History
In homozygous neonates, early-onset lethargy and, in some cases, seizures are often the first signs of abnormality. Because the fetus is generally anabolic and maternal metabolism can usually manage the additional ammonia load from the fetus, intrauterine development is completely unaffected. Therefore, infants are usually born at term following a completely uneventful pregnancy and delivery.
Ammonia levels begin to rise after the maternal-fetal circulation is interrupted at birth, with a brief period of fasting. The baby becomes irritable, then lethargic, and, if untreated, comatose. Without rapid recognition and aggressive treatment, the infant suffers devastating CNS damage, coma, and death.
Some individuals with carbamoyl phosphate synthetase (CPS) deficiency reach adulthood prior to diagnosis. One known case involved a college-educated homozygous woman whose clinical onset occurred within hours after childbirth and resulted in death. [5]
The multiple primary causes of hyperammonemia, specifically those due to urea cycle enzyme deficiencies, vary in manifestation, diagnostic features, and management. For these reasons, the urea cycle defects are considered individually in this article; however, hyperammonemia is the common denominator and generally manifests clinically as a common constellation of signs and symptoms. As a consequence, the most striking clinical findings of each individual urea cycle disorder relate to this constellation of symptoms and rough temporal sequence of events. Symptoms include 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)
Physical
General
Signs of severe hyperammonemia may be present (see Hyperammonemia).
Poor growth may be evident.
Head, ears, eyes, nose, and throat (HEENT)
Papilledema may be present if cerebral edema and increased intracranial pressure have occurred.
Pulmonary
See the list below:
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Tachypnea or hyperpnea may be present.
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Apnea and respiratory failure may occur in later stages.
Abdominal
Hepatomegaly may be present and is usually mild.
Neurologic
See the list below:
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Poor coordination
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Dysdiadochokinesia
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Hypotonia or hypertonia
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Ataxia
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Tremor
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Seizures and hypothermia
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Lethargy progressing to combativeness, obtundation, and coma
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Decorticate or decerebrate posturing
Causes
CPS I deficiency is autosomal recessive. The structural gene for the enzyme is assigned to chromosome 2 and mapped to band 2q35. It has been sequenced and cloned.
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 (see Arginase Deficiency).
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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.
