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Brain Diseases, Metabolic, InbornNCT00237315

Longitudinal Study of Urea Cycle Disorders

An observational study of Brain Diseases, Metabolic, Inborn and Amino Acid Metabolism, Inborn Errors, run by Andrea Gropman at 15 sites in 4 countries.

Unknown status

Status not confirmed. The sponsor has not verified this record for over two years, so it may be out of date.

Official record
Search all trials

Trial 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. Read more about this study

Who is it for?
Any age
How many people
1,500 participants
Where
15 sitesin 4 countries
Study dates
Feb 2006to Jul 2026
Phase
Observational
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages Any age
  • All sexes
  • No healthy volunteers
  • Child, Adult, Older adult

Study population: Enrollment goal: 1,100 participants

Who may be able to join

  • 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
Show all 9Show fewer
  • 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

Who cannot join

  • 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)

Trial locations and contacts

15 sites in 4 countries.

Jennifer Seminara, MPH contact

202-306-6489

jseminar@childrensnational.org

15 sites in 4 countries

United States12 sites, 12 recruiting

  • Children's Hospital Colorado

    Aurora, Colorado, 80045

    Christien Hernandez, 720-777-0440, Christien.Hernandez@childrenscolorado.org

    Shawn McCandless, MD

    Recruiting

  • Children's Hospital Boston (UCDC New England Center)

    Boston, Massachusetts, 02115

    Debbie Fu, 617-919-7631, Yu-Ting.Fu@childrens.harvard.edu

    Gerard Berry, MD

    Recruiting

  • Case Western Medical College

    Cleveland, Ohio, 44106

    Genya Kisin, 216-286-9202, Genya.Kisin@UHhospitals.org

    Laura Konczal, MD

    Recruiting

  • Baylor College of Medicine

    Houston, Texas, 77030

    Saima Ali, RN, FNP-C, 832-822-4183, sma1@bcm.edu

    Sandesh Nagamani, MD

    Recruiting

  • University of California, Los Angeles

    Los Angeles, California, 90095

    Julia Sloan, 310-794-3374, JSloan@mednet.ucla.edu

    Stephen Cederbaum, MD

    Recruiting

  • University of Minnesota

    Minneapolis, Minnesota, 55455

    Sara Elsbecker, MS, RN, CPNP, 612-626-5275, selsbeck10@umphysicians.umn.edu

    Susan Berry, MD

    Recruiting

  • Icahn School of Medicine at Mount Sinai

    New York, New York, 10029

    Alison Tiao, 212-659-8540, alison.tiao@mssm.edu

    Margo Breilyn, MD

    Recruiting

  • Children's Hospital of Philadelphia

    Philadelphia, Pennsylvania, 19104

    Mita Majumdar, 267-425-5876, majumdarm@chop.edu

    Can Ficicioglu, MD

    Recruiting

  • Oregon Health and Science University

    Portland, Oregon, 97239

    Ursula Kuhn, 503-494-4290, kuhnu@ohsu.edu

    Cary Harding, MD

    Recruiting

  • Children's Hospital and Regional Medical Center

    Seattle, Washington, 98105

    Hayden Vreugdenhil, 206-884-1264, Hayden.Vreugdenhil@seattlechildrens.org

    Christina Lam, MD, PhD

    Recruiting

  • Stanford University Medical Center

    Stanford, California, 94305

    Thu Quan, MBA, HCM, 650-736-8166, tquan@stanford.edu

    Gregory Enns, MD

    Recruiting

  • Children's National Medical Center

    Washington D.C., District of Columbia, 20010

    Kara Simpson, MS, CGC, 202-476-6216, ksimpson@childrensnational.org

    Nicholas Ah Mew, MD

    Recruiting

Other trials in United States

Canada1 site, 1 recruiting

  • The Hospital for Sick Children

    Toronto, Ontario, M5G 1X8

    Liora Caspi, 416-813-7654 ext. 202646, liora.caspi@sickkids.ca

    Andreas Schulze, MD

    Recruiting

Other trials in Canada

Germany1 site, 1 recruiting

  • University of Heidelberg

    Heidelberg

    Roland Posset, MD, +49 6221 56-36971, roland.posset@med.uni-heidelberg.de

    ++49 [0]6221/56-37733

    Recruiting

Other trials in Germany

Switzerland1 site, 1 recruiting

  • University Children's Hospital

    Zurich, CH-8032

    Tamar Stricker, MD, +41 44-266-7111, Tamar.stricker@kispi.uzh.ch

    Matthias Baumgartner, MD

    Recruiting

Other trials in Switzerland

About this study

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.

Read the 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 2025. 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.

Keywords
Urea, Inherited metabolic disorders
Medical subject headings
Brain Diseases, Metabolic, Inborn, Amino Acid Metabolism, Inborn Errors, Urea Cycle Disorders, Inborn

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Prevalence of specific morbid indicators of disease severity

    hyperammonemia, developmental disabilities, long-term renal and hepatic effects, and case-fatality associated with the various forms of UCD

    Measured: End of study

  2. Relationship between various biomarkers and disease severity and progression

    correlation between glutamine, ammonia, liver function (biomarkers) and severity scale and IQ in terms of outcome

    Measured: End of study

  3. Safety and efficacy of currently used and new UCD therapies

    Interim events related to treatments (drugs, diet or liver transplant)

    Measured: End of study

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted12 Oct 2005 (estimated)
  2. Study startFeb 2006
  3. Primary completionJul 2025 (estimated)
  4. Study completionJul 2026 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Observational
Observational model
Cohort
Time perspective
Prospective
Enrolment
1,500 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00237315
Sponsor's protocol ID
RDCRN 5101
Other IDs
U54RR019453, U54HD061221
Status last verified
Feb 2024
First submitted
10 Oct 2005
Last updated
13 Feb 2024
Results posted
No
Data monitoring committee
Yes

Publications

  • Patrick TB, Richesson R, Andrews JE, Folk LC. SNOMED CT coding variation and grouping for "other findings" in a longitudinal study on urea cycle disorders. AMIA Annu Symp Proc. 2008 Nov 6;2008:11-5.

    PubMed 18998949

  • Richesson RL, Lee HS, Cuthbertson D, Lloyd J, Young K, Krischer JP. An automated communication system in a contact registry for persons with rare diseases: scalable tools for identifying and recruiting clinical research participants. Contemp Clin Trials. 2009 Jan;30(1):55-62. doi: 10.1016/j.cct.2008.09.002. Epub 2008 Sep 7.

    PubMed 18804556

  • Mitchell S, Ellingson C, Coyne T, Hall L, Neill M, Christian N, Higham C, Dobrowolski SF, Tuchman M, Summar M; Urea Cycle Disorder Consortium. Genetic variation in the urea cycle: a model resource for investigating key candidate genes for common diseases. Hum Mutat. 2009 Jan;30(1):56-60. doi: 10.1002/humu.20813.

    PubMed 18666241

  • Jain-Ghai S, Nagamani SC, Blaser S, Siriwardena K, Feigenbaum A. Arginase I deficiency: severe infantile presentation with hyperammonemia: more common than reported? Mol Genet Metab. 2011 Sep-Oct;104(1-2):107-11. doi: 10.1016/j.ymgme.2011.06.025. Epub 2011 Jul 13.

    PubMed 21802329

  • Wilson JM, Shchelochkov OA, Gallagher RC, Batshaw ML. Hepatocellular carcinoma in a research subject with ornithine transcarbamylase deficiency. Mol Genet Metab. 2012 Feb;105(2):263-5. doi: 10.1016/j.ymgme.2011.10.016. Epub 2011 Nov 7.

    PubMed 22129577

  • Burrage LC, Jain M, Gandolfo L, Lee BH; Members of the Urea Cycle Disorders Consortium; Nagamani SC. Sodium phenylbutyrate decreases plasma branched-chain amino acids in patients with urea cycle disorders. Mol Genet Metab. 2014 Sep-Oct;113(1-2):131-5. doi: 10.1016/j.ymgme.2014.06.005. Epub 2014 Jul 3.

    PubMed 25042691

  • Burrage LC, Sun Q, Elsea SH, Jiang MM, Nagamani SC, Frankel AE, Stone E, Alters SE, Johnson DE, Rowlinson SW, Georgiou G; Members of Urea Cycle Disorders Consortium; Lee BH. Human recombinant arginase enzyme reduces plasma arginine in mouse models of arginase deficiency. Hum Mol Genet. 2015 Nov 15;24(22):6417-27. doi: 10.1093/hmg/ddv352. Epub 2015 Sep 10.

    PubMed 26358771

  • Krivitzky LS, Walsh KS, Fisher EL, Berl MM. Executive functioning profiles from the BRIEF across pediatric medical disorders: Age and diagnosis factors. Child Neuropsychol. 2016;22(7):870-88. doi: 10.1080/09297049.2015.1054272. Epub 2015 Jul 6.

    PubMed 26143938

  • Waisbren SE, He J, McCarter R. Assessing Psychological Functioning in Metabolic Disorders: Validation of the Adaptive Behavior Assessment System, Second Edition (ABAS-II), and the Behavior Rating Inventory of Executive Function (BRIEF) for Identification of Individuals at Risk. JIMD Rep. 2015;21:35-43. doi: 10.1007/8904_2014_373. Epub 2015 Feb 25.

    PubMed 25712381

  • Kolker S, Dobbelaere D, Haberle J, Burgard P, Gleich F, Summar ML, Hannigan S, Parker S, Chakrapani A, Baumgartner MR; E-IMD Consortium. Networking Across Borders for Individuals with Organic Acidurias and Urea Cycle Disorders: The E-IMD Consortium. JIMD Rep. 2015;22:29-38. doi: 10.1007/8904_2015_408. Epub 2015 Feb 22.

    PubMed 25701269

  • Posset R, Garbade SF, Boy N, Burlina AB, Dionisi-Vici C, Dobbelaere D, Garcia-Cazorla A, de Lonlay P, Teles EL, Vara R, Mew NA, Batshaw ML, Baumgartner MR, McCandless SE, Seminara J, Summar M, Hoffmann GF, Kolker S, Burgard P; Additional individual contributors of the UCDC and the E-IMD consortium. Transatlantic combined and comparative data analysis of 1095 patients with urea cycle disorders-A successful strategy for clinical research of rare diseases. J Inherit Metab Dis. 2019 Jan;42(1):93-106. doi: 10.1002/jimd.12031.

    PubMed 30740724

  • Shapiro E, Bernstein J, Adams HR, Barbier AJ, Buracchio T, Como P, Delaney KA, Eichler F, Goldsmith JC, Hogan M, Kovacs S, Mink JW, Odenkirchen J, Parisi MA, Skrinar A, Waisbren SE, Mulberg AE. Neurocognitive clinical outcome assessments for inborn errors of metabolism and other rare conditions. Mol Genet Metab. 2016 Jun;118(2):65-9. doi: 10.1016/j.ymgme.2016.04.006. Epub 2016 Apr 14.

    PubMed 27132782

  • Summar ML, Koelker S, Freedenberg D, Le Mons C, Haberle J, Lee HS, Kirmse B; European Registry and Network for Intoxication Type Metabolic Diseases (E-IMD). Electronic address: http://www.e-imd.org/en/index.phtml; Members of the Urea Cycle Disorders Consortium (UCDC). Electronic address: http://rarediseasesnetwork.epi.usf.edu/ucdc/. The incidence of urea cycle disorders. Mol Genet Metab. 2013 Sep-Oct;110(1-2):179-80. doi: 10.1016/j.ymgme.2013.07.008. Epub 2013 Jul 18.

    PubMed 23972786

  • Waisbren SE, Cuthbertson D, Burgard P, Holbert A, McCarter R, Cederbaum S; Members of the Urea Cycle Disorders Consortium. Biochemical markers and neuropsychological functioning in distal urea cycle disorders. J Inherit Metab Dis. 2018 Jul;41(4):657-667. doi: 10.1007/s10545-017-0132-5. Epub 2018 Feb 8.

    PubMed 29423830

  • Waisbren SE, Stefanatos AK, Kok TMY, Ozturk-Hismi B. Neuropsychological attributes of urea cycle disorders: A systematic review of the literature. J Inherit Metab Dis. 2019 Nov;42(6):1176-1191. doi: 10.1002/jimd.12146. Epub 2019 Aug 1.

    PubMed 31268178

Questions about this trial

What is this clinical trial studying?

An observational study of Brain Diseases, Metabolic, Inborn and Amino Acid Metabolism, Inborn Errors, run by Andrea Gropman at 15 sites in 4 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 9 inclusion and 2 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: status not confirmed, as of the sponsor's last update on 13 Feb 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 15 sites in United States, Canada, Germany, Switzerland. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

Are results available for this study?

Results are not available in the source record.

How can a doctor refer a patient or contact the research team?

Contact Jennifer Seminara, MPH (202-306-6489, jseminar@childrensnational.org), or a site near the patient. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Prevalence of specific morbid indicators of disease severity (time frame: End of study). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00237315, which also lists 39 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Feb 2024.

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