Each year, an estimated 1 in 50,000 babies in this country are born with Smith-Lemli-Optiz syndrome (SLOS), a syndrome of severe bone malformation, food intolerance and susceptibility to infection caused by a genetic defect in cholesterol metabolism.

Children with SLOS have extremely low blood levels of cholesterol and high levels of a precursor to cholesterol called 7-dehydrocholesterol (DHC), but the mechanism of cholesterol's involvement in the syndrome has not been clear. A new study supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) and the National Institute of Child Health and Human Development (NICHD) not only offers new insight into that mechanism, but also provides clues that could change and improve the way certain manifestations of the syndrome are treated.

Juan Rivera, Ph.D., director of the NIAMS Office of Science and Technology and chief of the Molecular Inflammation Section, became interested in SLOS because his lab had been studying a type of inflammatory cell called a mast cell, the principal cell in triggering allergies, including food intolerances. In previous studies, his group had found that cholesterol is a key component in mast cells' ability to initiate signals that tell other inflammatory cells to either rev up or slow down. "We made the hypothesis that one of the issues related to the food intolerance is that these mast cells are somewhat more hyper-responsive in these individuals and that led them to being easily triggered," he says.

Their hunch was right. Their subsequent studies, in collaboration with NICHD's Forbes D. Porter, M.D., Ph.D., have basically demonstrated that mast cells of a mouse model of SLOS are trigger-happy, he says. They have also shown that the accumulation of dehydrocholesterol is largely to blame. Normally, cholesterol on the cells' membranes helps regulate the inflammatory process, but in children with a mutation in the gene for 3Β-hydroxysterol Δ7 reductase, an enzyme that reduces dehydrocholesterol to cholesterol, dehydrocholesterol accumulates on the mast cell membranes, causing the cells to be more easily activated. Thus, something innocuous to most people - food, for example - sets off an immune reaction in a child with SLOS.

Rivera's research demonstrates for the first time that there is an immune function dysregulation in SLOS. "What's important about this is that it makes us rethink the therapeutic strategy for treating these individuals," he says. Traditionally, children were treated with high-cholesterol diets and supplements to increase blood levels of cholesterol, he explains. But a more appropriate therapy might be one that reduces dehydrocholesterol that accumulates on inflammatory cell membranes causing them to overreact.

Ironically, the solution to this low-cholesterol disease could be drugs that are marketed now to lower cholesterol. The reason is that some of these drugs may work in part by targeting the dehydrocholesterol that is needed to produce cholesterol. If further tests show that's the case, treatment with cholesterol-lowering drugs - along with a high-cholesterol diet and supplement to raise cholesterol levels - might help restore normal cellular responses to external signals that are normally mediated through cholesterol-rich areas in the cells' membranes.

"In a sense, we are treating symptoms at the moment," Dr. Rivera says. "This would allow us to treat the cause."

The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the Department of Health and Human Services' National Institutes of Health, is to support research into the causes, treatment, and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases. For more information about NIAMS, call the information clearinghouse at (301) 495-4484 or (877)22-NIAMS (free call) or visit the NIAMS Web site at http://www.niams.nih.gov


Kovarova M, et al. Cholesterol deficiency in a mouse model of Smith-Lemli-Opitz syndrome reveals increased mast cell responsiveness. J Exp Med2006;203:1161-1171.

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