Biochemical and Clinical Effects of Vitamin E Supplementation in Hungarian Smith-Lemli-Opitz Syndrome Patients.

Smith-Lemli-Opitz syndrome (SLOS) is a severe monogenic disorder resulting in low cholesterol and high 7-dehydrocholesterol (7-DHC) levels. 7-DHC-derived oxysterols likely contribute to disease pathophysiology, and thus antioxidant treatment might be beneficial because of high oxidative stress. In a three-year prospective study, we investigated the effects of vitamin E supplementation in six SLOS patients already receiving dietary cholesterol treatment. Plasma vitamin A and E concentrations were determined by the high-performance liquid chromatography (HPLC) method. At baseline, plasma 7-DHC, 8-dehydrocholesterol (8-DHC) and cholesterol levels were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The clinical effect of the supplementation was assessed by performing structured parental interviews. At baseline, patients were characterized by low or low-normal plasma vitamin E concentrations (7.19-15.68 µmol/L), while vitamin A concentrations were found to be normal or high (1.26-2.68 µmol/L). Vitamin E supplementation resulted in correction or significant elevation of plasma vitamin E concentration in all patients. We observed reduced aggression, self-injury, irritability, hyperactivity, attention deficit, repetitive behavior, sleep disturbance, skin photosensitivity and/or eczema in 3/6 patients, with notable individual variability. Clinical response to therapy was associated with a low baseline 7-DHC + 8-DHC/cholesterol ratio (0.2-0.4). We suggest that determination of vitamin E status is important in SLOS patients. Supplementation of vitamin E should be considered and might be beneficial.

Smith-Lemli-Opitz Syndrome in a newborn infant with developmental abnormalities and low endogenous cholesterol.

BACKGROUND: Patients with Smith-Lemli-Opitz Syndrome (SLOS) have defective endogenous cholesterol synthesis, and present with decreased cholesterol levels and multiple developmental dysmorphologies. CASE DESCRIPTION: A newborn infant with normal XY karyotype and normal microarray was born with multiple developmental defects and ambiguous genitalia. The patient was diagnosed with SLOS, following biochemical genetic analysis of serum 7-DHC concentrations. The clinical course of the patient was further complicated by the comorbidities associated with SLOS and the bacterial infections. CONCLUSION: We provide a detailed biochemical profile of the SLOS patient. The report can help us further understand the pathological impacts of cholesterol synthesis deficiency and provide relevant clinical management with outcome of this rare genetic disorder.

Unravelling new pathways of sterol metabolism: lessons learned from in-born errors and cancer.

PURPOSE OF REVIEW: To update researchers of recently discovered metabolites of cholesterol and of its precursors and to suggest relevant metabolic pathways. RECENT FINDINGS: Patients suffering from inborn errors of sterol biosynthesis, transport and metabolism display unusual metabolic pathways, which may be major routes in the diseased state but minor in the healthy individual. Although quantitatively minor, these pathways may still be important in healthy individuals. Four inborn errors of metabolism, Smith-Lemli-Opitz syndrome, cerebrotendinous xanthomatosis and Niemann Pick disease types B (NPB) and C (NPC) result from mutations in different genes but can generate elevated levels of the same sterol metabolite, 7-oxocholesterol, in plasma. How this molecule is metabolized further is of great interest as its metabolites may have an important role in embryonic development. A second metabolite, abundant in NPC and NPB diseases, cholestane-3ß,5α,6ß-triol (3ß,5α,6ß-triol), has recently been shown to be metabolized to the corresponding bile acid, 3ß,5α,6ß-trihydroxycholanoic acid, providing a diagnostic marker in plasma. The origin of cholestane-3ß,5α,6ß-triol is likely to be 3ß-hydroxycholestan-5,6-epoxide, which can alternatively be metabolized to the tumour suppressor dendrogenin A (DDA). In breast tumours, DDA levels are found to be decreased compared with normal tissues linking sterol metabolism to cancer. SUMMARY: Unusual sterol metabolites and pathways may not only provide markers of disease, but also clues towards cause and treatment.

Vitamin D levels in Smith-Lemli-Opitz syndrome.

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.

Sterols and oxysterols in plasma from Smith-Lemli-Opitz syndrome patients.

Smith-Lemli-Opitz syndrome (SLOS) is a severe autosomal recessive disorder resulting from defects in the cholesterol synthesising enzyme 7-dehydrocholesterol reductase (Δ7-sterol reductase, DHCR7, EC 1.3.1.21) leading to a build-up of the cholesterol precursor 7-dehydrocholesterol (7-DHC) in tissues and blood plasma. Although the underling enzyme deficiency associated with SLOS is clear there are likely to be multiple mechanisms responsible for SLOS pathology. In an effort to learn more of the aetiology of SLOS we have analysed plasma from SLOS patients to search for metabolites derived from 7-DHC which may be responsible for some of the pathology. We have identified a novel hydroxy-8-dehydrocholesterol, which is either 24- or 25-hydroxy-8-dehydrocholesterol and also the known metabolites 26-hydroxy-8-dehydrocholesterol, 4-hydroxy-7-dehydrocholesterol, 3ß,5α-dihydroxycholest-7-en-6-one and 7α,8α-epoxycholesterol. None of these metabolites are detected in control plasma at quantifiable levels (0.5ng/mL).

A placebo-controlled trial of simvastatin therapy in Smith-Lemli-Opitz syndrome.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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 Med 19 3, 297-305.

A Pilot Study of the Association of Markers of Cholesterol Synthesis with Disturbed Sleep in Smith-Lemli-Opitz Syndrome.

OBJECTIVE: Smith-Lemli-Opitz syndrome (SLOS) is a rare genetic disorder characterized by cholesterol synthesis impairment. A host of physical, developmental, and behavioral presentations are associated with SLOS, many of which have been related with disorder severity. Sleep disturbance is commonly reported in SLOS. This study is the first to examine the association between sleep disturbance and biomarkers of cholesterol synthesis defect. METHOD: Twenty youth with SLOS participated. Biomarkers of cholesterol synthesis were obtained, including plasma sterols (i.e., 7-dehydrocholesterol, 8-dehydrocholesterol, and cholesterol), mevalonic acid, and 24-S hydroxycholsterol. A ratio of plasma cholesterol precursors to cholesterol levels was used as a measure of biochemical severity. Parents reported their children's sleep problems using the Children's Sleep Habits Questionnaire. RESULTS: Most markers of cholesterol synthesis disruption were associated with overall sleep disturbance. Biochemical severity of SLOS was also associated with specific sleep problems (e.g., decreased sleep duration and increased sleep onset delay) and was identified as a significant predictor of these factors. CONCLUSION: This study is the first to demonstrate associative relationships between cholesterol levels and sleep disturbance in youth with SLOS. These results add to the current understanding of how cholesterol levels may contribute to the behavioral phenotype of SLOS. These findings may inform future studies related to the role cholesterol synthesis defects play in the behavioral phenotype of SLOS and, subsequently, modalities of intervention for behavioral symptoms.

[Inborn error of cholesterol biosynthesis: Smith-Lemli-Opitz syndrome]. / A koleszterin-bioszintézis veleszületett zavara: a Smith-Lemli-Opitz-szindróma.

Smith-Lemli-Opitz syndrome is an autosomal recessive mental retardation and multiple malformation syndrome caused by deficiency of the 7-dehydrocholesterol reductase, the enzyme catalyzing the last step in cholesterol biosynthesis. The authors summarize the pathophysiology, epidemiology, clinical picture, diagnostics and therapy of the disease based on a review of the international literature. Since 2004, fourteen patients have been diagnosed with Smith-Lemli-Opitz syndrome in Hungary, which suggests an underdiagnosis of the disease based upon estimated incidence data. Due to deficiency of the 7-dehydrocholesterol reductase, serum cholesterol concentration is low and 7-dehydrocholesterol concentration is elevated in blood and tissues; the latter being highly specific for the syndrome. Detection of disease-causing mutations makes the prenatal diagnosis possible. The clinical spectrum is wide, the most common symptom is syndactyly of the second and third toes. Standard therapy is cholesterol supplementation. Recent publications suggest that oxidative compounds of 7-dehydrocholesterol may play a role in the pathophysiology of the disease as well.

LC-MS/MS-based quantification of cholesterol and related metabolites in dried blood for the screening of inborn errors of sterol metabolism.

Smith-Lemli-Opitz syndrome (SLOS) is an inherited metabolic disease in the cholesterol biosynthesis pathway which is characterised by accumulation of 7- and 8-dehydrocholesterol and by reduced cholesterol concentrations in all tissues and body fluids. With this study, we developed a new, rapid, robust and high-throughput tandem mass spectrometric method as routine application for the selective SLOS screening and therapy monitoring in serum and dried blood. After protein precipitation of 10 µL serum or 4.7 mm dried blood spot, the sum of 7- and 8-dehydrocholesterol (DHC) was analysed by rapid chromatography combined with tandem mass spectrometry. Method comparison with GC-MS was performed for 46 serum samples. A comparison between serum and corresponding dried blood spots for DHC and cholesterol was performed with 40 samples from SLOS patients. Concentrations of DHC and cholesterol were analysed in 2 dried blood samples from newborns with SLOS and 100 unaffected newborns. Intra- and inter-assay variabilities ranged between 3.7 and 17.7% for serum and dried blood spots. Significant correlations between the new LC-MS/MS method and GC-MS were determined for DHC (r = 0.937, p < 0.001) and for cholesterol (r = 0.946, p < 0.001). Significant coefficients of correlation between serum and dried blood spot samples above 0.8 were calculated for both analytes. A cut-off value of 5.95 for the ratio of DHC/cholesterol (multiplied by 1000) was found to distinguish newborns diagnosed with SLOS from normal newborns in a retrospective analysis after 5 years. The developed method enables a rapid quantification of the sum parameter 7- and 8-DHC in newborns and SLOS patients under therapy in serum as well as dried blood spot samples.

Altered lipid subfraction profile and impaired antioxidant defense of high-density lipoprotein in Smith-Lemli-Opitz syndrome.

BACKGROUND: Smith-Lemli-Opitz syndrome (SLOS) is a rare disease caused by biallelic mutation in the 7-dehydrocholesterol (7DHC) reductase gene. High oxidizability of 7DHC and the appearance of small-sized low-density lipoprotein (LDL) subfractions indicate increased endogenous oxidative stress that is counterbalanced by natural antioxidant defense mechanisms including the high-density lipoprotein (HDL)-associated paraoxonase-1 (PON1) enzyme. PON1 prevents lipoproteins from oxidative modifications; however, PON1 activity and the distribution of lipoprotein subfractions have not been studied in SLOS. METHODS: 7DHC levels and PON1 arylesterase activities were measured spectrophotometrically in 11 SLOS patients and 10 healthy children. Lipoprotein subfractions were detected by polyacrylamide gel electrophoresis. RESULTS: Compared to controls, there was a shift towards the small-dense LDL subfraction and the large HDL subfraction in SLOS. PON1 arylesterase activity was significantly decreased in SLOS patients and correlated negatively with the proportion of small-dense LDL subfraction and the proportion of large HDL subfraction. Significant positive correlations were detected between PON1 arylesterase activity and the ratios of intermediate and small HDL subfractions. CONCLUSIONS: Decreased PON1 activity and the deleterious shift in the distribution of lipoprotein subfractions may contribute to the impaired antioxidant status observed in SLOS. Monitoring of serum PON1 arylesterase activity may be a complementary biomarker in SLOS.

Feeding impairments associated with plasma sterols in Smith-Lemli-Opitz syndrome.

OBJECTIVE: To quantitatively evaluate feeding impairment in children with Smith-Lemli-Opitz syndrome (SLOS) and to correlate feeding impairment with clinical and biochemical indices of disease severity. STUDY DESIGN: The study subjects were 26 children with SLOS ranging in age from 0.4 to 19 years. Clinical severity was measured using an existing scoring system. We created a tool to quantitatively evaluate feeding. Plasma sterol concentrations were measured, and statistical associations (correlations) with feeding scores were calculated. RESULTS: Oral hyposensitivity or hypersensitivity, adverse behaviors, and risk for dysphagia were seen in ∼65% of the children with SLOS. Thirteen of the 26 children experienced failure to thrive, and 10 children required gastrostomy. Plasma concentration of 7-dehydrocholesterol, as a measure of severity, was correlated with total feeding score and oral function subcategory score (P < .001) and less so with oral structure score, adverse behaviors, or dysphagia. Correlations with cholesterol concentrations were less statistically significant. A plasma 7-dehydrocholesterol concentration >0.24 mmol/L or cholesterol concentration <1.95 mmol/L was predictive of gastrostomy tube use. Feeding impairments may improve with age. CONCLUSION: Feeding impairment is common and complex in patients with SLOS. Our findings confirm that oral sensitivities, adverse feeding behaviors, and risk of oral phase dysphagia are amenable to quantitative evaluation and analysis. Feeding difficulties in children with SLOS are correlated with plasma sterol concentrations, suggesting a link between the biochemical severity of SLOS and feeding function. These findings expand the behavioral phenotype of SLOS and begin to provide insight into the biological causes of feeding difficulties.

On the formation of 7-ketocholesterol from 7-dehydrocholesterol in patients with CTX and SLO.

A new mechanism for formation of 7-ketocholesterol was recently described involving cytochrome P-450 (CYP)7A1-catalyzed conversion of 7-dehydrocholesterol into 7-ketocholesterol with cholesterol-7,8-epoxide as a side product. Some patients with cerebrotendinous xanthomatosis (CTX) and all patients with Smith-Lemli-Opitz syndrome (SLO) have markedly increased levels of 7-dehydrocholesterol in plasma and tissues. In addition, the former patients have markedly upregulated CYP7A1. We hypothesized that these patients may produce 7-ketocholesterol from 7-dehydrocholesterol with formation of cholesterol-7,8-epoxide as a side product. In accord with this hypothesis, two patients with CTX were found to have increased levels of 7-ketocholesterol and 7-dehydrocholesterol, as well as a significant level of cholesterol-7,8-epoxide. The latter steroid was not detectable in plasma from healthy volunteers. Downregulation of CYP7A1 activity by treatment with chenodeoxycholic acid reduced the levels of 7-ketocholesterol in parallel with decreased levels of 7-dehydrocholesterol and cholesterol-7,8-epoxide. Three patients with SLO were found to have markedly elevated levels of 7-ketocholesterol as well as high levels of cholesterol-7,8-epoxide. The results support the hypothesis that 7-dehydrocholesterol is a precursor to 7-ketocholesterol in SLO and some patients with CTX.

[Historical aspects of the Smith-Lemli-Opitz syndrome]. / Historické aspekty Smithovho-Lemliho-Opitzovho syndrómu.

The new malformation syndrome was first described approximately 50 years ago in three unrelated patients in Department of Pediatrics at the University of Wisconsin, Madison, (Smith, Lemli, Opitz 1964). This syndrome was called RSH syndrome after the first 3 patients studied. First Slovak patient with phenotypic features of this new syndrome was described by professor Srsen in 1972. In 1994 Tint from VA Medical Center, E. Orange, New Jersey analyzed plasma sterols of patient with Smith-Lemli-Opitz syndrome and found out that in addition to low plasma cholesterol level, the patient had 1000-fold increase of the plasma level of 7-dehydrocholesterol, the immediate precursor of cholesterol biosynthesis. After this biochemical discovery Smith-Lemli-Opitz syndrome became the metabolic-malformation syndrome with an exactly defined impairment of cholesterol metabolism. The first patient with biochemically proved Smith-Lemli-Opitz syndrome in Slovakia was described by Behulova et al. (1997) in cooperation with Department of Biochemistry and Medical Biotechnology, Federico II University in Naples, Italy. The three years later a screening method UV spectrometry of serum lipids for detection of 7-dehydrocholesterol was established in Department of Biochemistry, University Children´s Hospital in cooperation with the Institute of preventive and clinical medicine in Bratislava (Skodova et al.,2000). First results of molecular analysis of the 7-dehydrocholesterol reductase gene in 10 unrelated Czech and Slovak patients with Smith-Lemli-Opitz syndrome were reported by Kozak et al. (2000). The same year the first prenatal diagnosis of Smith-Lemli-Opitz syndrome by mutation analysis was achieved (Bzduch et al., 2000). Our research activities on this topic drew good response from abroad.

A highly sensitive method for analysis of 7-dehydrocholesterol for the study of Smith-Lemli-Opitz syndrome.

We describe a highly sensitive method for the detection of 7-dehydrocholesterol (7-DHC), the biosynthetic precursor of cholesterol, based on its reactivity with 4-phenyl-1,2,4-triazoline-3,5-dione (PTAD) in a Diels-Alder cycloaddition reaction. Samples of biological tissues and fluids with added deuterium-labeled internal standards were derivatized with PTAD and analyzed by LC-MS. This protocol permits fast processing of samples, short chromatography times, and high sensitivity. We applied this method to the analysis of cells, blood, and tissues from several sources, including human plasma. Another innovative aspect of this study is that it provides a reliable and highly reproducible measurement of 7-DHC in 7-dehydrocholesterol reductase (Dhcr7)-HET mouse (a model for Smith-Lemli-Opitz syndrome) samples, showing regional differences in the brain tissue. We found that the levels of 7-DHC are consistently higher in Dhcr7-HET mice than in controls, with the spinal cord and peripheral nerve showing the biggest differences. In addition to 7-DHC, sensitive analysis of desmosterol in tissues and blood was also accomplished with this PTAD method by assaying adducts formed from the PTAD "ene" reaction. The method reported here may provide a highly sensitive and high throughput way to identify at-risk populations having errors in cholesterol biosynthesis.

Aripiprazole and trazodone cause elevations of 7-dehydrocholesterol in the absence of Smith-Lemli-Opitz Syndrome.

Screening for Smith-Lemli-Opitz Syndrome (SLOS) using elevated 7-dehydrocholesterol (7DHC) as a marker is sensitive, but not always specific. Elevations of 7DHC can be seen in patients who do not have a defect in 7-dehydrocholesterol reductase. These results have often been attributed to medication artifacts, but specific causes have not been well reported. We examined the medical records of patients with elevated 7DHC to determine if they had been diagnosed with SLOS; and if they had not, to identify any common medications that may have caused the elevations. We found three individuals who were affected with SLOS, and 22 with elevated 7DHC in the absence of SLOS. Seven of these individuals underwent molecular testing which showed no mutations, while the other 15 were excluded based on clinical findings and other testing. The medication history of these individuals revealed aripiprazole and trazodone as common medications to all the false positive results.

Challenging behavior in Smith-Lemli-Opitz syndrome: initial test of biobehavioral influences.

OBJECTIVE: To study challenging behavior (destruction, aggression, self-injury, stereotypy) in children with Smith-Lemli-Opitz syndrome (SLOS) using a biobehavioral model that helps distinguish biological from socially mediated variables influencing the behavior. BACKGROUND: SLOS is an autosomal-recessive syndrome of multiple malformations and intellectual disability resulting from a genetic error in cholesterol synthesis in all cells and tissues, including brain. The exact cause of the challenging behavior in SLOS is unclear, but defective brain cholesterol synthesis may contribute. Because the precise genetic and biochemical etiology of SLOS is known, this disorder is a good model for studying biological causes of challenging behavior. METHOD: In a preliminary application of a biobehavioral model, we studied the association between cholesterol levels (as a biochemical indicator of disease severity) and behavior subtype ("biological" vs "learned") in 13 children with SLOS. Parents completed a questionnaire that categorized challenging behavior as influenced primarily by social or nonsocial (thus, presumably biological) factors. RESULTS: The severity of the cholesterol synthesis defect correlated significantly with behavior subtype classification for 1 of 2 challenging behaviors. Greater severity of the cholesterol synthesis defect was associated with behavior being classified as primarily influenced by biological factors. CONCLUSION: The interplay between challenging behavior and defective cholesterol synthesis in SLOS may help explain biological influences on the behavior. Our findings have implications for research on the effectiveness of behavioral and medical treatments for behavioral difficulties in SLOS and other neurodevelopmental disorders.

Prenatal presentation and diagnostic evaluation of suspected Smith-Lemli-Opitz (RSH) syndrome.

Smith-Lemli-Opitz (SLOS), or RSH syndrome, is an autosomal recessive deficiency of 7-dehydrocholesterol reductase (DHCR7) resulting in an accumulation of 7- and 8-dehydrocholesterol (7- and 8-DHC) in tissues and body fluids. At birth patients have variable malformations of CNS, heart, kidney, genitalia, and limbs, which may be life-limiting. In later course, psychomotor and mental retardation and behavior abnormalities become evident. Prenatally SLOS can be suspected on the basis of malformations and intrauterine growth retardation (IUGR) in prenatal ultrasonography and reduced maternal free estriol in serum. The diagnosis is confirmed by sterol analysis in a chorionic villus biopsy or amniotic fluid (AF). In this study, we evaluated the predictive value of the above mentioned criteria in combination with family history by quantification of sterols in AF in pregnancies with either a family history, ultrasonographical abnormalities typical for SLOS, or reduced maternal serum unconjugated estriol (MSuE3). The relative frequency of SLOS in fetuses with an affected sibling was 0.23, as to be expected for an autosomal recessive disease. The probability for SLOS was <0.6% when neither an affected sib nor more than one typical SLOS malformation was present. For safety reasons and for cost-effectiveness we recommend careful evaluation of history, MSuE3, and clinical presentation before determining sterols in AF.

Relation between biomarkers and clinical severity in patients with Smith-Lemli-Opitz syndrome.

UNLABELLED: Smith-Lemli-Opitz syndrome (SLOS), a multiple congenital anomaly with severe mental retardation, is caused by decreased activity of 7-dehydrocholesterol reductase. Fifteen Hungarian patients were diagnosed with SLOS on the basis of clinical symptoms, serum cholesterol, 7-dehydrocholesterol, and molecular genetic testing. Their age at the time of diagnosis in mild SLOS (n = 4, clinical score <20) was 0.5-18 years, cholesterol was 2.37 ± 0.8 mmol/L, and 7DHC was 0.38 ± 0.14 mmol/L. In the group of typical SLOS (n = 7, score 20-50), the diagnosis was set up earlier (age of 0.1-7 years); t-cholesterol was 1.47 ± 0.7 mmol/L, and 7DHC was 0.53 ± 0.20 mmol/L. Patients with severe SLOS (n = 4, clinical score > 50) died as newborns and had the lowest t-cholesterol (0.66 ± 0.27 mmol/L), and 7DHC was 0.47 ± 0.14 mmol/L. Correlation coefficient with clinical severity was 0.74 for initial t-cholesterol and 0.669 for Cho/7DHC. Statistically significant difference was between the initial t-cholesterol of mild and severe SLOS (p = 0.01), and between the Cho/7DHC ratios of groups (p = 0.004). In severe SLOS, the percentage of α-lipoprotein was significantly lower than in typical (p = 0.003) and mild SLOS (p = 0.004). Although serum albumin, total bilirubin, and hemostasis parameters remained in the reference range during cholesterol supplementation (n = 10) combined with statin therapy (n = 9), increase of aspartate aminotransferase and alanine aminotransferase in 50 % of the patients probably refers to a reversible alteration of liver function; therefore, statin therapy was suspended. CONCLUSION: life expectancy is fundamentally determined by the initial t-cholesterol, but dehydrocholesterol and α-lipoprotein have prognostic value. Accumulation of hepatotoxic DHC may inhibit the synthesis of α-lipoproteins, decreasing the reverse cholesterol transport. During statin therapy, we suggest monitoring of lipid parameters and liver function.

Hepatic isoprenoid metabolism in a rat model of Smith-Lemli-Opitz Syndrome.

Elevated (4 to 7-fold) levels of urinary dolichol and coenzyme Q and substantially longer chain lengths for urinary dolichols have been reported in Smith-Lemli-Opitz Syndrome (SLOS) patients, compared to normal subjects. We investigated the possibility of similar alterations in hepatic, nonsterol isoprenoids in a well-established rat model of SLOS. In this model, the ratio of 7-dehydrocholesterol (7DHC) to cholesterol (Chol) in serum approached 15:1; however, total sterol mass in serum decreased by >80 %. Livers from treated rats had 7DHC/Chol ratios of ~32:1, but the steady-state levels of total sterols were >40 % those of livers from age-matched (3-month-old) control animals. No significant differences in the levels of LDL receptor or HMG-CoA reductase were observed. The levels of dolichol and coenzyme Q were elevated only modestly (by 64 and 31 %, respectively; p < 0.05, N = 6) in the livers of the SLOS rat model compared to controls; moreover, the chain lengths of these isoprenoids were not different in the two groups. We conclude that hepatic isoprenoid synthesis is marginally elevated in this animal model of SLOS, but without preferential shunting to the nonsterol branches (dolichol and coenzyme Q) of the pathway and without alteration of normal dolichol chain lengths.