Longitudinal Study of Urea Cycle Disorders
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Purpose
Urea cycle disorders (UCD) are a group of rare inherited metabolism disorders. Infants and children with UCD commonly experience episodes of vomiting, lethargy, and coma. The purpose of this study is to perform a long-term analysis of a large group of individuals with various UCDs. The study will focus on the natural history, disease progression, treatment, and outcome of individuals with UCD.
| Condition | Phase |
|---|---|
|
Brain Diseases, Metabolic, Inborn Amino Acid Metabolism, Inborn Errors Urea Cycle Disorders |
Phase 2 |
| Study Type: | Observational |
| Study Design: | Observational Model: Cohort Time Perspective: Prospective |
| Official Title: | Longitudinal Study of Urea Cycle Disorders |
- Prevalence of specific morbid indicators of disease severity [ Time Frame: End of study ] [ Designated as safety issue: No ]hyperammonemia, developmental disabilities, long-term renal and hepatic effects, and case-fatality associated with the various forms of UCD
- Relationship between various biomarkers and disease severity and progression [ Time Frame: End of study ] [ Designated as safety issue: No ]correlation between glutamine, ammonia, liver function (biomarkers) and severity scale and IQ in terms of outcome
- Safety and efficacy of currently used and new UCD therapies [ Time Frame: End of study ] [ Designated as safety issue: Yes ]Interim events related to treatments (drugs, diet or liver transplant)
| Estimated Enrollment: | 1100 |
| Study Start Date: | February 2006 |
| Estimated Study Completion Date: | July 2014 |
| Estimated Primary Completion Date: | July 2014 (Final data collection date for primary outcome measure) |
Urea cycle disorders are a group of rare genetic diseases that affect how protein is broken down in the body. UCDs are caused by a deficiency in one of six enzymes or two mitochondrial membrane transporters responsible for removing ammonia, a waste product of protein metabolism, from the bloodstream. Normally, ammonia is converted into urea and then removed from the body in the form of urine. In UCDs, however, ammonia accumulates unchecked and is not removed from the body. It then reaches the brain through the blood, where it causes irreversible brain damage and/or death.
All UCDs, except for one (ornithine transcarbamylase deficiency), are inherited as recessive traits. There is a 50% risk of dying or acquiring a severe disability from UCDs, and currently therapy is considered inadequate. The purpose of this study is to perform a long-term analysis of a large group of individuals with various UCDs. Biochemical status, growth, and cognitive function will be assessed. Survival and cognitive outcome of the two most commonly used forms of treatment, alternate pathway therapy and transplantation, will be evaluated. In addition, this study will identify the biochemical changes that may predict future metabolic imbalances so that they may be corrected before clinical symptoms develop.
This observational study is funded through 2014. All participants will attend an initial study visit, which will include a medical and diet history, physical and neurological examinations, psychological testing, and blood tests. Participants will then be followed with subsequent study visits, which will last 2-3 hours each. Individuals with neonatal onset UCD will be assessed every 3 months until age 2 and every 6 months thereafter. Individuals with late onset UCD will be evaluated every 6 months. Psychological testing will take place at 6 months, 18 months, 4 years, 8 years, 15 years, and 18 years/adult of age. Psychological testing will take from 30 minutes (for younger children) up to 3 hours, depending on test battery.
Eligibility| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
| Sampling Method: | Non-Probability Sample |
>550 individuals with urea cycle disorders, up to a total of 1,100 enrolled
Inclusion Criteria:
- Diagnosis of NAGS deficiency, defined as the detection of a pathogenic mutation or decreased (less than 20 % of control) NAGS enzyme activity in liver
- Diagnosis of CPS I deficiency, defined as decreased (less than 20 % of control) CPS I enzyme activity in liver or an identified pathogenic mutation
- Diagnosis of OTC deficiency, defined as the identification of a pathogenic mutation, linkage analysis in an affected family, less than 20% of control of OTC activity in the liver, or elevated urinary orotate (greater than 20 uM/mM) following allopurinol loading with absence of argininosuccinic acid
- Diagnosis of AS deficiency (Citrullinemia), defined as a greater than or equal to 10-fold elevation of citrulline in plasma, decreased AS enzyme activity in cultured skin fibroblasts or other appropriate tissue, or identification of a pathogenic mutation in the AS gene
- Diagnosis of AL deficiency (Argininosuccinic Aciduria, ASA), defined as the presence of argininosuccinic acid in the blood or urine, decreased AL enzyme activity in cultured skin fibroblasts or other appropriate tissue, or identification of a pathogenic mutation in the AL gene
- Diagnosis of ARG deficiency (Hyperargininemia), defined as a greater than or equal to 5-fold elevated arginine levels in the blood, decreased arginase enzyme levels in red blood cells or other appropriate tissue, or identification of a pathogenic mutation in the ARG gene
- Diagnosis of HHH Syndrome or ORNT deficiency, defined as a greater than or equal to 5-fold elevated plasma ornithine and homocitrulline levels in the urine, or a pathogenic mutation in the ORNT1gene (SLC25A15)
- Diagnosis of CITR deficiency (Citrullinemia Type II), defined as elevated citrulline levels in the blood and a pathogenic mutation in the citrin gene
- Pending diagnosis of a UCD, defined as laboratory values highly suggestive of a UCD with symptomatic hyperammonemic episodes but without a verifiable diagnosis
Exclusion Criteria:
- Hyperammonemia caused by an organic academia, lysinuric protein intolerance, mitochondrial disorder, congenital lactic academia, fatty acid oxidation defects, or primary liver disease
- Rare and unrelated comorbidities (e.g., Down's syndrome, intraventricular hemorrhage in the newborn period, and extreme prematurity)
Contacts and Locations| Contact: Jennifer Seminara, MPH | 202-306-6489 | jseminar@childrensnational.org |
| United States, California | |
| University of California, Los Angeles | Recruiting |
| Los Angeles, California, United States, 90095 | |
| Contact: Naghmeh Dorrani, MS, CGC 310-825-8084 Ndorrani@mednet.ucla.edu | |
| Sub-Investigator: Stephen Cederbaum, MD | |
| Principal Investigator: Derek Wong, MD | |
| United States, Colorado | |
| The Children's Hospital, Aurora | Recruiting |
| Aurora, Colorado, United States, 80045 | |
| Contact: Curtis Coughlin, MS, CGC 303-724-2310 Coughlin.Curtis@tchden.org | |
| Principal Investigator: Renata C. Gallagher, MD, PhD | |
| United States, District of Columbia | |
| Children's National Medical Center | Recruiting |
| Washington, District of Columbia, United States, 20010 | |
| Contact: Kara Simpson, MS, CGC 202-476-6216 ksimpson@childrensnational.org | |
| Principal Investigator: Uta Lichter-Konecki, MD, PhD | |
| United States, Massachusetts | |
| Children's Hospital Boston (UCDC New England Center) | Recruiting |
| Boston, Massachusetts, United States, 02115 | |
| Contact: Vera Anastasoaie 617-355-7346 Vera.Anastasoaie@childrens.harvard.edu | |
| Principal Investigator: Susan Waisbren, MD | |
| Sub-Investigator: Harvey Levy, MD | |
| Sub-Investigator: Margretta Seashore, MD | |
| United States, Minnesota | |
| University of Minnesota | Recruiting |
| Minneapolis, Minnesota, United States, 55455 | |
| Contact: Susan Berry, MD berry002@umn.edu | |
| Contact: Sara Elsbecker, MS, RN, CPNP 612-626-5275 selsbeck10@umphysicians.umn.edu | |
| Principal Investigator: Susan Berry, MD | |
| United States, New York | |
| Mount Sinai School of Medicine | Recruiting |
| New York, New York, United States, 10029 | |
| Contact: Nina Schrager 212-241-6805 nina.schrager@mssm.edu | |
| Principal Investigator: George A. Diaz, MD | |
| United States, Ohio | |
| Case Western Medical College | Recruiting |
| Cleveland, Ohio, United States, 44106 | |
| Contact: Christine Heggie, BSN, ND 216-844-7124 Christine.Heggie@UHhospitals.org | |
| Principal Investigator: Douglas Kerr, MD | |
| Sub-Investigator: Shawn McCandless, MD | |
| United States, Oregon | |
| Oregon Health and Science University | Recruiting |
| Portland, Oregon, United States, 97239 | |
| Contact: Tina Marrone 503-418-3620 marronet@ohsu.edu | |
| Principal Investigator: Cary Harding, MD | |
| United States, Pennsylvania | |
| Children's Hospital of Philadelphia | Recruiting |
| Philadelphia, Pennsylvania, United States, 19104 | |
| Contact: Irma Payan, RN 215-590-6236 Payan@email.chop.edu | |
| Principal Investigator: Marc Yudkoff, MD | |
| United States, Texas | |
| Baylor College of Medicine | Recruiting |
| Houston, Texas, United States, 77030 | |
| Contact: Mary Mullins, RN, BSN 832-822-4263 mullins@bcm.edu | |
| Principal Investigator: Brendan Lee, MD, PhD | |
| United States, Washington | |
| Children's Hospital and Regional Medical Center | Recruiting |
| Seattle, Washington, United States, 98105 | |
| Contact: Linnea Brody, BS, MPH 206-987-3694 linnea.brody@seattlechildrens.org | |
| Principal Investigator: Lawrence Merritt, MD | |
| Canada, Ontario | |
| The Hospital for Sick Children | Recruiting |
| Toronto, Ontario, Canada, M5G 1X8 | |
| Contact: Munazzah Ambreen 416-813-7654 ext 2646 munazzah.ambreen@sickkids.ca | |
| Sub-Investigator: Annette Feigenbaum, MD | |
| Principal Investigator: Andreas Schulze, MD | |
| Germany | |
| University of Heidelberg | Recruiting |
| Heidelberg, Germany | |
| Contact: Peter Burgard, PhD ++49 [0]6221/56-32377 Peter.Burgard@med.uni-heidelberg.de | |
| Contact ++49 [0]6221/56-37733 | |
| Principal Investigator: Georg Hoffmann, MD | |
| Sub-Investigator: Peter Burgard, PhD | |
| Switzerland | |
| University Children's Hospital | Recruiting |
| Zurich, Switzerland, CH-8032 | |
| Contact: Tamar Stricker +41 44-266-7111 Tamar.stricker@kispi.uzh.ch | |
| Principal Investigator: Matthias Baumgartner, MD | |
| Sub-Investigator: Tamar Stricker, MD | |
| Principal Investigator: | Mark L. Batshaw, MD | Childrens National Medical Center |
| Principal Investigator: | Mendel Tuchman, MD | Childrens National Medical Center |
More Information
Additional Information:
Publications:
| Responsible Party: | Children's Research Institute |
| ClinicalTrials.gov Identifier: | NCT00237315 History of Changes |
| Other Study ID Numbers: | RDCRN 5101, U54RR019453, U54HD061221 |
| Study First Received: | October 10, 2005 |
| Last Updated: | February 13, 2013 |
| Health Authority: | United States: Federal Government |
Keywords provided by Children's Research Institute:
|
Urea Inherited metabolic disorders |
Additional relevant MeSH terms:
|
Amino Acid Metabolism, Inborn Errors Brain Diseases Brain Diseases, Metabolic Metabolic Diseases Metabolism, Inborn Errors |
Urea Cycle Disorders, Inborn Brain Diseases, Metabolic, Inborn Genetic Diseases, Inborn Central Nervous System Diseases Nervous System Diseases |
ClinicalTrials.gov processed this record on May 22, 2013