In 2003, the National Institutes of Health (NIH) developed the Rare Diseases Clinical Research Network (RDCRN) in order to promote and fund research on rare diseases.  Dr. Mark L. Batshaw of Children’s National Medical Center was awarded one of the original grants to study urea cycle disorders.  As a result, the Urea Cycle Disorders Consortium (UCDC) was established as part of the national network of the RDCRN.  The purpose of the UCDC is to perform cutting-edge clinical research into the causes and treatment of urea cycle disorders.  The UCDC includes a team of doctors, nurses, research coordinators and research laboratories throughout the United States, working together and in close collaboration with the National Urea Cycle Disorders Foundation to ensure that the needs and wishes of the patients and families are met as we strive to improve their lives and learn more about urea cycle disorders. The UCDC now consists of eight academic centers, headed by national experts in the field of urea cycle research and treatment:

Children’s National Medical Center, Washington, D.C. (Mark Batshaw, M.D., Mendel Tuchman, M.D.)
Children’s Hospital of Philadelphia, Philadelphia, PA (Marc Yudkoff, M.D)
Baylor College of Medicine (Brendan Lee, M.D.)
University of California at Los Angeles (UCLA), Los Angeles, CA (Stephen Cederbaum, M.D.)
Yale University School of Medicine, New Haven, CT (Gretta Seashore, M.D.)
Vanderbilt University Medical Center, Nashville, TN (Marshall Summar, M.D.)
Mount Sinai School of Medicine, New York, NY (George Diaz, M.D.)
Rainbow and Babies Hospital, Cleveland, OH (Douglas Kerr, M.D.)

As a first step to research that will lead to a better understanding the nature of these disorders, the UCDC has established a Research Registry for patients.  This Research Registry was created to inform patients and parents of patients about clinical research studies being performed by the UCDC.  If you choose to join the Research Registry, you will be notified about new research studies you are or child are eligible to participate in.  You may then contact the UCDC researcher directly if you are interested in participating in that study.  For more information, click UCDC RESEARCH REGISTRY.

Over the past two years the UCDC has been developing a number of critical research studies, including:

Longitudinal Study of Urea Cycle Disorders:  The goal of the Longitudinal Study is to improve the treatment and overall health of persons with UCD by collecting information on the growth and development of the study participants over time.  Participation in this study is critical; the more information that is collected, the better we will be able to understand the disorders, how they affect patients and families, and how treatment and short and long-term outcomes can be improved. The Longitudinal Study will attempt to determine:

	How effective are the different treatments and diets that are currently in use and are there better treatments that could be used?
	What are the triggers that lead to hyperammonemia and subsequent hospital stays?
	Which of the biochemical laboratory tests commonly ordered during a metabolic clinic visit are the best at determining the severity of the urea cycle disorder?
	How common are hyperammonemic episodes, developmental disabilities and various other long-term health concerns for people with UCD?
	How common are the different UCDs in the general population (incidence and prevalence)?
	How do persons with UCD and family members cope with the disease and how can their physicians improve the coping process?

After enrolling in the Research Registry, if a parent/individual is interested in participating in the Longitudinal Study, the individual/parent will be screened by telephone to make sure that the potential participant is definitely diagnosed with a UCD.  Once eligibility is confirmed, the individual will be asked to visit one of the eight UCDC sites for an initial study visit.  Follow-up visits will be arranged at the participant’s local metabolic physician’s office if possible.  Participants will return to the UCDC center for a study visit every three to six months, depending on their age.  Study visits will be very similar to any regular metabolic clinic visit.  Participants and their families will be asked to provide information about the participant’s medical history and family history.  A physical examination will be done and blood and urine will be collected for standard biochemical studies, and a small blood sample will be sent to Vanderbilt University to study the level of phenylacetate and phenylbutyrate if the participant takes Buphenyl.  Parents/guardians/individuals will be asked to fill out a brief questionnaire about how their daily life is going.  Participants will also undergo neuropsychological testing at 6 and 18 months old, and at ages 4, 8, 15 and 18 years old.  This testing is used to identify differences in how a person’s brain processes information and learns.  Some of these processes include how well a person can solve problems, how well language is expressed or understood, memory and attention, and ability to plan and organize.  This information will assist researchers in understanding the effects of UCD on brain function and in developing new treatments and therapies to improve the lives of patients.

Neuroimaging Study - Mechanisms of Brain Injury in Inborn Errors of Metabolism:  Many inborn errors of metabolism, including urea cycle disorders, are associated with irreversible brain injury.  It is not clear how metabolite intoxication or depletion of substrates accounts for the specific cognitive and neurologic findings observed in patients with UCDs.  Neuroimaging is a powerful diagnostic and research tool which can provide information about the timing, extent, reversibility, and possible mechanism of neural injury in a non-invasive manner.  The goal of the study is to use neuroimaging (MRI, fMRI, MRS) to improve understanding of underlying neural mechanisms that contribute to cognitive, pathologic (white matter disturbances) and metabolic abnormalities observed in OTC deficiency by evaluating heterozygous female carriers and late onset males.  Research will also focus on:

	Ammonia, a well recognized neurotoxin, and the manner in which it exerts effects on the central nervous system (CNS).
	Effects of acute versus chronic hyperammonemia at the cell and neurocircuitry level.
	Role of glutamine in hyperammonemic encephalopathy (rise in plasma glutamine levels preceding hyperammonemia; difference between plasma levels and CNS levels; why is glutamine chronically elevated in brain even with normal ammonia levels).
	Determine patterns of neuroanatomic damage in OTCD, and examine neural mechanism of cognitive and motor system abnormalities.

Participants in the study will be required to travel to the study site at Children’s National Medical Center, provide a 3-day diet history, undergo physical and neurological examinations and laboratory testing (ammonia, plasma amino acids, urine organic acids) and MRI scanning.

N-carbamylglutamate (NCLG) treatment in N-acetylglutamate synthetase deficiency (NAGS) and partial carbamoylphosphate synthetase deficiency (CPS):  This recent study showed Carbaglu® to be effective and/or curative for NAGS deficiency in limited patient studies. This research study is now being expanded to partial CPS deficiency, and two other inborn errors of metabolism, propionic acidemia and methylmalonic aciduria.  The study measures the effect of the medication Carbaglu on the rate at which the body converts ammonia into urea (ureagenesis).  Participants must travel to study site.  Participants will be studied twice, off NCLG, and three days following oral administration of the drug.  A labeled stable isotope will be administered to the participant and blood samples will be obtained at several time intervals. (M. Tuchman, Potential cure for N-acetylglutamate deficiency with N-carbamylglutamate. NUCDF Newsletter Vol XIV 2005; L. Caldovic, H. Marizono, Y. Daikhn, I. Nissim, R. McCarter, M. Yudkoff, M. Tuchman, Restoration of ureagenesis in N-acetylglutamate synthetase deficiency by N-carbamylglutamate. J Pediatr 2004; 145:552-4; Help Isn’t Just for Kids at Children’s, Washington Post 12/28/05)

Phase III, Open-Label Study Using Buphenyl in Argininosuccinic Aciduria (ASA):  Unlike the other urea cycle disorders, ASA can cause liver damage or hepatitis leading to liver failure.  The cause of this damage is not known.  Since argininosuccinic acid is found in this disorder and not the other urea cycle disorders, it is theorized that it may be the toxic substance causing liver damage.  The study would test the effects of sodium phenylbutyrate (Buphenyl™) treatment on the frequency of hyperammonemia and magnitude of hepatic transaminase, argininosuccinate and citrulline levels in patients with argininosuccinic aciduria (ASA). The research study is sponsored by Ucyclyd Pharma, manufacturer of Buphenyl.

Participants must have a confirmed diagnosis of ASA and be between 1 and 21 years old.  Participants must travel to Baylor College of Medicine in Houston, Texas, for initial evaluation and every six months thereafter.  Laboratory studies (including liver function, phenylbutyrate and phenylacetate levels) will be monitored every two months.

Other UCD research projects at Baylor College of Medicine (if you are interested in participating in any of these Baylor studies, please contact Susan Carter, R.N., Research Coordinator, scarter@bcm.tmc.edu or 832-822-1630):

	Use of stable isotope tracer techniques to understand the metabolism of urea and protein in patients with UCDs.
	Ongoing studies comparing the effectiveness of sodium benzoate to sodium phenylbutyrate, the two primary alternative pathway medications for UCDs.
	Study of the metabolism of branched chain amino acids (isoleucine, valine, leucine) and need for supplementation in persons taking sodium phenylbutyrate.  (F. Scaglia, S. Carter, WE O’Brien, B. Lee, Effect of alternative pathway therapy on branched chain amino acid metabolism in urea cycle disorder patients.  Molecular Genetics and Metabolism 82 (2004) S79-85).
	Effect of UCDs on the metabolism of arginine and nitric oxide.  Arginine is one of the primary products of the urea cycle, and it is important in the generation of nitric oxide, a very important molecule that has been implicated in many biological process including controlling blood pressure, immunity, and degeneration of brain cells.  The study will focus on nitric oxide metabolism using stable isotope tracer techniques in patients with Argininemia and Argininosuccinic aciduria to determine whether disturbances of nitric oxide metabolism may explain some of the complex manifestations of UCDs that are not directly related to hyperammonemia.  Recruitment early 2006.