The Urea Cycle Disorders Consortium
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Urea Cycle Disease Overview:

Overview

The urea cycle disorders (UCD) result from defects in the metabolism of the extra nitrogen produced by the breakdown of protein and other nitrogen-containing molecules. Severe deficiency or total absence of activity of any of the first four enzymes (CPSI, OTC, ASS, ASL) in the urea cycle or the cofactor producer (NAGS) results in the accumulation of ammonia and other precursor metabolites during the first few days of life. Infants with a urea cycle disorder often initially appear normal but rapidly develop cerebral edema and the related signs of lethargy; anorexia; hyperventilation or hypoventilation; hypothermia; seizures; neurologic posturing; and coma. In milder (or partial) urea cycle enzyme deficiencies, ammonia accumulation may be triggered by illness or stress at almost any time of life, resulting in multiple mild elevations of plasma ammonia concentration [Bourrier et al 1988]. The hyperammonemia is less severe and the symptoms more subtle. Patients with Arginase Deficiency may present with hyperammonemia with severe stress, but are more likely to present with progressive neurologic symptoms unrelated to hyperammonemic episodes. The mainstays of treatment for all urea cycle disorders are 1) reducing plasma ammonia concentration, 2) pharmacologic management to allow alternative pathway excretion of excess nitrogen, 3) reducing the amount of nitrogen in the diet, 4) reducing catabolism through the introduction of calories supplied by carbohydrates and fat, and 5) reducing the risk of neurologic damage.

Diagnosis/testing

The diagnosis of a urea cycle disorder is based on evaluation of clinical, biochemical, and molecular data. A plasma ammonia concentration of 150 mmol/L or higher, associated with a normal anion gap and a normal serum glucose concentration, is a strong indication for the presence of a UCD. Plasma quantitative amino acid analysis can be used to diagnose a specific urea cycle disorder. Plasma concentration of arginine may be reduced in all urea cycle disorders, except arginase deficiency, in which it is elevated. Plasma concentration of citrulline helps discriminate between the proximal and distal urea cycle defects, as citrulline is the product of the proximal enzymes (OTC and CPSI) and a substrate for the distal enzymes (ASS, ASL, ARG). Urinary orotic acid is measured to distinguish CPSI deficiency and NAGS deficiency from OTC deficiency. A definitive diagnosis of CPSI deficiency, OTC deficiency, or NAGS deficiency depends on determination of enzyme activity from a liver biopsy specimen; however, the combination of family history, clinical presentation, amino acid and orotic acid testing, and molecular genetic testing are often sufficient for diagnostic confirmation, eliminating the risks of liver biopsy. Molecular genetic testing is clinically available for all urea cycle disorders.

Severe deficiency of any of the first four enzymes (CPSI, OTC, ASS, ASL) in the urea cycle or the cofactor producer (NAGS) results in the accumulation of ammonia and other precursor metabolites during the first few days of life. Since no effective secondary clearance system for ammonia exists, disruption of this pathway results in the rapid development of symptoms. Severity of the disease is influenced by the position of the defective enzyme in the pathway and the severity of the enzyme defect. The catabolism normally present in the newborn period combines with the immaturity of the neonatal liver to accentuate defects in these enzymes [Batshaw 1984, Summar 2001, Summar & Tuchman 2001]. Infants with a urea cycle disorder often initially appear normal but rapidly develop cerebral edema and the related signs of lethargy; anorexia; hyperventilation or hypoventilation; hypothermia; seizures; neurologic posturing; and coma.

Because newborns are usually discharged from the hospital within one to two days after birth, the symptoms of a urea cycle disorder are often not seen until the child is at home and may not be recognized in a timely manner by the family and primary care physician. The typical initial symptoms of a child with hyperammonemia are non-specific: failure to feed, loss of thermoregulation with a low core temperature, and somnolence [Brusilow 1985, Batshaw & Berry 1991, Summar 2001].

Symptoms

Symptoms progress from somnolence to lethargy and coma. Abnormal posturing and encephalopathy are often related to the degree of central nervous system swelling and pressure upon the brain stem [Brusilow 1985, Batshaw & Berry 1991, Summar 2001]. About 50% of neonates with severe hyperammonemia have seizures. Hyperventilation, secondary to cerebral edema, is a common early finding in a hyperammonemic attack, which causes a respiratory alkalosis. Hypoventilation and respiratory arrest follow as pressure increases on the brain stem [Batshaw 1984, Brusilow 1985, Batshaw & Berry 1991, Summar 2001, Summar & Tuchman 2001].

In milder (or partial) urea cycle enzyme deficiencies, ammonia accumulation may be triggered by illness or stress at almost any time of life, resulting in multiple mild elevations of plasma ammonia concentration [Bourrier et al 1988]. The hyperammonemia is less severe and the symptoms more subtle. In patients with partial enzyme deficiencies, the first recognized clinical episode may be delayed for months or years. Although the clinical abnormalities vary somewhat with the specific urea cycle disorder, in most the hyperammonemic episode is marked by loss of appetite, cyclical vomiting, lethargy, and behavioral abnormalities. Sleep disorders, delusions, hallucinations, and psychosis may occur. An encephalopathic (slow wave) EEG pattern may be observed during hyperammonemia and non-specific brain atrophy may be seen subsequently on MRI [Batshaw 1984, Brusilow 1985, Bourrier et al 1988].