Defects In Cholesterol Metabolism Research Articles

Five years' experience of cholesterol treatment for the Smith-Lemli-Opitz Syndrome (SLOS): What have we learned, where are we going?

Since January of 1994, following the discovery of the defect in cholesterol metabolism now known to cause SLOS, we have been treating SLOS patients with a concentrated suspension of cholesterol in soybean oil. Eighteen patients with SLOS, ranging in age from birth to mid teens, and ranging in pretreatment cholesterol levels from 8-90 mg/dl have been followed by us every 1-3 months for up to five years while on treatment.We will present data to show benefits of treatment in this cohort of patients. No adverse reactions to therapy have been noted. Benefits of therapy include improved growth and nutritional status, better tolerance of infection, and improvement in behavioral disturbances. Adrenal function and neutrophil function have been investigated, and both are normal. Ongoing studies are documenting neuropsychological course, CNS myelinization on MRI, and hearing status with ABR.We have discovered problems in our patients which were not previously known to occur in SLOS. These include photosensitivity, which we are now studying both in vitro in skin fibroblasts, and in vivo using timed exposure to UV light. We have also documented abnormal red cell shape (acanthocytosis), and the development of hypersplenism with thrombocytopenia in some patients. We are now accumulating experience in the management of profoundly ill neonates using fresh frozen plasma, and in prenatal diagnosis, by assessing low maternal serum estriol levels. Future plans include studies of cholesterol absorption, and the use of MR spectroscopy to assess CNS cholesterol metabolism. Our close follow-up of this patient cohort has allowed us to appreciate the complexities of issues seen in children with severe cholesterol deficiency, and to develop a greater understanding of the natural course of SLOS.

Changes in cholesterol metabolism with dietary cholesterol in children with familial hypercholesterolaemia.

1. Possible defects in cholesterol metabolism were sought in children with familial hypercholesterolaemia. 2. In nine affected children (eight heterozygotes and one homozygote) and in five healthy children, cholesterol synthesis and bile acid synthesis were determined from the excretion of steroids in the faeces during a low cholesterol diet. Cholesterol synthesis of 10.1 +/- 4.4 mg day-1 kg-1 in the hypercholesterolaemic children was similar to that in these and other normal children. Mean bile acid synthesis of 4.0 +/- 2.1 mg day-1 kg-1 also resembled normal values though three severely affected heterozygotes excreted substantially less. 3. The response to 4 weeks' additional 450 mg of dietary cholesterol/day led to variable changes in the plasma cholesterol and in the sterol balance. On average the affected children showed a rise in plasma cholesterol which resembled that in healthy subjects. The sterol balance fell in most, suggesting a reduction in cholesterol synthesis, which is the normal response to dietary cholesterol. 4. The response to dietary cholesterol was therefore at least qualitatively similar in the hypercholesterolaemic children to that reported in healthy subjects.

Mutations affecting the binding, internalization, and lysosomal hydrolysis of low density lipoprotein in cultured human fibroblasts, lymphocytes, and aortic smooth muscle cells

Studies comparing the metabolism of low density lipoprotein (LDL) in normal cells and in cells cultured from patients with homozygous familial hypercholesterolemia have disclosed the existence of a receptor for plasma LDL. This receptor has been identified on the surface of human fibroblasts, lymphocytes, and aortic smooth muscle cells. An extension of these studies to cell strains derived from patients with other single gene defects in cholesterol metabolism has provided additional insight into the normal mechanisms by which cells regulate their cholesterol content and how alterations in these genetic control mechanisms may predispose to atherosclerosis in man.

Schilder's disease: abnormal cholesterol retention and accumulation in cultivated fibroblasts.

Extract: Schilder's disease (SD) with adrenal insufficiency is a fatal X-linked recessive disorder for which the basic defect is as yet unknown. To investigate the hypothesis that Schilder's disease might be associated with a generalized defect in cholesterol metabolism, the uptake and disappearance of labeled cholesterol and cholesterol esters were studied in cultivated fibroblasts from patients with Schilder's disease, patients with familial hypercholesterolemia, and normal control subjects. Over a 10–12-day period of exposure to the labeled compound, SD fibroblasts accumulated significantly more cholesterol than did normal fibroblasts (P < 0.001). In addition, after a 24-hr exposure to the labeled cholesterol, the SD fibroblasts retained significantly more of the label than did control cells over a 5-day period of study (P < 0.001). The retained label was still located in the cholesterol fraction on thin layer chromatography in both SD and normal cells. The total cholesterol content of SD cells when measured directly after 12 days in tissue culture was significantly greater than that of normal cells.Speculation: The results of these studies support the concept that Schilder's disease may indeed be related to a generalized defect in cholesterol metabolism or transport. An alternative explanation for these findings is that Schilder's disease may be associated with a defect in membrane structure or turnover that is not directly related to cholesterol metabolism but can be followed in vitro by cholesterol accumulation and retention.