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Cholesterol and development: the RSH ("Smith-Lemli-Opitz") syndrome and related conditions
John M Opitz1, Enid Gilbert-Barness, Jeanie Ackerman
1Pediatrics (Division of Medical Genetics), University of Utah, Salt Lake City, 84132, USA. john.opitz@hsc.utah.edu
Insights
Infants deprived of breast milk may lack essential cholesterol for development. Genetic defects in cholesterol synthesis, like Smith-Lemli-Opitz syndrome, cause severe developmental issues, highlighting the need for early diagnosis and intervention.
Area of Science:
- Biochemistry
- Developmental Biology
- Genetics
Background:
- Dietary fat discussions have historically influenced infant nutrition.
- Cholesterol is crucial for infant development, including nervous system myelination and steroid hormone synthesis.
- Breast milk is a rich source of cholesterol, while some infant formulas are deficient.
Observation:
- Infants fed cholesterol-poor formulas may not receive adequate cholesterol for critical growth periods.
- Mutations in cholesterol biosynthesis pathways during embryogenesis lead to a spectrum of severe developmental pathologies.
- Smith-Lemli-Opitz syndrome, a common cholesterol biosynthesis error, has high prenatal/perinatal mortality.
Findings:
- A significant percentage of infants with cholesterol synthesis defects experience mortality before or shortly after birth.
- Biochemical and molecular tests for 7-dehydrocholesterol and specific mutations are available for diagnosis.
- Developmental pathology is integral to identifying and managing these genetic disorders.
Implications:
- Accurate diagnosis, even post-mortem, is vital for genetic counseling and carrier detection.
- Prenatal diagnosis and intervention can improve outcomes for affected infants.
- Understanding cholesterol's role in development is key for preventive medicine and improved infant health.
Abstract:
The half-century of lipophobia in the United States may be abating with some return of sanity on the discussion of health and dietary fat [Taubes, 2001]. The youngest victims of this collective, decades long madness are those infants deprived for one reason or another of breast milk. They are unable to speak for themselves at a time of greatest need for cholesterol during growth, the most critical period of myelination of central and peripheral nervous system, formation of bone and bile, and of every steroid hormone. Some of the commercial formulas they are fed contain only 1 or 2 mg of cholesterol per 100 g edible portion contrasted with almost 14 mg in breast milk. One can only hope that the confidence in their endogenous ability to synthesize sufficient amounts of cholesterol is not misplaced. Pediatric pathology has learned that when this endogenous ability fails during embryogenesis on the basis of mutations in the postsqualene biosynthesis of cholesterol, a startling variety of developmental pathology may present itself ranging from lethal forms of "idiopathic" hydrops, microcephaly with cerebral dysgenesis and dysmyelinization, agenesis of corpus callosum, cerebellar vermis dysgenesis, cataracts, cleft palate, many different forms of congenital heart defect, pyloric stenosis and/or Hirschsprung dysganglionosis, adrenal (cortical) insufficiency, cholestatic liver disease, limb malformations, and genital ambiguity in genetic males. Population genetic considerations suggest a hypothetical birth prevalence of the RSH (so-called Smith-Lemli-Opitz) syndrome, the commonest of these Garrodian errors of cholesterol biosynthesis, of 1/2500; since only about 1/15,000 to 1/20,000 homozygotes are liveborn and biochemically confirmed, over 80% prenatal or perinatal mortality must occur and deserves the most discerning of services from birth attendants, perinatologists, neonatologists, and fetal/pediatric pathologists. An easy, reliable, economical biochemical test for the presence of 7-dehydrocholesterol is available and the commonest mutation, the IVS8-1G-->C mutation, is quickly and reliably tested for molecularly. Thus, the successful diagnosis, even after death, will contribute substantially to correct genetic counseling, carrier detection, prenatal diagnosis, and treatment in those known to be affected prenatally andplanned to be liveborn. Thus, developmental pathology plays an integral, vital role in preventive medicine.