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.

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.

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

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.

• Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Rare Diseases Clinical Research Network