biosynthesis results in elevated serum and tissue 7-DHC levels. The 3beta-hydroxysterol Delta(7)-reductase gene (DHCR7) maps to chromosome 11q12-13, and to date 66 different mutations of this gene have been identified in RSH/SLOS patients. Identification of the biochemical basis of RSH/SLOS has led to development of therapeutic regimens based on dietary cholesterol supplementation and has increased our understanding of the role cholesterol plays during embryonic development.
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PMID:RSH/Smith-Lemli-Opitz syndrome: a multiple congenital anomaly/mental retardation syndrome due to an inborn error of cholesterol biosynthesis. 1100 7


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