Cholesterol metabolism in the RSH/Smith‐Lemli‐Opitz syndrome: Summary of an NICHD conference

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Abstract
During the evolution of multicellularity and attendant processes of development, cholesterol played a key role in the formation of the plasma membrane and outer mitochondrial membrane of every cell in the organism. Later functions include pivotal involvement in steroid, bile acid, and vitamin D metabolism and myelination of the nervous system. In the CNS myelination does not begin until the third trimester, and subcortical myelination not until after birth. The cholesterol of the cell membrane of the ovum is maternally derived. It is not known when the zygote begins making its own cholesterol during morphogenesis and histogenesis, but it must occur early to keep up with the dramatic rate of cell division in the embryo. Thus, it is a startling surprise that human embryos and fetuses apparently able to synthesize little cholesterol (because of a presumed defect of the Δ5,7‐sterol, Δ7‐reductase that converts 7‐dehydrocholesterol (7‐DHC) into cholesterol) frequently live to term and, rarely, may be so mildly affected as to attend school with only mild MR. The discovery by G. Stephen Tint and his co‐workers of the apparent 7‐DHC reductase deficiency makes the RSH (Smith‐Lemli‐Opitz) syndrome the first true metabolic malformation syndrome. A teratological animal model which has been known for 30 years now appears applicable to the RSH/SLO syndrome. A multidisciplinary NICHD conference held on September 20–21, 1993 reviewed the numerous implications of this discovery and agreed unanimously that research in this field be given highest priority in order to better understand cholesterol synthesis in the mammalian brain, cholesterol transport from mother to embryo and fetus, pre‐and postnatal metabolic compensation in structure and function for a profound block in cholesterol synthesis, the nature of the blood–brain barrier for cholesterol, treatment of affected infants, children, and adults, structure and genetic specification of a 7‐DHC reductase enzyme (which has never been purified!) and its evolution, the variability of the syndrome and whether it is genetically homo‐ or heterogeneous, the population genetics of the RSH syndrome, possible selective advantages (or disadvantages) of heterozygotes, and means of newborn screening, carrier detection, and prenatal diagnosis.