Ornithine transcarbamylase deficiency also known as OTC deficiency is the most common urea cycle disorder in humans. Ornithine transcarbamylase, the defective enzyme in this disorder, is the final enzyme in the proximal portion of the urea cycle, responsible for converting carbamoyl phosphate and ornithine into citrulline. OTC deficiency is inherited in an X-linked recessive manner, meaning males are more commonly affected than females.

In severely affected individuals, ammonia concentrations increase rapidly causing ataxia, lethargy and death without rapid intervention. OTC deficiency is diagnosed using a combination of clinical findings and biochemical testing, while confirmation is often done using molecular genetics techniques.

Once an individual has been diagnosed, the treatment goal is to avoid precipitating episodes that can cause an increased ammonia concentration. The most common treatment combines a low protein diet with nitrogen scavenging agents. Liver transplant is considered curative for this disease. Experimental trials of gene therapy using adenoviral vectors resulted in the death of one participant, Jesse Gelsinger, and have been discontinued.

Signs and symptoms

As with several other metabolic conditions, OTC deficiency can have variable presentations regarding age of onset and the severity of symptoms. This is compounded when considering heterozygous females and the possibility of non-random X-inactivation.

Males with some residual function of the enzyme can present later in life.

In the classic and most well-known presentation, a male newborn infant appears well initially, but by the second day of life they are irritable, lethargic and stop feeding. A metabolic encephalopathy develops, which can progress to coma and death without treatment.

Later onset forms of OTC deficiency can have variable presentations. Although late onset forms of the disease are often considered milder than the classic infantile presentation, any affected individual is at risk for an episode of hyperammonemia that could still be life-threatening, if presented with the appropriate stressors. These individuals will often present with headaches, nausea, vomiting, growth delay and a variety of psychiatric symptoms (confusion, delirium, aggression, or self-injury). OTC codes for the mitochondrial enzyme ornithine transcarbamylase, which is expressed only in liver. The functional enzyme consists of three identical subunits. OTC is the last enzyme in the proximal portion of the urea cycle, which consists of the reactions that take place in the mitochondria. The substrates of the reaction catalyzed by ornithine transcarbamylase are ornithine and carbamyl phosphate, while the product is citrulline.

Gene therapy had been considered a possibility for curative treatment for OTC deficiency, and clinical trials were taking place at the University of Pennsylvania in the late 1990s. These were halted after the death of Jesse Gelsinger, a young man taking part in a phase I trial using an adenovirus vector. Currently, the only option for curing OTC deficiency is a liver transplant, which restores normal enzyme activity. A 2005 review of 51 patients with OTC deficiency who underwent liver transplant estimated 5-year survival rates of greater than 90%.

Society and culture

Ornithine transcarbamylase deficiency was the final diagnosis of a patient treated in the 15th episode of 1st season of House, M. D. It was also the final diagnosis of a patient that died in the 3rd episode of 3rd season of Chicago Med.

References

  • http://www.nucdf.org
  • http://www.otcdeficiency.com