Oxidative Stress, Inflammation and Acute Decompensation in Urea Cycle Disorders

The primary purpose of the proposed study is to characterize the oxidative stress and inflammatory cytokine status in UCD during baseline and decompensated states.

Study Overview

• Status: Terminated
• Conditions: Urea Cycle Disorders

Detailed Description

Protein turnover is a cyclic process with a net loss of protein in the fasting state and a net gain in the fed state contributing to nitrogen balance. These physiologic processes are impacted during infection; whole-body protein catabolism exceeds protein synthesis, resulting in net loss of whole-body protein. Patients with urea cycle disorders suffer episodes of periodic hyperammonemic crisis, often in association with intercurrent infections. The immediate cause of this decompensation is the increase in endogenous protein catabolism that is the endpoint of a cascade triggered by intercurrent illness. This increase in protein catabolism leads to elevations of serum amino acids and ammonia production, which cannot be eliminated by a dysfunctional urea cycle.

It is well known that infectious illnesses play a significant role in precipitating metabolic crises in urea cycle defects, presumably by triggering a cascade of events involving the release of inflammatory cytokines that lead to increased protein catabolism. Cytokines have also been implicated as distant mediators of oxidative stress. However, the correlation between oxidative stress, cytokine levels, and severity of a crisis is currently unclear.

The primary purpose of the proposed study is to characterize the oxidative stress and inflammatory cytokine status in UCD during baseline and decompensated states. The investigators will undertake measurements of selected markers of oxidative stress and cytokines in serum and urine during baseline and decompensated states in subjects with UCD in order to establish their prognostic value as biomarkers for disease severity and/or predictors of metabolic decompensation.

• Study Type: Observational
• Enrollment (Actual): 10

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5G 1X8
      • The Hospital for Sick Children
• United States
  • California
    • Los Angeles, California, United States, 90095
      • University of California, Los Angeles
  • Colorado
    • Aurora, Colorado, United States, 80045
      • The Children's Hospital, Aurora
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Medical Center
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota
  • New York
    • New York, New York, United States, 10029
      • Mount Sinai School of Medicine
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Case Western Medical College
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
  • Texas
    • Houston, Texas, United States, 77030
      • Baylor College of Medicine
  • Washington
    • Seattle, Washington, United States, 98105
      • Children's Hospital and Regional Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Urea cycle disorders Inherited metabolic disorders N-acetylglutamate synthase (NAGS) deficiency Carbamyl phosphate synthetase I (CPSI) deficiency Ornithine transcarbamylase (OTC) deficiency Argininosuccinate synthetase (AS) deficiency (Citrullinemia) Argininosuccinate lyase (AL) deficiency (argininosuccinic aciduria Arginase (ARG) deficiency (hyperargininemia) Hyperornithinemia, hyperammonemia and homocitrullinuria (HHH) syndrome, or mitochondrial ornithine carrier (ORNT) deficiency Citrullinemia type II, mitochondrial aspartate/glutamate carrier (CITR) deficiency

Description

Inclusion Criteria:

• Confirmed or highly-likely diagnosis of one of the eight UCDs as established for the Longitudinal Study (5101) (See section 4.2 Inclusion Criteria, Table 4 for diagnostic criteria for patients with UCD)
• Enrolled in Longitudinal Study of Urea Cycle Disorders (RDCRN UCDC #5101)

Exclusion Criteria:

• UCD patients who have undergone orthotopic liver transplantation
• Significant chronic medical co-morbidity that might confound the analysis as determined by the site investigators.

• Significant co-morbidities include but are not limited to:

  • diabetes, liver failure + cirrhosis
  • renal failure
  • cardiac disease
  • chronic inflammatory diseases
  • asthma requiring daily long-term control medications
  • significant respiratory disease.

Study Plan

How is the study designed?

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Laboratory values indicating oxidative stress	Laboratory values that indicate oxidative stress include IL-1, IL-2, IL-6, and IL-8. These values will be analyzed as a panel (not individually) comparing baseline values to values during periods of decompensation.	Change from baseline to period of decompensation up to one year

Collaborators and Investigators

• Sponsor: Mark Batshaw
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); Rare Diseases Clinical Research Network
• Investigators: Principal Investigator: George Diaz, Icahn School of Medicine at Mount Sinai

Study record dates

Study Major Dates

• Study Start: February 1, 2012
• Primary Completion (Actual): January 1, 2015
• Study Completion (Actual): July 1, 2015

Study Registration Dates

• First Submitted: February 8, 2012
• First Submitted That Met QC Criteria: February 29, 2012
• First Posted (Estimate): March 1, 2012

Study Record Updates

• Last Update Posted (Estimate): October 2, 2015
• Last Update Submitted That Met QC Criteria: October 1, 2015
• Last Verified: October 1, 2015

More Information

Terms related to this study

• Keywords: Urea cycle disorders
• Additional Relevant MeSH Terms: Pathologic Processes; Metabolic Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Genetic Diseases, Inborn; Metabolism, Inborn Errors; Brain Diseases, Metabolic; Brain Diseases, Metabolic, Inborn; Amino Acid Metabolism, Inborn Errors; Disease; Inflammation; Urea Cycle Disorders, Inborn
• Other Study ID Numbers: RDCRN 5109; U54HD061221 (U.S. NIH Grant/Contract)