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Key Points

  • Disease summary:

    • Hyperammonemia in adults has many different causes. Most are nongenetic. Infrequent but important genetic causes are defects in the urea cycle which are life threatening and treatable.

    • Urea cycle disorders (UCDs) are caused by defects in the metabolic cycle which converts ammonia to urea.

    • The adult phenotype may present dramatically or subtly with hyperammonemia of varying degree that can produce cerebral edema. The clinical features include psychosis, altered mental status, vomiting, and focal neurologic signs, or lethargy progressing to obtundation and coma. Acute episodes are often precipitated by surgery, pregnancy, or more likely the postpartum, trauma, and infection.

    • Chronic features include cognitive and learning deficits, intermittent headaches, intermittent visual disturbances, and focal neurologic signs. There may also be a lifelong aversion to dietary protein.

  • Hereditary basis:

    • All the UCDs are inherited in an autosomal recessive manner with the exception of ornithine transcarbamylase (OTC) deficiency which is X-linked.

  • Differential diagnosis:

    • Liver failure

    • Sepsis

    • Valproate therapy

Diagnostic Criteria and Clinical Characteristics

Diagnostic Criteria

  • High ammonia (>100 μmol/L)

  • Abnormal plasma amino acid profile

    • Low or high citrulline

    • Presence of argininosuccinic acid

    • Low or high arginine

  • Low or high orotic acid in urine

  • In the absence of

    • Liver failure

    • Overwhelming sepsis

    • Metabolic acidosis

Clinical Characteristics

UCDs interrupt the conversion of ammonia to urea (Fig. 91-1). Ammonia is generated as a by-product of protein catabolism and elevated ammonia levels (>100 μmol/L) appear to be extremely toxic to the central nervous system. UCD in adults can present with chronic symptoms of intermittent headaches, intermittent visual disturbances, cognitive and learning deficits, and focal neurologic signs. These adults have self-selective dietary protein aversion. Acute episodes can be triggered by increased dietary intake of protein or secondary to increased protein breakdown related to catabolic states, such as infection, trauma, surgery, pregnancy, or the postpartum. These symptoms may resolve spontaneously or may progress to hyperammonemic encephalopathy. Patients may present acutely with vomiting, anorexia, lethargy, altered mental status, seizures, focal neurologic signs, or psychosis. Hepatomegaly may be present on clinical examination. Hyperammonemia can produce cerebral edema and patients, if untreated, continue to deteriorate, become comatose, and may die from cerebral herniation. Upon recovery, patients may be left with significant neurologic deficits.

Figure 91-1
Urea Cycle. Enzymes are labeled in bold. Defect in the enzymes causes urea cycle disorders.

While the urea cycle disorders usually present in infancy or childhood, often dramatically, all have a late-onset form that presents in adulthood with hyperammonemia and is related to partial (hypomorphic) rather than complete enzyme deficiencies. Due to random X-chromosome inactivation, approximately 15% of female carriers with a defect in OTC develop hyperammonemia. Arginase (ARG) deficiency typically presents as a chronic neurologic problem with cognitive reduction and spastic diplegia. Unlike the dramatic clinical ...

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