What is ornithine transcarbamylase deficiency?

Risk Factors

There are no known risk factors for OTC deficiency. As an X-linked defect, the incidence in males is higher than in females; however, heterozygous females may be affected.

Etiology and Genetics

Ornithine transcarbamylase, found primarily in liver mitochondria, is an early enzyme in the urea cycle. In this cycle, ammonia, produced by the degradation of proteins and the subsequent deamination of their constituent amino acids, is converted to urea, which can be safely eliminated. When ornithine transcarbamylase is missing, carbamyl phosphate, formed in part from ammonia released by deamination of amino acids, cannot combine with ornithine. As carbamyl phosphate concentrations rise in the liver, ammonia is released into the circulatory system.

The gene coding for ornithine transcarbamylase is located on the short arm of the X chromosome at position p21.1. As with all X-linked genes, since males have only a single X chromosome, alleles on this X are expressed whether they are dominant or recessive. Females have two X chromosomes and thus can be heterozygous for X-linked genes. More than three hundred different mutations of the ornithine transcarbamylase gene are known. Males who inherit an X chromosome that leads to little or no enzyme activity have severe early-onset symptoms with high morbidity and mortality. Most males with late-onset symptoms have mutations that lead to enzymes with lowered activity ranging from 26 to 74 percent of normal.

Expression of the OTC deficiency phenotype in females is quite variable and depends on both the pattern of X chromosome inactivation in the liver and the type of mutation inherited. If a female is heterozygous for a normal and a deficient OTC allele, then her liver is a mosaic, since one X chromosome is randomly inactivated in each cell. If, in a heterozygous female’s liver, the majority of cells have the normal X turned off, then she will show more symptoms of her OTC deficient allele. If, on the other hand, more of the OTC deficient X chromosomes are turned off, then she may have few if any symptoms. Females thus can vary from being severely affected to being asymptomatic.

The estimated incidence of early-onset OTC deficiency is 1 in 80,000 live births. When male late-onset OTC deficiency and variable female expression are included, estimates run as high as 1 in 20,000 live births.

Symptoms

The primary symptom of OTC deficiency is hyperammonemia. In early-onset OTC deficiency, as the excess ammonia reaches the central nervous system, lethargy, anorexia, and a general failure to thrive are often the first readily apparent symptoms. These are followed by disorientation, seizures, combativeness, somnolence, coma, and finally death. In those that survive, mental retardation is common. Many of these same symptoms, sometimes less severe, are seen in late-onset OTC deficiency. Often symptoms appear after stressors such as infections, surgery, and high-protein meals. Because of mosaicism, symptoms in female heterozygotes vary widely. Symptoms can be as severe as in affected males, or can be quite minor. In some women, the only symptom is migraine headaches after eating meals rich in protein. Some asymptomatic women show hyperammonemia during pregnancy or shortly after childbirth.

Screening and Diagnosis

The primary diagnostic characteristic of OTC deficiency is the demonstration of hyperammonemia. In addition, elevated urinary output of orotic acid can be used to identify patients and sometimes asymptomatic carriers. Levels of OTC can be measured in the fetus for prenatal diagnosis. Genetic counseling is recommended for families in which this disease has occurred.

Treatment and Therapy

Several treatment options are available to prevent or lessen the severity of the hyperammonemia. First, a patient needs to be on a very low protein diet, which must be maintained for life. Deviation from the diet, especially during infancy, childhood, and adolescence, can lead to coma and death. Sodium benzoate, arginine, and sodium phenylacetate may be administered intravenously and citrulline may be taken orally to reduce ammonia levels in the blood. Hemodialysis can be used on comatose patients with extremely high ammonia levels and liver transplant can also be an effective treatment.

Prevention and Outcomes

Symptoms can be lessened by diet and medication but the disease itself cannot be prevented. Unfortunately, unless the disease is diagnosed prenatally, some nervous system damage usually occurs before diagnosis. Without treatment, the early-onset disease is lethal in infancy. With treatment, children can survive longer but often succumb at an early age because the correct balance of diet and medication is difficult to maintain. Late-onset OTC deficiency can often be managed with dietary restrictions since many late-onset patients are not completely enzyme-deficient; however, late-onset deficiency can lead to sudden death when ammonia levels rise sharply.

Bibliography

Arranz, J. A., et al. “The Relationship of OTC Structure to Disease Severity.” Journal of Inherited Metabolic Disease 30 (2007): 217–26. Print.

Nightengale, Scott, et al. "Late-Onset Ornithine Transcarbamylase Deficiency Presenting with Asymptomatic Liver Dysfunction." Journal of Pediatric Gastroenterology and Nutrition 58.6 (2014): e55–e57. Print

Rush, Eric T., et al. "Late-Onset Ornithine Transcarbamylase Deficiency: An Under Recognized Cause of Metabolic Encephalopathy." SAGE: Open Medical Case Reports 2 (July 2014): 1–4. Print.

Tuchman, M., et al. “The Molecular Basis of OTC Deficiency.” European Journal of Pediatrics 159 Suppl. 3 (2000): S196–98. Print.

Wilemon, Tom. "Weight-loss Surgery Triggered Rare Genetic Wasting Disorder." USA Today. Gannett, 15 May 2012. Web. 4 Aug. 2014.

Wilken, B. “Management of Patients with OTC Deficiency.” Molecular Genetics and Metabolism 81 Suppl 1 (2004): S86–91. Print.