Longitudinal Study of Urea Cycle Disorders - Full Text View

Sponsors and Collaborators:	Office of Rare Diseases (ORD) Rare Diseases Clinical Research Network
Information provided by:	Office of Rare Diseases (ORD)
ClinicalTrials.gov Identifier:	NCT00237315

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 II

Genetics Home Reference related topics: argininosuccinic aciduria citrullinemia N-acetylglutamate synthase deficiency ornithine translocase deficiency

MedlinePlus related topics: Brain Diseases Metabolic Disorders

U.S. FDA Resources

Study Type:	Observational
Study Design:	Cohort, Prospective
Official Title:	Longitudinal Study of Urea Cycle Disorders

Further study details as provided by Office of Rare Diseases (ORD):

Biospecimen Retention: None Retained

Biospecimen Description:

Estimated Enrollment:	440
Study Start Date:	February 2006
Estimated Study Completion Date:	September 2010
Estimated Primary Completion Date:	September 2009 (Final data collection date for primary outcome measure)

Detailed Description:

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 2009. 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

Study Population

440 individuals with urea cycle disorders

Criteria

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

Please refer to this study by its ClinicalTrials.gov identifier: NCT00237315

Locations

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
Principal Investigator: Stephen Cederbaum, MD
United States, Colorado
The Children's Hospital, Aurora	Recruiting
Aurora, Colorado, United States, 80045
Contact: Renata C. Gallagher, MD, PhD 303-724-2338
Principal Investigator: Renata C. Gallagher, MD, PhD
United States, Connecticut
Yale University	Recruiting
New Haven, Connecticut, United States, 06520
Contact: Kristin DeFrancesco 203-737-2585 kristin.defrancesco@yale.edu
Principal Investigator: Margretta R. Seashore, MD
United States, District of Columbia
Children's National Medical Center	Recruiting
Washington, District of Columbia, United States, 20010
Contact: Kara Lord, MS, CGC 202-476-6216 klord@cnmc.org
Principal Investigator: Uta Lichter-Konecki, MD, PhD
United States, Massachusetts
Boston Children's Hospital	Recruiting
Boston, Massachusetts, United States, 02115
Contact: Vera Anastasoaie 617-355-7346 Vera.Anastasoaie@childrens.harvard.edu
Principal Investigator: Susan Waisbren, MD
United States, New York
Mount Sinai School of Medicine	Recruiting
New York, New York, United States, 10029
Contact: Christina Guzman 212-241-6805 christina.guzman@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
Contact: Shawn E. McCandless, MD 216-844-1612 Shawn.mccandless@case.edu
Principal Investigator: Douglas Kerr, MD
United States, Oregon
Oregon Health and Science University	Recruiting
Portland, Oregon, United States, 97239
Contact: Lori Paradise, CMA 503-494-2777 paradise@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, Tennessee
Vanderbilt University Medical Center	Recruiting
Nashville, Tennessee, United States, 37232
Contact: Teresa Welch-Burke, RN, BSN 615-936-2089 teresa.welch@vanderbilt.edu
Principal Investigator: Marshall Summar, MD
United States, Texas
Baylor College of Medicine	Recruiting
Houston, Texas, United States, 77030
Contact: Mary Mullins, RN, BSN 800-364-5437 ext 24263 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: Annette Feigenbaum, MD 416-813-5340 annette.feigenbaum@sickkids.ca
Principal Investigator: Annette Feigenbaum, MD
Switzerland
University Children's Hospital	Recruiting
Zurich, Switzerland, CH-8032
Contact: Tamar Stricker +41 44-266-7310 Tamar.stricker@kispi.uzh.ch
Principal Investigator: Matthias Baumgartner, MD

Sponsors and Collaborators

Office of Rare Diseases (ORD)

Rare Diseases Clinical Research Network

Investigators

Principal Investigator:	Mark L. Batshaw, MD	Childrens National Medical Center
Principal Investigator:	Mendel Tuchman, MD	Childrens National Medical Center

More Information

Publications:

Mitchell S, Ellingson C, Coyne T, Hall L, Neill M, Christian N, Higham C, Dobrowolski SF, Tuchman M, Summar M; the Urea Cycle Disorder Consortium. Genetic variation in the urea cycle: a model resource for investigating key candidate genes for common diseases. Hum Mutat. 2008 Jul 29; [Epub ahead of print]

Tuchman M, Lee B, Lichter-Konecki U, Summar ML, Yudkoff M, Cederbaum SD, Kerr DS, Diaz GA, Seashore MR, Lee HS, McCarter RJ, Krischer JP, Batshaw ML; Urea Cycle Disorders Consortium of the Rare Diseases Clinical Research Network. Cross-sectional multicenter study of patients with urea cycle disorders in the United States. Mol Genet Metab. 2008 Aug;94(4):397-402. Epub 2008 Jun 17.

Responsible Party:	Children's Research Institute ( Mendel Tuchman, MD )
Study ID Numbers:	RDCRN 5101, U54RR019453
Study First Received:	October 10, 2005
Last Updated:	November 17, 2008
ClinicalTrials.gov Identifier:	NCT00237315
Health Authority:	United States: Federal Government

Keywords provided by Office of Rare Diseases (ORD):

Urea
Inherited metabolic disorders

Study placed in the following topic categories:

Metabolism, Inborn Errors
Inborn amino acid metabolism disorder
Metabolic Diseases
Urea cycle disorders
Genetic Diseases, Inborn
Amino Acid Metabolism, Inborn Errors

Central Nervous System Diseases
Brain Diseases, Metabolic, Inborn
Metabolic disorder
Brain Diseases
Brain Diseases, Metabolic

Additional relevant MeSH terms:

Pathologic Processes
Disease
Nervous System Diseases

ClinicalTrials.gov processed this record on January 16, 2009