Drug Combo Overcoming Rare Genetic Disorders

84% now survive urea cycle dysfunction, which causes toxic buildup of ammonia

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HealthDay Reporter

WEDNESDAY, May 30, 2007 (HealthDay News) -- Doctors are recording a remarkable victory over a set of rare but potentially fatal inherited conditions affecting what's known as the urea cycle.

That cycle uses six enzymes to get rid of the nitrogen that builds up as the body processes proteins and other chemicals. If something goes wrong with any one of those enzymes, "after a certain point, you get ammonia, which is very damaging to the brain," explained said Dr. Ada Hamosh, clinical director of the Johns Hopkins University Institute of Genetic Medicine.

She's the lead author of a report that found that people with these conditions now experienced a 25-year survival rate of 84 percent.

The findings are published in the May 31 New England Journal of Medicine.

Estimates of the incidence of urea cycle disorders range from 1 in 3,000 births to 1 in 40,000 births. Because such disorders can be difficult to diagnose, and because patients die early, "we can't really get good incidence data," Hamosh noted.

One indication of the rarity of the disorder is the fact that the 100 hospitals involved in the study accumulated just 299 cases over the quarter-century of the study.

There was one key development boosting the effective treatment of urea cycle disorders, Hamosh said. In 1979, a researcher, Dr. Saul W. Brusilow, a Baltimore pediatrician, "had the really brilliant and very elegant idea of using the body's own methods of getting rid of the extra nitrogen," she said. Brusilow was then at Hopkins and has since retired.

The treatment uses a combination of two chemicals -- sodium phenylacetate and sodium benzoate -- delivered intravenously to bring down ammonia levels.

"Those two chemicals had been used for many years," said Dr. Gregory M. Enns, director of the biochemical genetics program at Stanford University and another author of the paper. "Dr. Brusilow had the vision to combine them. The beauty of these compounds is that they work by shunting ammonia away from the urea cycle, shunting nitrogen out of the body. Instead of having urea come into the liver, the medications shunt it away."

Other treatments, including kidney dialysis, can also be used. In very severe cases of the condition, "the standard of care now is to get the young patients big enough for a liver transplant," Hamosh said. Persons with mild forms of the disorders can survive for many years on the two medications, which now are available in a combination product approved by the U.S. Food and Drug Administration.

"The data set in this paper is what was presented to get FDA approval of the drug," Hamosh said. The paper was published in the journal this week because of a report from Europe two years ago that showed worse results there than in the United States, indicating that some doctors were not familiar with the treatment, she said.

There are indications that cases are still being missed in the United States as well, because of the elusive nature of the disorder, Enns said. Often, there is no specific set of symptoms that mark a child with a disorder of the urea cycle, he said, "and in my personal experience, the thing that makes the most difference is to identify it quickly."

If tests show that a child is carrying high levels of ammonia, "you typically start [him or her] on medication," Enns said. "If the ammonia level comes down nicely, that often is enough, with no need for dialysis."

More information

More information on urea cycle disorders is available at the National Urea Cycle Disorders Foundation.

SOURCES: Ada Hamosh, M.D., clinical director, Johns Hopkins University Institute of Genetic Medicine, Baltimore; Gregory M. Enns, M.D., director, Stanford University biochemical genetic progrgam, Stanford, Calif; May 31, 2007, New England Journal of Medicine

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