N-Acetylglutamate Synthetase Deficiency Clinical Presentation

Updated: Feb 18, 2019
  • Author: Karl S Roth, MD; Chief Editor: Luis O Rohena, MD, MS, FAAP, FACMG  more...
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Presentation

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:

  • Anorexia
  • Irritability
  • Heavy or rapid breathing
  • Lethargy
  • Vomiting
  • Disorientation
  • Somnolence
  • Asterixis (rare)
  • Combativeness
  • Obtundation
  • Coma
  • Cerebral edema
  • 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.

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Physical

See the list below:

  • General

    • Signs of severe hyperammonemia may be present.

    • Poor growth may be evident.

  • Head, ears, eyes, nose, and throat (HEENT): Papilledema may be present if cerebral edema and increased intracranial pressure have ensued.

  • Pulmonary

    • Tachypnea or hyperpnea may be present.

    • Apnea and respiratory failure may occur in later stages.

  • Abdominal: Hepatomegaly may be present and is usually mild.

  • Neurologic

    • Poor coordination

    • Dysdiadochokinesia

    • Hypotonia or hypertonia

    • Ataxia

    • Tremor

    • Seizures and hypothermia

    • Lethargy progressing to combativeness to obtundation to coma

    • Decorticate or decerebrate posturing

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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.

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Complications

Possible complications include cerebral edema with resulting brain damage or death.

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