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.

Isolated Conglutin γ from Lupin, but not Phytate, Lowers Serum Cholesterol Without Influencing Vascular Lesion Development in the ApoE-deficient Mouse Model.

Conglutin γ and phytate are considered as potential biofunctional compounds of lupin protein isolate, but their impact on vascular health is unknown. This study aimed to investigate the effect of conglutin γ and phytate, respectively, on circulating levels of sterols, markers of cholesterol biosynthesis and minerals, and on the development and progression of aortic lesions in apoE-deficient mice. To this end, mice were fed a western diet with either casein (200 g/kg; served as a control), conglutin γ from L. angustifolius (200 g/kg) or casein (200 g/kg) supplemented with phytate (5 g/kg) for 16 weeks. Here we found that conglutin γ but not phytate was capable of reducing the circulating concentration of cholesterol. Plasma levels of desmosterol and lathosterol as markers of the cholesterol synthesis were not affected, and 7-dehydrocholesterol was even higher in mice fed conglutin γ than in mice fed casein or casein + phytate. All mice developed pronounced aortic lesions, but histological characterization of plaque area and composition showed no differences between the three groups of mice. Conclusively, conglutin γ exerts cholesterol-lowering effects but appears to have no anti-atherosclerotic properties in the apoE-deficient mice. Phytate neither affected plasma cholesterol nor aortic lesion development.

No evidence for mevalonate shunting in moderately affected children with Smith-Lemli-Opitz syndrome.

Smith-Lemli-Opitz syndrome (SLOS) is caused by a genetic deficiency in 7-dehydrocholesterol (7-DHC) reductase (EC 1.3.1.21), the last enzyme of the cholesterol synthetic pathway. In SLOS, plasma cholesterol concentration is reduced and immediate precursor concentration (7-DHC) is elevated. Surprisingly, total sterol synthesis is reduced but HMG-CoA reductase activity, a rate-limiting enzyme in cholesterol synthesis is unaltered as judged by normal urinary excretion of mevalonic acid (MVA) (Pappu et al. J Lipid Res 43:1661-1669, 2002). These findings raise the possibility of increased diversion of MVA into the MVA shunt pathway away from sterol synthesis, by activation of the shunt pathway enzymes. To test this hypothesis, we measured the urinary excretion of 3-methylglutaconic acid (U-3MGC), a by-product of the shunt pathway, in 19 mildly to moderately severely affected SLOS subjects (ten males, nine females) receiving either a cholesterol-free or a high cholesterol diet, and in 20 age- and sex-matched controls. U-3MGC was similar in SLOS and controls, and was unaffected by dietary cholesterol intake. Further, no change in U-3MGC was observed in a subset of SLOS subjects (n = 9) receiving simvastatin. In contrast, U-MVA was reduced by cholesterol supplementation (~54%, p < 0.05) and by simvastatin (~50%, p < 0.04). There was no correlation between U-3MGC and either plasma sterol concentrations, urinary isoprenoids, or the subjects' clinical severity score. However U-3MGC was inversely correlated with age (p < 0.04) and body weight (p < 0.02), and higher in females than in males (~65%, p < 0.025). The data show that DHCR7 deficiency does not result in 3MGC accumulation in SLOS and suggest that the MVA shunt pathway is not activated in patients with the condition.

Cholesterol treatment forever? The first Scandinavian trial of cholesterol supplementation in the cholesterol-synthesis defect Smith-Lemli-Opitz syndrome.

OBJECTIVES: To investigate if exogenous cholesterol affects sterol turnover in the cholesterol-synthesis defect Smith-Lemli-Opitz syndrome (SLOS) and if clinical effects justify long-time supplementation. The SLOS is caused by a deficiency of the enzyme 7-dehydrocholesterol-7-reductase with markedly reduced cholesterol levels and greatly increased levels of 7-dehydrocholesterol (7-DHC). DESIGN: Treatment with dietary cholesterol in patients with SLOS in a case series study. SETTING: All biochemical analyses were performed in one laboratory. The clinical follow-up was carried out by one of the authors (LS), a paediatric neurologist. SUBJECTS: Seven patients with biochemically verified SLOS have been diagnosed in Sweden and all of them are included in the study. INTERVENTIONS: Six patients were treated for 0.5-6 years orally with cholesterol and the bile acid taurocholate and one patient was supplemented with cholesterol only. MAIN OUTCOME MEASURES: In addition to cholesterol, 7- and 8-DHC, lathosterol was used as a marker of endogenous cholesterol synthesis and the patients were followed clinically. Nerve conduction velocities (NCV) were measured before treatment in all patients and a UVA-light test was performed in one of them. RESULTS: Lathosterol was initially increased by cholesterol supply in subjects with very low cholesterol levels with subsequent rise of 7- and 8-DHC. Photosensitivity clinically improved in all, verified by UVA-light testing in one. Progressive polyneuropathy improved, whilst stationary forms did not. CONCLUSION: Dietary cholesterol can up-regulate sterol turnover in severely affected patients. Although some specific features are treatable and verifiable by objective methods, data supporting life-long treatment dietary cholesterol in all SLO patients are still lacking.

Observations on serum 25-hydroxyvitamin D and calcium concentrations from wild-caught and captive neotropical bats, Artibeus jamaicensis.

Most bats of the suborder Microchiroptera are nocturnal, actively avoid sunlight, and eat mineral-poor diets. In those bats previously studied with respect to mineral metabolism, extensive bone remodeling occurs, and it has been suggested that calcium has been an important constraint on reproduction. There have been no previous studies of vitamin D or its metabolites in microchiropteran bats with respect to calcium metabolism. Reported is the utilization of current advances for the determination of serum levels of the vitamin D metabolite 25-hyroxyvitamin D (25-OH-D) in a neotropical bat, Artibeus jamaicensis. Serum from wild-caught animals contained low levels of 25-OH-D (5.6 +/- 3.0 ng/ml, n = 8). Bats maintained on a vitamin-D-supplemented diet had higher serum 25-OH-D levels and when the diet containing vitamin D was discontinued, mean serum 25-OH-D levels declined significantly after 6 months. Serum calcium concentrations in wild-caught bats (8.5 +/- 0.4 mg%) showed very little variation and were not significantly different in any of the vitamin-D-supplemented animals. A pairwise correlation analysis between 25-OH-D and serum calcium levels revealed no linear correlation. The results indicate either that 25-OH-D does not appear to play a key role or that low levels of 25-OH-D may be adequate in regulating serum calcium levels in this bat.

[Calcium homeostasis and calcium-regulating hormones in young children with phenylketonuria]. / Sostoianie kaltsievogo gomeostaza i kaltsiireguliruiushchikh gormonov u detei rannego vozrasta, bolnykh fenilketonuriei.

Calcium and calcium-regulating hormones were investigated in 19 infants with phenylketonuria. Parathyroid hormone, osteocalcin, dehydrocholecalciferol were found elevated while calcitonin reduced in the serum of the infants prior to the diet. Total calcium and phosphorus remained stable in the course of the study. Element diet resulted in reduced serum parathormone levels though surpassing those of healthy subjects. This fact is attributed to primary metabolic disorders responsible for the onset of hyperparathyroidism. The conclusion is made that element diet is unable to change calcium homeostasis and that of calcium-regulating hormones in infants with phenylketonuria.