Longitudinal Study of Urea Cycle Disorders

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2015 by Children's Research Institute
National Center for Research Resources (NCRR)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Rare Diseases Clinical Research Network
Information provided by (Responsible Party):
Mendel Tuchman, Children's Research Institute
ClinicalTrials.gov Identifier:
First received: October 10, 2005
Last updated: April 21, 2015
Last verified: April 2015

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

Resource links provided by NLM:

Further study details as provided by Children's Research Institute:

Primary Outcome Measures:
  • 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: December 2019
Estimated Primary Completion Date: July 2019 (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 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.


Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population

>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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

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

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
Children's Hospital Colorado Recruiting
Aurora, Colorado, United States, 80045
Contact: Curtis Coughlin, MS, CGC    303-724-2310    Coughlin.Curtis@tchden.org   
Principal Investigator: James Weisfeld-Adams, MD         
Principal Investigator: Curtis Coughlin, MS, CGC         
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         
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
Icahn School of Medicine at Mount Sinai Recruiting
New York, New York, United States, 10029
Contact: Luca Fierro    212-659-1477    luca.fierro@mssm.edu   
Principal Investigator: George A. Diaz, MD         
United States, Ohio
Case Western Medical College Recruiting
Cleveland, Ohio, United States, 44106
Contact: Audrey Lynn, PhD    216-844-7124    Audrey.Lynn@UHhospitals.org   
Principal Investigator: Shawn McCandless, MD         
United States, Oregon
Oregon Health and Science University Recruiting
Portland, Oregon, United States, 97239
Contact: Julie Martin    503-494-5313    martijul@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: Sandesh Nagamani, MD         
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: Liora Caspi    416-813-7654 ext 328027    liora.caspi@sickkids.ca   
Principal Investigator: Andreas Schulze, MD         
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         
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         
Sponsors and Collaborators
Mendel Tuchman
National Center for Research Resources (NCRR)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Rare Diseases Clinical Research Network
Principal Investigator: Mark L. Batshaw, MD Childrens National Medical Center
Principal Investigator: Mendel Tuchman, MD Childrens National Medical Center
  More Information

Additional Information:

Responsible Party: Mendel Tuchman, MD, 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: April 21, 2015
Health Authority: United States: Federal Government

Keywords provided by Children's Research Institute:
Inherited metabolic disorders

Additional relevant MeSH terms:
Amino Acid Metabolism, Inborn Errors
Brain Diseases
Brain Diseases, Metabolic
Brain Diseases, Metabolic, Inborn
Metabolic Diseases
Metabolism, Inborn Errors
Urea Cycle Disorders, Inborn
Central Nervous System Diseases
Genetic Diseases, Inborn
Nervous System Diseases

ClinicalTrials.gov processed this record on October 07, 2015