• Inborn error of metabolism
• X chromosome inactivation
• Manifesting heterozygotes
• Asymptomatic carriers
• Germline mutation rate much greater in spermatogenesis than in oogenesis
Major Phenotypic Features
• Age at onset: Hemizygous male with null mutation—neonatal; heterozygous female—with severe intercurrent illness, postpartum, or never
History and Physical Findings
J.S. is a 4-day-old male infant brought to the emergency department because he could not be aroused. The parents reported a history of 24 hours of decreased intake, vomiting, and increasing lethargy. He was the 3-kg, full-term product of an uncomplicated gestation born to a healthy 26-year-old primiparous woman. Physical examination showed a comatose, hyperpneic, nondysmorphic male newborn. Initial laboratory evaluation revealed a blood NH3 concentration of 900 μM (normal in a newborn is <75) and elevated venous pH of 7.48, with a normal bicarbonate concentration and anion gap. A urea cycle disorder was suspected, so plasma amino acid levels were determined on an emergency basis. Glutamine was elevated at 1700 μM (normal, <700 μM), and citrulline was undetectable (normal is 7 to 34 μM) (Fig. C-36). Analysis of urine for organic acids was normal; urinary orotic acid was extremely elevated. Elevated urine orotic acid levels with low citrulline indicates a diagnosis of ornithine transcarbamylase deficiency pending confirmation by mutation analysis.
FIGURE C-36 The urea cycle. AL, Argininosuccinate lyase; AS, argininosuccinate synthetase; CAP, carbamoyl phosphate; CPS I, carbamoyl phosphate synthetase I; OTC, ornithine transcarbamylase.
Further questioning of J.S.'s mother revealed that she had a lifelong aversion to protein and a brother who died in the first week of life of unknown causes. J.S. was started on intravenous sodium benzoate and sodium phenylacetate (Ammonul) and arginine hydrochloride supplementation. The child was transported by air to a tertiary care center equipped for neonatal hemodialysis. On arrival, his plasma NH3 level had dropped to 700 μM. The parents were counseled about the high risk for brain damage from this degree of hyperammonemia. They elected to proceed with hemodialysis, which was well tolerated and resulted in decline of the blood NH3 to less than 200 μM after 4 hours. The child was maintained on Ammonul and high calories from intravenous dextrose and intralipids until the NH3 level was normal, at which point he was slowly started on a protein-restricted diet and monitored for hyperammonemia, especially during intercurrent illnesses. His prognosis remains guarded.
Disease Etiology and Incidence
Ornithine transcarbamylase (OTC) deficiency (MIM 311250) is a panethnic X-linked disorder of urea cycle metabolism caused by mutations of the gene encoding ornithine transcarbamylase (OTC). It has an incidence of 1 in 30,000 males. The exact incidence of manifesting females is unknown.
Ornithine transcarbamylase is an enzyme in the urea cycle (see Fig. C-36). The urea cycle is the mechanism by which waste nitrogen is detoxified and excreted. Complete deficiency of any enzyme within the cycle (except arginase) leads to severe hyperammonemia in the neonatal period. For patients with urea cycle defects, arginine becomes an essential amino acid (see Fig. C-36). In utero, excess nitrogen is metabolized by the mother. Postnatally, however, accumulation of waste nitrogen in the extremely catabolic period after birth leads to elevation of glutamine and alanine, the body's natural pools for nitrogen, and ultimately to elevated levels of NH3 ion. Plasma NH3 levels above 200 micromolar may cause brain damage; the degree of brain damage is related to how high the concentrations of NH3 and glutamine in the blood rise and how long the elevations persist. Thus early detection and treatment are critical to outcome.
Males are hemizygous for the OTC gene and are therefore more severely affected by mutations in this gene. Because OTC undergoes random X chromosome inactivation (see Chapter 6), females are mosaic for expression of the mutation and can demonstrate a wide range of enzyme function and clinical severity. Female heterozygotes can be completely asymptomatic and able to eat as much protein as they wish. Alternatively, if their loss of OTC activity is more significant, they may find themselves avoiding dietary protein and subject to recurrent, symptomatic hyperammonemia.
Phenotype and Natural History
Males with complete OTC deficiency are born normal but begin vomiting, become lethargic, and eventually lapse into coma between 48 and 72 hours of age. Because they have been vomiting, they are usually dehydrated as well. Untreated males with null mutations usually die in the first week of life. Even if the patient with OTC deficiency is promptly and successfully treated in the neonatal period, the risk remains high for recurrent bouts of hyperammonemia, particularly during intercurrent illnesses, because complete control of severe OTC deficiency is difficult, even with dietary protein restriction and medications that divert the NH3 to nontoxic pathways (see Chapter 13). With each episode of hyperammonemia, the patient may suffer brain damage or die in a matter of only a few hours after the onset of metabolic decompensation.
Girls (or boys with partial OTC deficiency) are usually asymptomatic in the neonatal period but may develop hyperammonemia during intercurrent febrile illnesses, such as influenza, or with excessive dietary protein intake. Other catabolic stresses, such as surgery, pregnancy, or long bone fracture, may also precipitate hyperammonemia. Like affected males, symptomatic females are at risk for brain damage and intellectual disability, but these serious complications can usually be prevented by anticipating them and instituting aggressive interventions to prevent catabolism.
OTC deficiency and carbamoyl phosphate synthetase deficiency (see Fig. C-36) cannot be detected by newborn screening. Abnormal metabolites that occur in other enzyme deficiencies within the urea cycle, however, can be detected by tandem mass spectrometry of serum amino acids (see Chapter 18).
Plasma NH3 concentration should be measured in any sick neonate. For most urea cycle defects, the pattern of abnormalities on quantitative amino acid determination is diagnostic. To distinguish between OTC deficiency and carbamoyl phosphate synthetase deficiency, both of which are characterized by very low or absent citrulline, it is necessary to measure urine orotic acid, which is elevated in OTC deficiency. Determination of urine organic acids is also important to rule out an organic aciduria, which can also present with hyperammonemia in the newborn period. Molecular testing is available to confirm the diagnosis.
Acutely hyperammonemic patients should be treated with a four-pronged approach: (1) 10% dextrose at twice the maintenance rate to provide calories in the form of sugar for gluconeogenesis and thereby reduce catabolism of endogenous proteins, and elimination of dietary protein intake; (2) intravenous Ammonul, a solution of sodium benzoate and sodium phenylacetate, both of which provide diversion therapy by driving the excretion of nitrogen independently of the urea cycle (see Chapter 13); (3) intravenous arginine hydrochloride to provide adequate amounts of arginine, an essential amino acid, and to drive any residual enzyme activity by ensuring adequate substrate to the urea cycle; and (4) if a patient does not respond to the initial bolus of these medications, hemodialysis.
Chronic management entails careful control of dietary calories and protein as well as oral phenylbutyrate. Maintenance of a high carbohydrate intake spares endogenous protein from being catabolized for gluconeogenesis; dietary protein restriction reduces the load of NH3 requiring detoxification through the urea cycle. Phenylbutyrate is readily converted to phenylacetate, which promotes non–urea cycle dependent nitrogen excretion. The family must be carefully trained to look for early signs of hyperammonemia, such as irritability, vomiting, and sleepiness, so that the patient can be promptly brought to the hospital for intravenous treatment.
Because of the great difficulty in achieving metabolic control and the substantial risk for brain damage or death within hours of the onset of metabolic decompensation, liver transplantation to provide a functioning urea cycle should be presented as an option as soon as a patient has grown sufficiently (>10 kg) to tolerate the procedure.
OTC deficiency is inherited as an X-linked trait. Because OTC deficiency is nearly always a genetic lethal disorder, approximately 67% of the mothers of affected infants would be expected to be carriers, as discussed in Chapters 7 and 16. Surprisingly, studies in families with OTC deficiency indicate that 90% of the mothers of affected infants are carriers. The reason for this discrepancy between the theoretical and actual carrier rates is that the underlying assumption of equal male and female mutation rates used for the theoretical calculation is incorrect. In fact, mutations in the OTC gene are much more frequent (≈50-fold) in the male germline than in the female germline. Most of the mothers of an isolated boy with OTC deficiency are carriers as a result of a new mutation inherited on the X chromosome they received from their fathers.
In a woman who is a carrier of a mutant OTC deficiency allele, her sons who receive the mutant allele will be affected and her daughters will be carriers who may or may not be symptomatic, depending on random X inactivation in the liver. Males with partial OTC deficiency who reproduce will have all carrier daughters and no affected sons. When the mutation in the family is known, prenatal testing by examination of the gene is available. Prenatal diagnosis by assay of the OTC enzyme is not practical because the enzyme is not expressed in chorionic villi or amniotic fluid cells.
Questions for Small Group Discussion
1. Discuss the Lyon hypothesis and explain the variability of disease manifestations in females.
2. Why is arginine an essential amino acid in this disorder? Arginine is ordinarily not an essential amino acid in humans.
3. What organic acidurias cause hyperammonemia?
4. What are some of the reasons both for and against performing a liver transplant for OTC deficiency? Is a liver transplant for OTC deficiency more or less helpful than for other inborn errors of metabolism?
Lichter-Konecki U, Caldovic L, Morizono H, et al. Ornithine transcarbamylase deficiency. [Available from] http://www.ncbi.nlm.nih.gov/books/NBK154378/.