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D.K. Vaughan, D.J. Slotten, M.J. Richards, B.A. Nagel, N.S. Peachey, S.J. Fliesler; Effects of Fat-Soluble Vitamins and Cholesterol Supplementation on Retinal Structure and Function in an Animal Model of Smith-Lemli-Opitz Syndrome . Invest. Ophthalmol. Vis. Sci. 2003;44(13):3596.
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Purpose: Patients afflicted with Smith-Lemli-Opitz syndrome (SLOS, an autosomal recessive metabolic disease caused by defective cholesterol biosynthesis) have abnormally low levels of cholesterol (Chol) and excessive levels of 7-dehydrocholesterol (7DHC) in all bodily tissues. The sterol metabolic defect is accompanied by inefficient absorption of dietary fat-soluble compounds (e.g., vitamins and sterols). We evaluated the ability of systemically administered fat-soluble vitamins and/or Chol to ameliorate or prevent retinal degeneration in a rat model of SLOS. Methods: Pregnant Sprague-Dawley rats (6 days sperm-positive; N=8) were given AY9944 (an inhibitor of the defective enzyme in SLOS) in their diet and their progeny were injected 3X per wk with AY9944 as an aqueous-olive oil emulsion (Fliesler et al., IOVS 40:1792, 1999). In parallel, 2 control groups received vehicle injections only and no drug. Four drug treatment groups were established, according to supplementation of the vehicle with: A) no additions; B) vitamins A, D, and E; C) 2% (w/v) Chol; D) vitamins plus Chol. Rats were maintained under dim cyclic light (12L:12D, 20-40 lux) and fed Chol-free chow and water ad lib. At 9 postnatal weeks, dark- and light-adapted ERGs were recorded; one eye from each rat was taken for histological and quantitative morphometric analysis, while the contralateral retina, as well as serum, liver, and brain, were harvested for sterol analysis. Results: 7DHC/Chol mole ratio values for retinas from all treatment groups were comparable, and were >500X higher than for control retinas. Rod and cone function were markedly compromised (decreased amplitudes, increased implicit times), relative to controls, and retinal degeneration (particularly photoreceptor loss) was substantial and comparable in all treatment groups. Conclusions: Under the given conditions, systemic administration of fat-soluble vitamins (A, D, E) and/or Chol does not ameliorate or prevent retinal degeneration in this animal model of SLOS. Higher concentrations of these supplements, in combination with dietary administration, may be required to overcome the cholesterol biosynthesis defect and reduce the severity of the associated retinal degeneration and dysfunction.
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