This Article  • Full text  • PDF  • Reply to article  • Send to a friend  • Save in My Folder  • Save to citation manager  • Permissions  Citing Articles  • Citation map  • Citing articles on HighWire  • Citing articles on ISI (11)  • Contact me when this article is cited  Related Content  • Similar articles in this journal  Topic Collections  • Retinal/ Chorioretinal Disorders  • Alert me on articles by topic  Social Bookmarking   What's this?

Electrophysiologic, Biochemical, and Morphologic Features

Steven J. Fliesler, PhD; Neal S. Peachey, PhD; Michael J. Richards, BA; Barbara A. Nagel, BA, MS; Dana K. Vaughan, PhD

Arch Ophthalmol. 2004;122:1190-1200.

Objective  To assess the electrophysiologic, histologic, and biochemical features of an animal model of Smith-Lemli-Opitz syndrome (SLOS).

Methods  Sprague-Dawley rats were treated with AY9944, a selective inhibitor of 3-hydroxysterol-⁷-reductase (the affected enzyme in SLOS). Dark- and light-adapted electroretinograms were obtained from treated and control animals. From each animal, 1 retina was analyzed by microscopy, and the contralateral retina plus serum samples were analyzed for sterol composition. The main outcome measures were rod and cone electroretinographic amplitudes and implicit times, outer nuclear layer (ONL) thickness, rod outer segment length, pyknotic ONL nucleus counts, and the 7-dehydrocholesterol/cholesterol mole ratio in the retina and serum.

Results  By 10 weeks' postnatal age, rod and cone electroretinographic wave amplitudes in AY9944-treated animals were significantly reduced and implicit times were significantly increased relative to controls. Maximal rod photoresponse and gain values were reduced approximately 2-fold in treated animals relative to controls. The ONL thickness and average rod outer segment length were reduced by approximately 18% and 33%, respectively, and ONL pyknotic nucleus counts were approximately 4.5-fold greater in treated animals relative to controls. The retinal pigment epithelium of treated animals contained massive amounts of membranous/lipid inclusions not routinely observed in controls. The 7-dehydrocholesterol/cholesterol mole ratios in treated retinas and serum samples were approximately 5:1 and 9:1, respectively, whereas the ratios in control tissues were essentially zero.

Conclusions  This rodent model exhibits the key biochemical hallmarks associated with SLOS and displays electrophysiologic deficits comparable to or greater than those observed in the human disease.

Clinical Relevance  These results predict retinal degeneration in patients with SLOS, particularly those with the more severe (type II) form of the disease, and may be more broadly relevant to other inborn errors of cholesterol biosynthesis. This animal model may also be of use in evaluating therapeutic treatments for SLOS and in understanding the slow phototransduction kinetics observed in patients with SLOS.

From the Departments of Ophthalmology (Dr Fliesler, Mr Richards, and Ms Nagel) and Pharmacological and Physiological Sciences (Dr Fliesler), Saint Louis University School of Medicine, St Louis, Mo; Cleveland Veterans Administration Medical Center (Dr Peachey) and Cole Eye Institute, The Cleveland Clinic Foundation, (Dr Peachey), Cleveland, Ohio; and the Department of Biology, University of Wisconsin–Oshkosh (Dr Vaughan). The authors have no relevant financial interest in this article.

CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati     What's this?

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES

Age-Related Cone Abnormalities in Zebrafish with Genetic Lesions in Sonic Hedgehog
Stenkamp et al.
IOVS 2008;49:4631-4640.
ABSTRACT | FULL TEXT  

Alteration of retinal rod outer segment membrane fluidity in a rat model of Smith-Lemli-Opitz syndrome
Boesze-Battaglia et al.
J. Lipid Res. 2008;49:1488-1499.
ABSTRACT | FULL TEXT