Urea cycle disorders (UCD) are a group of genetic diseases that prevent the body from safely detoxifying ammonia. Ammonia is produced by natural turnover of proteins and nucleic acids in our bodies as well as by the breakdown of dietary proteins. When ammonia levels are elevated in the blood, it triggers swelling of the brain, which can lead to cognitive impairment, coma and death. The urea cycle genes and proteins form a metabolic pathway that begin with ammonia, and after a series of steps, produce urea, which can be safely excreted.
Children’s National is considered the world leader in the diagnosis, treatment, and research of urea cycle disorders with three renowned experts in this field. Mendel Tuchman, MD, Mark Batshaw, MD, and Marshall Summar, MD, lead nation-wide research and clinical programs for these disorders. The Center for Genetic Medicine Research and the Center for Translational Science continue to collaborate on the NIH-funded Rare Diseases Clinical Research Center for the study of UCD. This Center is following more than 500 individuals with UCD in 15 sites across the U.S., Canada, and Europe in a 5-10 year longitudinal study to understand the medical and cognitive outcome of these devastating disorders. The UCD program is also collaborating with several biotechnology and pharmaceutical companies to test new treatments for these disorders.
Our research is in the following areas:
- Characterization of nitrogen metabolism. We are searching for the “nitrogen sensor,” the biomolecule or regulatory network that regulates ureagenesis in response to changes in the amount of ammonia produced in our bodies. We are studying how the expression of urea cycle enzymes and the body’s ability to detoxify ammonia are affected when there is excessive breakdown of cellular proteins or high protein diet.
- Effects of genotype on the phenotype of patients with urea cycle disorders. Patient data helps us to understand how different mutations can have different severity and effects. The Urea Cycle Disorders Consortium, part of the NIH sponsored Rare Disease Network, is a multi-institution research team that is systematically coordinating clinical trials, and best practices for treating patients with urea cycle disorders.
- Carbamylglutamate therapy for urea cycle defects. Carbamylglutamate is a chemical analog of NAG that can activate CPS1 and restore ureagenesis in patients with a deficient NAGS. We are examining the effectiveness of carbamylglutamate at increasing urea production in patients with hyperammonemia.
- Gene therapy for urea cycle disorders. Gene therapy is used to introduce a healthy copy of a gene into a patient with a defect in that gene. For patients with severe ornithine transcarbamylase deficiency, liver transplantation is recommended, with all of its associated risks and shortcomings. We are using adeno-associated viral vectors to treat ornithine transcarbamylase deficiency in a mouse model of the disease. The objectives are to show the efficacy and safety of the vector so that it may be eventually used to stabilize patients to reduce the number of hyperammonemic episodes while they await transplantation.
Discoveries by our research includes:
The discovery, cloning, and characterization of the vertebrate NAGS gene, the last gene of the urea cycle to be found. This allowed us to perform and report the first molecular diagnosis of a patient with NAGS deficiency. Discovery of a family of novel bifunctional NAGS-kinase, and two new transcarbamylase families used by special classes of bacteria for arginine biosynthesis. These discoveries have implications for the origins and evolution of the urea cycle. X-ray crystallography is another approach that yielded a number of “firsts” for researchers in the Center including the first X-ray crystallographic structures of a vertebrate OTCase, the first structures of novel transcarbamylases, and the first crystal structures of NAGS.
Faculty interests in urea cycle disorders include:
Urea Cycle Disorders Institute
N-acetylglutamate synthetase (NAGS)
Ornithine transcarbamylase (OTC)