Longitudinal Study of Urea Cycle Disorders

Sponsor

Andrea Gropman (Other)

Overall Status

Recruiting

CT.gov ID

NCT00237315

Collaborator

National Center for Research Resources (NCRR) (NIH), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) (NIH), Rare Diseases Clinical Research Network (Other)

1,009

Enrollment

Locations

226

Anticipated Duration (Months)

63.1

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

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	Intervention/Treatment	Phase
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

Study Type:

Observational

Anticipated Enrollment :

1009 participants

Observational Model:

Cohort

Time Perspective:

Prospective

Official Title:

Longitudinal Study of Urea Cycle Disorders

Actual Study Start Date :

Feb 1, 2006

Anticipated Primary Completion Date :

Jul 1, 2024

Anticipated Study Completion Date :

Dec 1, 2024

Outcome Measures

Primary Outcome Measures

Prevalence of specific morbid indicators of disease severity [End of study]
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 [End of study]
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 [End of study]
Interim events related to treatments (drugs, diet or liver transplant)

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

Locations

	Site	City	State	Country	Postal Code
1	University of California, Los Angeles	Los Angeles	California	United States	90095
2	University of California San Francisco	San Francisco	California	United States	94143
3	Stanford University Medical Center	Stanford	California	United States	94305
4	Children's Hospital Colorado	Aurora	Colorado	United States	80045
5	Children's National Medical Center	Washington	District of Columbia	United States	20010
6	Children's Hospital Boston (UCDC New England Center)	Boston	Massachusetts	United States	02115
7	University of Minnesota	Minneapolis	Minnesota	United States	55455
8	Icahn School of Medicine at Mount Sinai	New York	New York	United States	10029
9	Case Western Medical College	Cleveland	Ohio	United States	44106
10	Oregon Health and Science University	Portland	Oregon	United States	97239
11	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
12	Baylor College of Medicine	Houston	Texas	United States	77030
13	Children's Hospital and Regional Medical Center	Seattle	Washington	United States	98105
14	The Hospital for Sick Children	Toronto	Ontario	Canada	M5G 1X8
15	University of Heidelberg	Heidelberg		Germany
16	University Children's Hospital	Zurich		Switzerland	CH-8032

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

Study Chair: Andrea Gropman, MD, Children's National Research Institute
Study Chair: Susan Berry, MD, University of Minnesota Masonic Children's Hospital