PATHOGENESIS OF MALFORMATIONS IN A RODENT MODEL FOR SMITH-LEMLI-OPITZSYNDROME

The fact that Smith-Lemli-Opitz syndrome (SLOS), a syndrome comprising major malformations involving a number of organ systems, results fi o m an abnormality in cholesterol biosynthesis, was discovered only rece ntly. Utilizing a drug (BM 15.766) to inhibit the same step in cholest erol biosynthesis as is abnormal in those affected with SLOS, we have developed a rat model that presents with abnormalities observed as ear ly as gestational day 12 that appear to be consistent with some of tho se subsequent malformations that comprise the human syndrome. Abnormal ities of the brain and face include deficiency in the midline region o f the upper face, narrowing of the forebrain hemispheres and of the ce rebral aqueduct, and deficiency in the developing lower jaw. Associate d pathogenesis, as observed on gestational day 11 in histological sect ions and with scanning electron microscopy, involves abnormal cell pop ulations at the rim of the developing forebrain and in the alar plate of the lower midbrain and hindbrain. The affected cells appear abnorma lly rounded up, having apparently lost their normal cell contacts. The potential basis for the selective vulnerability of this cell populati on and the impact of its vulnerability relative to subsequent dysmorph ogenesis is discussed. (C) 1997 Wiley-Liss, Inc.