Longitudinal Study of Urea Cycle Disorders

Condition(s) targeted: Brain Diseases, Metabolic, Inborn; Amino Acid Metabolism, Inborn Errors; Urea Cycle Disorders

Phase: Phase 2

Status: Recruiting

Sponsored by: Children's Research Institute

Official(s) and/or principal investigator(s):
Mark L. Batshaw, MD, Principal Investigator, Affiliation: Childrens National Medical Center
Mendel Tuchman, MD, Principal Investigator, Affiliation: Childrens National Medical Center

Overall contact:
Jennifer Seminara, MPH, Phone: 202-306-6489, Email: jseminar@childrensnational.org

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.

Official title: Longitudinal Study of Urea Cycle Disorders

Study design: Observational Model: Cohort, Time Perspective: Prospective

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.

Minimum age: N/A. Maximum age: N/A. Gender(s): Both.

Criteria:

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)

Jennifer Seminara, MPH, Phone: 202-306-6489, Email: jseminar@childrensnational.org

University of Heidelberg, Heidelberg, Germany; Recruiting
Peter Burgard, PhD, Phone: ++49 [0]6221/56-32377, Email: Peter.Burgard@med.uni-heidelberg.de
Phone: ++49 [0]6221/56-37733
Georg Hoffmann, MD, Principal Investigator
Peter Burgard, PhD, Sub-Investigator

University Children's Hospital, Zurich CH-8032, Switzerland; Recruiting
Tamar Stricker, Phone: +41 44-266-7111, Email: Tamar.stricker@kispi.uzh.ch
Matthias Baumgartner, MD, Principal Investigator
Tamar Stricker, MD, Sub-Investigator

University of California, Los Angeles, Los Angeles, California 90095, United States; Recruiting
Naghmeh Dorrani, MS, CGC, Phone: 310-825-8084, Email: Ndorrani@mednet.ucla.edu
Stephen Cederbaum, MD, Sub-Investigator
Derek Wong, MD, Principal Investigator

The Children's Hospital, Aurora, Aurora, Colorado 80045, United States; Recruiting
Curtis Coughlin, MS, CGC, Phone: 303-724-2310, Email: Coughlin.Curtis@tchden.org
Renata C. Gallagher, MD, PhD, Principal Investigator

Children's National Medical Center, Washington, District of Columbia 20010, United States; Recruiting
Kara Simpson, MS, CGC, Phone: 202-476-6216, Email: ksimpson@childrensnational.org
Uta Lichter-Konecki, MD, PhD, Principal Investigator

Children's Hospital Boston (UCDC New England Center), Boston, Massachusetts 02115, United States; Recruiting
Vera Anastasoaie, Phone: 617-355-7346, Email: Vera.Anastasoaie@childrens.harvard.edu
Susan Waisbren, MD, Principal Investigator
Harvey Levy, MD, Sub-Investigator
Margretta Seashore, MD, Sub-Investigator

University of Minnesota, Minneapolis, Minnesota 55455, United States; Recruiting
Susan Berry, MD, Email: berry002@umn.edu
Sara Elsbecker, MS, RN, CPNP, Phone: 612-626-5275, Email: selsbeck10@umphysicians.umn.edu
Susan Berry, MD, Principal Investigator

Mount Sinai School of Medicine, New York, New York 10029, United States; Recruiting
Nina Schrager, Phone: 212-241-6805, Email: nina.schrager@mssm.edu
George A. Diaz, MD, Principal Investigator

Case Western Medical College, Cleveland, Ohio 44106, United States; Recruiting
Christine Heggie, BSN, ND, Phone: 216-844-7124, Email: Christine.Heggie@UHhospitals.org
Douglas Kerr, MD, Principal Investigator
Shawn McCandless, MD, Sub-Investigator

The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada; Recruiting
Munazzah Ambreen, Phone: 416-813-7654, Ext: 2646, Email: munazzah.ambreen@sickkids.ca
Annette Feigenbaum, MD, Sub-Investigator
Andreas Schulze, MD, Principal Investigator

Oregon Health and Science University, Portland, Oregon 97239, United States; Recruiting
Tina Marrone, Phone: 503-418-3620, Email: marronet@ohsu.edu
Cary Harding, MD, Principal Investigator

Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, United States; Recruiting
Irma Payan, RN, Phone: 215-590-6236, Email: Payan@email.chop.edu
Marc Yudkoff, MD, Principal Investigator

Baylor College of Medicine, Houston, Texas 77030, United States; Recruiting
Mary Mullins, RN, BSN, Phone: 832-822-4263, Email: mullins@bcm.edu
Brendan Lee, MD, PhD, Principal Investigator

Children's Hospital and Regional Medical Center, Seattle, Washington 98105, United States; Recruiting
Linnea Brody, BS, MPH, Phone: 206-987-3694, Email: linnea.brody@seattlechildrens.org
Lawrence Merritt, MD, Principal Investigator

Urea Cycle Disorders Consortium website

Related publications:

Tuchman M, Lee B, Lichter-Konecki U, Summar ML, Yudkoff M, Cederbaum SD, Kerr DS, Diaz GA, Seashore MR, Lee HS, McCarter RJ, Krischer JP, Batshaw ML; Urea Cycle Disorders Consortium of the Rare Diseases Clinical Research Network. Cross-sectional multicenter study of patients with urea cycle disorders in the United States. Mol Genet Metab. 2008 Aug;94(4):397-402. Epub 2008 Jun 17.

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;:11-5.

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. Epub 2008 Sep 7.

Mitchell S, Ellingson C, Coyne T, Hall L, Neill M, Christian N, Higham C, Dobrowolski SF, Tuchman M, Summar M; the Urea Cycle Disorder Consortium. Genetic variation in the urea cycle: a model resource for investigating key candidate genes for common diseases. Hum Mutat. 2008 Jul 29; [Epub ahead of print]

Starting date: February 2006
Last updated: February 8, 2012