Smith-Lemli-Opitz syndrome in Japan Tsukahara, M; Fujisawa, K; Yamamoto, K ...
American journal of medical genetics,
6 January 1998, Letnik:
75, Številka:
1
Journal Article
EEG in cerebrotendinous xanthomatosis (CTX) Berginer, V M; Radwan, H; Korczyn, A D ...
Clinical EEG electroencephalography,
04/1982, Letnik:
13, Številka:
2
Journal Article
Sitosterolemia is an inherited recessive disease characterized by abnormally increased plasma and tissue plant sterol concentrations. Patients hyperabsorb sitosterol. In addition, hepatic, ileal, and ...mononuclear leukocyte 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-controlling enzyme in the cholesterol biosynthetic pathway, is markedly suppressed in this disease. It is still controversial whether the down-regulation is due to accumulated sitosterol, but the effect of sitosterol on HMG-CoA reductase activity has not been studied in sitosterolemic tissues. To investigate whether sitosterol inhibits HMG-CoA reductase activity in sitosterolemia, we measured the enzyme activities in liver and cultured skin fibroblasts from patients. Hepatic HMG-CoA reductase activities in patients were decreased 76% (P <.05) as compared with results in control subjects. In contrast, HMG-CoA reductase activities in sitosterolemic fibroblasts were not decreased as compared with results in control fibroblasts, and the activities in all cells were up-regulated similarly when they were exposed to delipidated medium. Because the cultured sitosterolemic fibroblasts contained only trace amounts of plant sterols, we added 20 μg/mL sitosterol directly to the cell medium. Raising the intracellular sitosterol concentration to 7% of cellular cholesterol level increased HMG-CoA reductase activity 23% (P <.05), while the addition of the same amount of cholesterol to the cells reduced the activity 46% (P <.05). Thus, when sitosterolemic skin fibroblasts were used, it was possible to distinguish between the effects of cholesterol and those of sitosterol on the activity of HMG-CoA reductase. These results suggest that reduced HMG-CoA reductase activity in this disease is caused by secondary effects of unknown regulator(s) other than sitosterol. (J Lab Clin Med 2000;135:174-9)
Liver specimens from two patients with cerebrotendinous xanthomatosis revealed intracellular inclusions that appeared either as amorphous pigment or in a crystalloid form. The pigment was usually ...found in assoication with the smooth endoplasmic reticulum and occasionally free floating in the cytosol. The chemical nature of these inclusions has not yet been determined. However, the accumulation of such material may indicate the presence of nonmetabolizable bile alcohols resulting from a defect in bile acid synthesis.
The Smith-Lemli-Opitz syndrome is a common birth defect syndrome caused by a deficiency of 7-dehydrocholesterol delta 7-reductase, an essential enzyme in the biosynthesis of cholesterol. The syndrome ...can usually be diagnosed easily from the plasma markers of markedly elevated 7-dehydrocholesterol and reduced cholesterol concentrations. However, atypical cases with normal plasma levels of cholesterol with only moderately elevated 7-dehydrocholesterol have been reported. To establish a sensitive method for the biochemical diagnosis of the atypical cases of the syndrome, we measured sterol concentrations of cultured skin fibroblasts. 7-Dehydrocholesterol concentrations in patients' fibroblasts grown in the presence of 10% fetal bovine serum were significantly higher than those in controls and parents (P < 0.0005), but they were not elevated proportionately as much as in plasma. To re-produce the accumulation of 7-dehydrocholesterol, the cells were exposed to delipidated medium to induce sterol biosynthesis. After 4 weeks, 7-dehydrocholesterol concentrations in patients' fibroblasts increased from 2.8 +/- 0.3% to 34 +/- 3% of total sterols (cholesterol + 7-dehydrocholesterol + 8-dehydrocholesterol). The increase was also observed in fibroblasts from an atypical patient who has a normal plasma cholesterol level and a 7-dehydrocholesterol concentration of only 0.15 mg/dl. In contrast, cells from parents and controls accumulated very little 7-dehydrocholesterol (< 1% of total sterols). These results demonstrate that cultured fibroblasts exhibit abnormally high accumulation of 7-dehydrocholesterol after cells are exposed to delipidated medium not only in typical patients, but also in an atypical case. The present method is a sensitive procedure for the biochemical diagnosis of this syndrome.
We performed a sural nerve biopsy in a patient with cerebrotendinous xanthomatosis (CTX) because of electrophysiologic evidence of peripheral neuropathy. The sections showed a striking loss of ...myelinated axons, the distribution of which suggested a compressive and/or ischemic process. Biochemical analysis disclosed large amounts of cholestanol, a cholesterol derivative that characteristically accumulates in CTX. However, the biochemical abnormality was not associated with any obvious structural alterations in the myelin lamellae or with abnormal storage material in Schwann's cells.
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