Smith-Lemli-Opitz syndrome - a disorder of cholesterol synthesis : Diagnosis, treatment and pathogenetic aspects

Detta är en avhandling från Stockholm : Karolinska Institutet, Department of Laboratory Sciences and Technology

Sammanfattning: In 1993 it was first suggested that the Smith-Lemli-Opitz syndrome (SLOS), described almost 30 years earlier as a malformation syndrome, is caused by defective synthesis of cholesterol. Hypocholesterolaemia and accumulation of the immediate precursor 7dehydrocholesterol was consistent with deficient activity of the enzyme in the last step of the synthesis, 7-dehydrocholesterol-7-reductase. The discovery raised hopes of developing diagnostic methods, finding strategies for treatment and increasing our understanding of the pathogenetic mechanisms. The aims of the present study were to identify children with SLOS in Sweden, to initiate and evaluate different treatments and to study the connection between the clinical presentation, biochemical parameters and the basal defect. Seven children with SLOS in Sweden were diagnosed by analysing the plasma sterol composition by combined gas chromatography-mass spectrometry. Two cases were verified several years after their death by using stored paper blood specimens from the routine neonatal screening programme. A diagnostic method based on the conversion of lathosterol to cholesterol in fibroblasts was developed. The elimination of cholesterol by the oxysterol pathway was studied in SLOS patients. Serum levels of 24- hydroxycholesterol, almost exclusively originating from brain cholesterol, were decreased. The levels were not as low as expected from the hypocholesterolaemia, however, probably due to slow metabolism. Since no hydroxylated 7-dehydrocholesterol species could be identified in the circulation of SLOpatients, limited information can be obtained from analyses of oxysterols in this disease. To increase body cholesterol and thereby down-regulate cholesterol synthesis with less accumulation of possible toxic precursors, we treated the patients with dietary cholesterol and bile acids. Surprisingly, patients with extreme hypocholesterolemia initially increased their synthesis of cholesterol, resulting in an increase of the accumulated dehydrocholesterols. Some clinical improvement was seen in all patients, especially as regards photosensitivity. In one case, a progressive course with polyneuropathy, precocious puberty and general deterioration was stopped, at least temporarily, during the dietary supplementation. In an attempt to decrease the dehydrocholesterols more efficiently, an inhibitor of cholesterol synthesis, simvastatin, was added to the dietary treatment in 2 patients. In one of them no obvious clinical benefit was seen and in the other hepatic side effects led to interruption of the medication. A scoring system based on clinical symptoms related to possible pathogenetic mechanisms is proposed as a complement to the commonly used malformation scores. Conclusions: There are most probably cases of Smith-Lemli-Opitz syndrome in Sweden which have not yet been identified. The moderate beneficial effects of the present therapy do not appear to justify general neonatal screening. It seems reasonable, however, to consider testing for SLOS when investigating patients with severe feeding difficulties, photosensitivity, unknown liver disease, polyneuropathy and increased susceptibility to infection. Such testing is recommended even if typical stigmata are not obvious, and particularly if there is any degree of developmental delay or behaviour problems. It is also suggested that SLOS has to be excluded in cases with severe foetal or neonatal malformations of unknown aetiology, especially if these are lethal.

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