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Longitudinal Study of Urea Cycle Disorders

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2014 by Children's Research Institute
Sponsor:
Collaborators:
Rare Diseases Clinical Research Network
Information provided by (Responsible Party):
Mendel Tuchman, Children's Research Institute
ClinicalTrials.gov Identifier:
NCT00237315
First received: October 10, 2005
Last updated: September 19, 2014
Last verified: September 2014

October 10, 2005
September 19, 2014
February 2006
July 2019   (final data collection date for primary outcome measure)
  • 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)
Not Provided
Complete list of historical versions of study NCT00237315 on ClinicalTrials.gov Archive Site
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Longitudinal Study of Urea Cycle Disorders
Longitudinal Study of Urea Cycle Disorders

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.

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.

Observational
Observational Model: Cohort
Time Perspective: Prospective
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Non-Probability Sample

>550 individuals with urea cycle disorders, up to a total of 1,100 enrolled

  • Brain Diseases, Metabolic, Inborn
  • Amino Acid Metabolism, Inborn Errors
  • Urea Cycle Disorders
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*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
1100
December 2019
July 2019   (final data collection date for primary outcome measure)

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)
Both
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No
Contact: Jennifer Seminara, MPH 202-306-6489 jseminar@childrensnational.org
United States,   Canada,   Germany,   Switzerland
 
NCT00237315
RDCRN 5101, U54RR019453, U54HD061221
Yes
Mendel Tuchman, Children's Research Institute
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
Children's Research Institute
September 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP