New treatment strategy for Smith-Lemli-Opitz syndrome

Abstract

Smith-Lemli-Opitz syndrome is caused by deficient activity of ▵7-dehydrocholesterol reductase, the final enzyme of the cholesterol biosynthesis pathway, resulting in low cholesterol and high concentrations of its precusors, 7-dehydrocholesterol (7DHC) and 8DHC in blood and tissues. 1 Irons M Elias ER Salen G Tint GS Bastta AK Defective cholesterol biosynthesis associated with the Smith-Lemli-Opitz-Syndrome. Lancet. 1993; 341: 1414 Abstract PubMed Scopus (319) Google Scholar , 2 Tint GS Salen G Batta AK et al. Correlation of severity and outcome with plasma sterol levels in variants of the Smith-Lemli-Opitz syndrome. J Pediatr. 1995; 127: 82-87 Summary Full Text Full Text PDF PubMed Scopus (126) Google Scholar Cholesterol fulfils an essential role during embryogenesis where it functions as a transporter-molecule for hedgehog signalling proteins required for normal morphogenesis. 3 Porter JA Young KE Beachy PA Cholesterol modification of hedgehog signalling proteins in animal development. Science. 1996; 274: 255-259 Crossref PubMed Scopus (1077) Google Scholar Without cholesterol their transport is impaired. 3 Porter JA Young KE Beachy PA Cholesterol modification of hedgehog signalling proteins in animal development. Science. 1996; 274: 255-259 Crossref PubMed Scopus (1077) Google Scholar These findings may explain the phenotypic consequences of ▵7-reductase deficiency as observed in Smith-Lemli-Opitz syndrome: microcephaly, distinctive facies, organ malformations, syndactyly/polydactyly, and genital abnormalities. Once morphogenesis is complete, it is not known whether the low cholesterol or the increased concentration of precursors is more harmful. In abetalipoproteinaemia, cholesterol concentrations are similar to those in Smith-Lemli-Opitz syndrome without clinical side-effects; we thus postulated that 7DHC, 8DHC, or both may be the toxic substances. Therapeutic trials of dietary supplementation of cholesterol with or without bile acids have shown that plasma cholesterol concentration can be increased in some patients. Concentrations of the precursors 7DHC and 8DHC, however, were only marginally altered and clinical results so far have been disappointing. 4 Irons M Elias ER Abuelo D Tint GS Salen G Clinical features of the Smith-Lemli-Opitz syndrome and treatment of the cholesterol metabolic defect. Int Pediatr. 1995; 10: 28-32 Google Scholar , 5 Ullrich K Koch HG Meschede D Flotmann U Seedorf U Smith-Lemli-Opitz syndrome; treatment with cholesterol and bile acids. Neuropediatrics. 1996; 27: 111-112 Crossref PubMed Scopus (14) Google Scholar