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Longitudinal Study of Urea Cycle Disorders

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ClinicalTrials.gov Identifier: NCT00237315
Recruitment Status : Recruiting
First Posted : October 12, 2005
Last Update Posted : April 15, 2021
Sponsor:
Collaborators:
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):
Andrea Gropman, Children's National Research Institute

Study Description
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Brief Summary:
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 or disease
Brain Diseases, Metabolic, Inborn Amino Acid Metabolism, Inborn Errors Urea Cycle Disorders

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. 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 2024. 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 every 2 years. Psychological testing will take from 30 minutes (for younger children) up to 3 hours, depending on test battery.

Study Design
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Study Type : Observational
Estimated Enrollment : 1009 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: Longitudinal Study of Urea Cycle Disorders
Actual Study Start Date : February 2006
Estimated Primary Completion Date : July 2024
Estimated Study Completion Date : December 2024

Resource links provided by the National Library of Medicine


Groups and Cohorts
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Outcome Measures
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Primary Outcome Measures :
  1. Prevalence of specific morbid indicators of disease severity [ Time Frame: End of study ]
    hyperammonemia, developmental disabilities, long-term renal and hepatic effects, and case-fatality associated with the various forms of UCD

  2. Relationship between various biomarkers and disease severity and progression [ Time Frame: End of study ]
    correlation between glutamine, ammonia, liver function (biomarkers) and severity scale and IQ in terms of outcome

  3. Safety and efficacy of currently used and new UCD therapies [ Time Frame: End of study ]
    Interim events related to treatments (drugs, diet or liver transplant)


Eligibility Criteria
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Ages Eligible for Study:   Child, Adult, Older Adult
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
Enrollment goal: 1,009 participants
Criteria

Inclusion Criteria:

  • Diagnosis of NAGS deficiency, defined as the detection of a pathogenic mutation, and/or decreased (less than 20 % of control) NAGS enzyme activity in liver ,and/or hyperammonemia and first degree relative meets at least one of the criteria for NAGS deficiency
  • Diagnosis of CPS I deficiency, defined as decreased (less than 20 % of control) CPS I enzyme activity in liver, and/or an identified pathogenic mutation, and/or hyperammonemia and first degree relative meets at least one of the criteria for CPS I deficiency
  • Diagnosis of OTC deficiency, defined as the identification of a pathogenic mutation, and/or less than 20% of control of OTC activity in the liver, and/or elevated urinary orotate (greater than 20 uM/mM) in a random urine sample or after allopurinol challenge test, and/or hyperammonemia and first degree relative meets at least one of the criteria for OTC deficiency
  • Diagnosis of AS deficiency (Citrullinemia), defined as a greater than or equal to 10-fold elevation of citrulline in plasma, and/or decreased AS enzyme activity in cultured skin fibroblasts or other appropriate tissue, and/or identification of a pathogenic mutation in the AS gene, and/or hyperammonemia and first degree relative meets at least one of the criteria for AS Deficiency
  • Diagnosis of AL deficiency (Argininosuccinic Aciduria, ASA), defined as the presence of argininosuccinic acid in the blood or urine, and/or decreased AL enzyme activity in cultured skin fibroblasts or other appropriate tissue, and/or identification of a pathogenic mutation in the AL gene, and/or hyperammonemia and first degree relative meets at least one of the criteria for AL Deficiency
  • Diagnosis of ARG deficiency (Hyperargininemia), defined as a greater than or equal to 5-fold elevated arginine levels in the blood, and/or decreased arginase enzyme levels in red blood cells or other appropriate tissue, and/or identification of a pathogenic mutation in the ARG gene, and/or hyperammonemia and first degree relative meets at least one of the criteria for ARG Deficiency
  • 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, and/or a pathogenic mutation, and/or less than 20% residual labeled ornithine incorporation into protein in cultured fibroblasts, and/or hyperammonemia and first degree relative meets at least one of the criteria for HHH Syndrome or ORNT Deficiency
  • Diagnosis of CITR deficiency (Citrullinemia Type II), defined as elevated citrulline levels in the blood and a pathogenic mutation and/or hyperammonemia and first degree relative meets criteria for CITR Deficiency
  • Pending diagnosis of a UCD (UCD highly likely), 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
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00237315


Contacts
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Contact: Jennifer Seminara, MPH 202-306-6489 jseminar@childrensnational.org

Locations
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United States, California
University of California, Los Angeles Recruiting
Los Angeles, California, United States, 90095
Contact: Ruby Escalante, MS, RD, CSP    310-206-4037    rubyescalante@mednet.ucla.edu   
Sub-Investigator: Stephen Cederbaum, MD         
Principal Investigator: Derek Wong, MD         
University of California San Francisco Recruiting
San Francisco, California, United States, 94143
Contact: Quinn Spencer    415-476-7748    quinn.spencer@ucsf.edu   
Principal Investigator: Renata C Gallagher, MD, PhD         
Stanford University Medical Center Recruiting
Stanford, California, United States, 94305
Contact: Thu Quan, MBA, HCM    650-736-8166    tquan@stanford.edu   
Principal Investigator: Gregory Enns, MD         
United States, Colorado
Children's Hospital Colorado Recruiting
Aurora, Colorado, United States, 80045
Contact: Brittany Murphy    720-777-8591    Brittany.Murphy@childrenscolorado.org   
Principal Investigator: Shawn McCandless, MD         
Principal Investigator: Curtis Coughlin, MS, CGC         
Sub-Investigator: Johan Van Hove, MD, PhD         
Sub-Investigator: Greta Wilkening, PhD         
Sub-Investigator: Janet Thomas, MD         
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: Nicholas Ah Mew, MD         
Sub-Investigator: Jacqueline Sanz, 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: Gerard Berry, MD         
Sub-Investigator: Harvey Levy, MD         
United States, Minnesota
University of Minnesota Recruiting
Minneapolis, Minnesota, United States, 55455
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: Catherine Miller    212-659-1456 ext 81456    Catherine.miller@mssm.edu   
Principal Investigator: George A. Diaz, MD         
United States, Ohio
Case Western Medical College Recruiting
Cleveland, Ohio, United States, 44106
Contact: Genya Kisin    216-286-9202    Genya.Kisin@UHhospitals.org   
Principal Investigator: Jirair Bedoyan, MD,PhD,FACMG         
Sub-Investigator: Laura Konczal, MD         
Sub-Investigator: Rachel Tangen, PhD         
Sub-Investigator: Lori-Anne Schillaci, MD         
United States, Oregon
Oregon Health and Science University Recruiting
Portland, Oregon, United States, 97239
Contact: Sondra Bloxam    503-494-4290    bloxam@ohsu.edu   
Principal Investigator: Cary Harding, MD         
United States, Pennsylvania
Children's Hospital of Philadelphia Recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Erika Rodriguez-Guzman, CRNP    215-590-6236    RODRIGUEE4@EMAIL.CHOP.EDU   
Principal Investigator: Can Ficicioglu, MD         
United States, Texas
Baylor College of Medicine Recruiting
Houston, Texas, United States, 77030
Contact: Saima Ali, RN, FNP-C    832-822-4183    sma1@bcm.edu   
Principal Investigator: Sandesh Nagamani, MD         
United States, Washington
Children's Hospital and Regional Medical Center Recruiting
Seattle, Washington, United States, 98105
Contact: Hayden Vreugdenhil    206-884-1264    Hayden.Vreugdenhil@seattlechildrens.org   
Principal Investigator: Christina Lam, MD, PhD         
Canada, Ontario
The Hospital for Sick Children Recruiting
Toronto, Ontario, Canada, M5G 1X8
Contact: Ashley Wilson    416-813-7654 ext 202646    ashley.wilson@sickkids.ca   
Principal Investigator: Andreas Schulze, MD         
Sub-Investigator: Annette Feigenbaum, MD         
Germany
University of Heidelberg Recruiting
Heidelberg, Germany
Contact: Roland Posset, MD    +49 6221 56-36971    roland.posset@med.uni-heidelberg.de   
Contact    ++49 [0]6221/56-37733      
Principal Investigator: Georg Hoffmann, MD         
Sub-Investigator: Peter Burgard, PhD         
Sub-Investigator: Stefan Kölker, MD         
Switzerland
University Children's Hospital Recruiting
Zurich, Switzerland, CH-8032
Contact: Tamar Stricker, MD    +41 44-266-7111    Tamar.stricker@kispi.uzh.ch   
Principal Investigator: Matthias Baumgartner, MD         
Sub-Investigator: Tamar Stricker, MD         
Sponsors and Collaborators
Andrea Gropman
National Center for Research Resources (NCRR)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
Rare Diseases Clinical Research Network
Investigators
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Study Chair: Andrea Gropman, MD Children's National Research Institute
Study Chair: Susan Berry, MD University of Minnesota Masonic Children's Hospital
More Information
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Additional Information:

Publications of Results:

Other Publications:

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Responsible Party: Andrea Gropman, Principal Investigator, Children's National Research Institute
ClinicalTrials.gov Identifier: NCT00237315    
Other Study ID Numbers: RDCRN 5101
U54RR019453 ( U.S. NIH Grant/Contract )
U54HD061221 ( U.S. NIH Grant/Contract )
First Posted: October 12, 2005    Key Record Dates
Last Update Posted: April 15, 2021
Last Verified: April 2021
Keywords provided by Andrea Gropman, Children's National Research Institute:
Urea
Inherited metabolic disorders
Additional relevant MeSH terms:
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Brain Diseases
Urea Cycle Disorders, Inborn
Brain Diseases, Metabolic
Brain Diseases, Metabolic, Inborn
Metabolism, Inborn Errors
Amino Acid Metabolism, Inborn Errors
 Metabolic Diseases
Disease
Pathologic Processes
Central Nervous System Diseases
Nervous System Diseases
Genetic Diseases, Inborn