"Patients with this disorder often spend most of their lives in restraints to prevent them from injuring themselves."
Researchers at Johns Hopkins, using high-tech medical imaging techniques, have found the suspected fingerprint of a devastating disorder that afflicts patients with uncontrollable urges to hurt themselves.
Hopkins scientists showed that brains of patients with the disorder, Lesch-Nyhan disease, may have much fewer nerve endings containing dopamine, an important chemical messenger.
The finding is an important step in developing future treatments, the researchers say. Newly developed drugs to treat other dopamine-related disorders already exist and may be useful for Lesch-Nyhan patients.
The study also may help researchers better understand the biological causes of a major behavioral problem of the severely mentally retarded.
"Many of the severely mentally retarded injure themselves," says Dean F. Wong, M.D., Ph.D., a Hopkins professor of radiology and lead author of the new study. "We're hoping that research into this rare disease may give us insights into the larger self-injurious population."
Lesch-Nyhan was first characterized at Johns Hopkins in the 1960s, when Hopkins physicians saw two brothers whose symptoms included mental retardation and self-biting--uncontrollable urges to bite their lips, fingers, tongue, arms and shoulders.
"Patients with this disorder often spend most of their lives in restraints to prevent them from injuring themselves," says James Harris, M.D., an author on the new study and director of the Hopkins Developmental Neuropsychiatry Program.
"The majority of these patients are very much aware of their predicament--the first patient I saw asked if his hands could be amputated to prevent himself from self-injury. Like many of these patients, his teeth had already been removed to prevent self-biting."
Lesch-Nyhan afflicts 1 in every 400,000 children, almost always occurring in males. Patients usually test in the mild to moderately retarded intelligence range, but some have normal intelligence levels.
In 1979, researchers at other institutions found the gene for Lesch-Nyhan on the X chromosome. Autopsies of three patients at another institution later suggested that the brains of Lesch-Nyhan patients might have unusually low levels of dopamine.
Hopkins investigators, working in conjunction with researchers at the University of North Carolina-Chapel Hill and the Montreal Neurological Institute, used positron emission tomography or PET to study brain levels of a dopamine transporter in normal adults and Lesch-Nyhan patients. The transporter recycles dopamine, removing it from its area of activity and preparing it for reuse. The Lesch-Nyhan patients had, on average, 75 percent less of the dopamine transporters in an area of the brain involved in controlling movement. This suggests they also have less dopamine in this area of the brain.
Researchers believe this dopamine reduction in Lesch-Nyhan patients changes the growth of nerve cell branches in the developing brain, mis-wiring an important area of the brain.
Drugs that affect the development of the dopamine system in early life may one day be used to ease or prevent the symptoms of Lesch-Nyhan, according to Wong.
"What still isn't clear, though, is how the Lesch-Nyhan mutation reduces dopamine levels," Harris notes. "The mutation alters an enzyme that is involved in the body's use of uric acid, causing kidney stones. We aren't sure how that metabolic alteration is linked to a reduction in dopamine levels."
To help solve this mystery, Harris is working with other researchers at Hopkins and North Carolina who have animal models of Lesch-Nyhan. In collaboration with researchers at Albert Einstein University, Harris is also looking for clues in the three-dimensional shape of the mutated Lesch-Nyhan protein.
This study was funded by a grant from the National Institute for Child Health and Development and support from the Mental Retardation Research Center, a joint Hopkins/Kennedy Krieger Institute project supported by the National Institutes of Health.
The findings are published in the May 28 issue of the Proceedings of the National Academy of Sciences. Other authors on the study were Sakkubai Naidu, Fuji Yokoi, Stefano Marenco, Robert Dannals, Hayden Ravert, Myron Yaster, Alan Evans, Olivier Rousset, R. Nick Bryan, Albert Gjedde, Michael Kuhar, and George Breese.