Inborn errors of cholesterol biosynthesis.

Abstract

Disorders of cholesterol biosynthesis have recently emerged as important errors of metabolism that collectively have taught us many new genetic and biochemical lessons. Whereas most metabolic diseases are characterized by exclusively or largely postnatal biochemical toxicities or deficiencies, disorders of cholesterol biosynthesis are notable for their severe effects on prenatal development. The remarkable embryonic consequences of abnormal cholesterol biosynthesis are exemplified by Smith-Lemli-Opitz syndrome (SLOS), a well-known multiple congenital anomaly syndrome only recently discovered to be caused by a deficiency in the last step in cholesterol biosynthesis. Equally surprising has been the discovery that primary defects of cholesterol biosynthesis cause several different forms of congenital skeletal dysplasia, most notably X-linked dominant chondrodysplasia punctata, or Conradi-Hünermann syndrome. Yet another sterol disorder, desmosterolosis, caused by defective activity of desmosterol reductase, combines a severe osteosclerotic skeletal dysplasia with multiple embryonic malformations similar to those of SLOS. The discovery of the biochemical basis of these diverse genetic disorders has provided not only accurate biochemical methods for their diagnosis and prenatal diagnosis, but also new insights into the biochemistry of vertebrate embryonic development. Among the lessons we have learned from the study of inborn errors of cholesterol biosynthesis, one of the most important is that the abnormal cholesterol metabolism of SLOS impairs the function of "Sonic hedgehog" and other related embryonic "signaling proteins" that help determine the vertebrate body plan during the earliest weeks of embryonic development. Most significant clinically has been the realization that many of the postnatal clinical problems of patients with SLOS are direct consequences of the inability to synthesize the large amounts of cholesterol needed for growth and for the synthesis of compounds derived from cholesterol, such as steroid hormones. In addition to the important finding that supplementary cholesterol eliminates or ameliorates many of the feeding and growth problems of SLOS, the discovery that the autistic behaviors of children with SLOS can be reduced or even eliminated by treatment with supplementary dietary cholesterol has been one of the most startling. Moreover, clinical and basic research on prenatal cholesterol nutrition in SLOS and various animal model systems has delineated a previously unrecognized system for the delivery of low-density lipoprotein cholesterol from the mother to the developing embryo. The many discoveries engendered by these experiments of nature argue that there are heretofore unrecognized beneficial effects of cholesterol, especially in children, and that we should consider very carefully possible adverse effects that the popular war against cholesterol may have on the prenatal and postnatal development of children.