History
The multiple primary causes of hyperammonemia, specifically those due to urea cycle enzyme deficiencies, somewhat vary in presentation, diagnostic features, and treatment. For these reasons, the family of urea cycle defects is considered individually in this article; however, the common denominator, hyperammonemia, can be manifested clinically by some or all of the following:
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Anorexia
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Irritability
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Heavy or rapid breathing
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Lethargy
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Vomiting
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Disorientation
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Somnolence
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Asterixis (rare)
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Combativeness
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Obtundation
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Coma
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Cerebral edema
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Death, if treatment is not forthcoming or effective
As a consequence, the most striking clinical findings of each urea cycle disorder relate to this constellation of symptoms and rough temporal sequence of events.
Physical
See the list below:
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General
Signs of severe hyperammonemia may be present.
Poor growth may be evident.
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Head, ears, eyes, nose, and throat (HEENT): Papilledema may be present if cerebral edema and increased intracranial pressure have ensued.
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Pulmonary
Tachypnea or hyperpnea may be present.
Apnea and respiratory failure may occur in later stages.
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Abdominal: Hepatomegaly may be present and is usually mild.
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Neurologic
Poor coordination
Dysdiadochokinesia
Hypotonia or hypertonia
Ataxia
Tremor
Seizures and hypothermia
Lethargy progressing to combativeness to obtundation to coma
Decorticate or decerebrate posturing
Causes
The mode of inheritance is an autosomal recessive inheritance pattern.
The NAGS gene was the last one of the urea cycle to be cloned. The gene locus is 17q21.31, spans 4.5 kb, and contains 6 introns and 7 exons. The 534 amino acid residues contained in the ribosomal protein are reduced to 486 by cleavage at the N -terminus upon import to the mitochondrion. At least 22 pathogenic mutations have been reported, 10 of which were associated with acute neonatal presentation. [5] Interestingly, no mutations were found in exon 1, which is believed to code for the 50 amino acid mitochondrial-targeting segment that is cleaved.
Urea cycle defects with resulting hyperammonemia are due to deficiencies of the enzymes involved in the metabolism of waste nitrogen. The enzyme deficiencies lead to disorders with nearly identical clinical presentations. The exception is arginase, the last enzyme of the cycle; arginase deficiency causes a somewhat different set of signs and symptoms.
Complications
Possible complications include cerebral edema with resulting brain damage or death.
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Compounds comprising the urea cycle are numbered sequentially, beginning with carbamyl phosphate (1). At this step, the first waste nitrogen is incorporated into the cycle; at this step, N-acetylglutamate exerts its regulatory control on the mediating enzyme, carbamyl phosphate synthetase (CPS). Compound 2 is citrulline, the product of condensation between carbamyl phosphate (1) and ornithine (8); the mediating enzyme is ornithine transcarbamylase. Compound 3 is aspartic acid, which is combined with citrulline to form argininosuccinic acid (ASA) (4); the reaction is mediated by ASA synthetase. Compound 5 is fumaric acid generated in the reaction that converts ASA to arginine (6), which is mediated by ASA lyase.
