Second NIH Conference on SLO/RSH Syndrome

Not long after the joint SLO/RSH research and family meeting held in Baltimore last June, most of the scientists who attended that meeting plus an equal number of "new recruits" to SLO/RSH research met again in Bethesda, MD, on September 26th and 27th for the Second NIH Conference on SLO/RSH syndrome. In this larger forum, more than thirty scientists and clinicians - about the twice the number who attended the first NIH Conference in 1993 - had the opportunity to discuss many different aspects of the genetics and biochemistry of SLO/RSH syndrome. Dr. John Opitz, who chaired the NIH Meeting, is currently preparing a special section of the American Journal of Medical Genetics that will contain many of the papers and abstracts from the Bethesda meeting. The brief synopsis of the meeting that follows should give a good picture of the scientific forces that have gathered to help solve the many questions that the recent biochemical discoveries in SLO/RSH syndrome have raised.

For many, isolation of the gene responsible for SLO/RSH syndrome is the most important immediate goal for SLO/RSH research. Dr. Margaret Wallace (University of South Florida) described her laboratory's many efforts toward this goal. Having recently isolated a relatively large piece of DNA from the suspected location of the SLO/RSH gene on the long arm of chromosome #7, Dr. Wallace and her colleagues have set about analyzing the specific genes contained in that segment. This can be a tedious process, but Dr. Wallace's group is making good progress and it is only a matter of time before the right gene is identified. Dr. James Metherall (University of Utah) presented some of his own work on the search for the SLO/RSH gene among the genes for a group of proteins that serve to move cholesterol within cells. Once these investigators have the SLO/RSH gene in hand, many new avenues of SLO/RSH research will open.

The basics of cholesterol biochemistry in SLO/RSH syndrome was another major focus of the meeting. Some of the topic discussed included sterol chemistry in cultured cells (Dr. Sankhavarum Panini, Roosevelt Institute, Denver), cholesterol metabolism in the brain (Dr. Pierre Morell, University of North Carolina; and Dr. William Conner, Oregon Health Sciences University), and cholesterol transport in cells (Dr. Metherall) Drs. Stephen Tint, Sarah Shefer, Ashok Batta, and Gerald Salen (East Orange, New Jersey), the discoverers of the cholesterol defect in SLO/RSH syndrome, presented their extensive work characterizing the enzymatic deficiency in SLO/RSH syndrome. Dr. Salen also described a very important series of experiments designed to test different possible therapies for SLO/RSH syndrome (cholesterol vs. cholesterol + bile salts) using a rat model of SLO/RSH syndrome produced by treating rats with a medication that inhibits the enzyme believed to be deficient in SLO/RSH syndrome. The results of Dr. Salen's studies will be most important for the future design of diets and medications for treatment of SLO/RSH syndrome

Dr. Richard Kelley (Kennedy Krieger Institute, Baltimore) reported on the results of a SLO/RSH syndrome carrier test that was developed using the many blood samples contributed by SLO/RSH children and parents at the Baltimore meeting. Dr. Kelley was able to show that all of the parents had levels of 7&endash;dehydrocholesterol in their cultured white blood cells that were significantly increased compared to cells of individuals with no family history of SLO/RSH syndrome. This test should be most useful for testing parents of SLO/RSH children who died before 1993, when biochemical diagnosis of SLO/RSH syndrome first became possible. A reliable carrier test for SLO/RSH syndrome is important for genetic counseling because, as also shown at the Bethesda meeting, up to 25% of patients given a clinical diagnosis of SLO/RSH syndrome may not have the abnormal of cholesterol metabolism that we now equate with SLO/RSH syndrome.

To close the NIH conference, Drs. Diane Abuelo (Providence, RI), Mira Irons, Ellen Elias (New England Medical Center), Ngozi Nwokoro (Cleft Palate-Craniofacial Center, Pittsburgh), and Elizabeth McPherson (Magee Women's Hospital, Pittsburgh) presented a comprehensive review of their experiences with dietary therapy for SLO/RSH syndrome. Treatment with dietary cholesterol has now extended to almost three years for some patients. Although the benefits of cholesterol treatment appear to be unmistakable - improved growth, reduced skin sensitivity, better behavior - there is less certainty about the best way to supply the cholesterol and whether or not other supplements, such as bile salts, provide additional benefits. Part of the uncertainly derived from the recognition that blood cholesterol levels may have little correlation with the delivery of cholesterol to the tissues where it is needed. For example, some children with SLO/RSH syndrome have grown rapidly immediately after beginning supplementation with cholesterol while their blood cholesterol and 7&endash;dehydrocholesterol levels have remained essentially unchanged. Supplementation with bile salts appears to be associated with significantly higher blood cholesterol levels in some patients but not necessarily with more rapid growth or faster improvement in other areas. Several of the scientists pointed out that another cause of higher blood cholesterol levels could be an inhibition of cholesterol "transport," i.e., an interference in movement of dietary cholesterol in lipoprotein particles from the blood into the tissues. Until we know more about cholesterol nutrition in RSH/SLO syndrome, they cautioned against placing too much importance on the change or lack of change in the blood cholesterol levels in the SLO/RSH patients on any of the several treatment protocols. Some of these more important questions about treatment of SLO/RSH syndrome were also discussed in Minneapolis at the October meeting of the American Society of Human Genetics, where plans were completed to coordinate the individual treatment protocols so that the maximum amount of information can be shared among the several clinical research groups. Details about the protocols are available from any of the principal investigators (Drs. Irons/Elias, Nwokoro, or Kelley).

Other Research News

Prior to the discovery of the sterol abnormalities in SLO/RSH syndrome, the diagnosis of the syndrome could only be made in those children who physically resembled the patients first described by Smith, Lemli, and Opitz. With the availability of a biochemical test for SLO/RSH syndrome, however, the diagnosis can now be confirmed or rejected with a simple blood sample. Since 1993, a biochemical diagnosis of SLO/RSH syndrome has been made in an unusual variety of clinical conditions - both severe and mild - not previously recognized as variants of SLO/RSH syndrome. For example, SLO/RSH syndrome was diagnosed the last year in several stillborn fetuses with severe physical abnormalities, such as massive edema or absent fingers, not heretofore associated with SLO/RSH syndrome. Another disorder that has come to light as a presentation of SLO/RSH syndrome is fatal liver cirrhosis in the newborn period, a condition that in the past has gone unexplained in most cases. At the other clinical extreme, children with typical biochemical findings of SLO/RSH syndrome but almost normal development and an absence of malformations other than 2/3 toe syndactyly have been found. Two of these mildly affected children have had completely normal blood cholesterol levels but diagnostically increased 7&endash;dehydrocholesterol levels at birth. This rapidly expanding spectrum of clinical presentations of SLO/RSH syndrome confirms the suspicions of Dr. Opitz and other geneticists that SLO/RSH syndrome is one of the most common autosomal recessive genetic disorders.

In addition to the work of many US investigators described above, physicians in England, Europe, and elsewhere have begun treatment programs and clinical research on SLO/RSH syndrome. Laboratories in England, The Netherlands, Sweden, Finland, Israel, and Belgium, among others, have now set up the methods for biochemical diagnosis of SLO/RSH syndrome and are finding the same high incidence of the syndrome. Dr. Raoul Hennekam (Amsterdam), who attended the Baltimore SLO/RSH meeting, has been coordinating much of the European work and has also collaborated with Drs. Chris Cunniff (Tucson, AZ) and Richard Kelley in developing a new severity scoring system for SLO/RSH syndrome. The scoring system will be used for correlating clinical and laboratory data with the intrinsic severity of the highly variable disorder that we now recognize SLO/RSH syndrome to be.

SLO/RSH Research in 1996

We are hopeful that 1996 will see great progress in the quest to isolate the SLO/RSH gene. Many physicians have already contributed patient DNA samples to Dr. Wallace for her DNA studies, but DNA samples from additional families are needed by Dr. Wallace, especially from families with two or more affected children. Any family that is able to help should contact their geneticist or other physician to arrange to have samples for DNA testing sent to Dr. Wallace. If cell cultures have already been established, the cells can usually be recovered from freezer storage and forwarded to Dr. Wallace without difficulty.

Late in January, the Kennedy Krieger Institute received notification of a grant award from the National Organization of Rare Diseases ("NORD") for the study of SLO/RSH syndrome. This grant will pay for many of the costs for treatment and monitoring of treatment for children with SLO/RSH syndrome. The project will also benefit from the resources of the Johns Hopkins Pediatric Clinical Research Center, where patients in the central Atlantic region can be evaluated. For information about this study, please contact Dr. Kelley.

Richard I. Kelley, M.D., Ph.D.
Kennedy Krieger Institute

February 7, 1996