History
The neonatal presentation of argininosuccinate (ASA) lyase deficiency is consistent with the clinical manifestations of hyperammonemia. The multiple primary causes of hyperammonemia, specifically the 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 can manifest clinically as some or all of the following symptoms:
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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)
The most striking clinical findings of each individual urea cycle disorder consequently relate to the foregoing constellation of symptoms and their temporal sequence.
Delayed development and mental retardation are among the long-term consequences in survivors who do not receive proper treatment.
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: Papilledema may be present if cerebral edema and increased intracranial pressure have occurred.
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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 is common.
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Neurologic
Poor coordination
Dysdiadochokinesia
Hypotonia or hypertonia
Ataxia
Tremor
Seizures and hypothermia
Lethargy progressing to combativeness, obtundation, and coma
Decorticate or decerebrate posturing
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Other: A distinguishing feature in the newborn period, unique to urea cycle defects, is the presence of trichorrhexis nodosa (friable hair). This may be observed clinically and is identifiable with microscopic examination. Trichorrhexis nodosa is likely to be much more apparent in older infants, who may also have a choreoathetotic movement disorder.
Causes
ASA lyase deficiency is an autosomal recessive genetic disorder. The gene for ASA lyase deficiency is located on chromosome 7 and has been mapped to the locus 7q11.2. The normal gene has been cloned and comprises approximately 35 kilobases and 16 exons. Approximately 160 mutational variants have been reported, most of which are private and vary widely in nature, from missense to deletions.
Urea cycle defects with resulting hyperammonemia are due to deficiencies of the enzymes involved in waste nitrogen metabolism. These 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).
Complications
In a follow-up study of patients with ASA lyase deficiency, hepatic fibrosis was reported in some cases [9] ; however, other studies have not confirmed this as a regular long-term complication, [10] while EEG changes progress independently of hyperammonemic control.
Untreated patients may develop cerebral edema and die, and some patients die despite treatment.
Mental retardation is a common sequela.
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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.
