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  • Writer's pictureDr Edin Hamzić

🧬 Key Facts You Must Know About OTC Deficiency?

Updated: Jan 6

❓What Is OTC Deficiency?

  • ⚠️ Ornithine transcarbamylase (OTC) deficiency is a genetic disorder that affects the urea cycle. Urea cycle can be defined as a series of biochemical processes in the liver responsible for converting ammonia into urea for excretion.

  • In the case of OTC deficiency, the enzyme ornithine transcarbamylase (OTC) is either missing or not working correctly, leading to a buildup of ammonia in the blood. 

  • ⚠️ Ornithine transcarbamylase (OTC) deficiency is the most common urea cycle defect. OTC is the enzyme that catalyzes the condensation of carbamyl phosphate and ornithine to form citrulline. As already mentioned, deficiency of OTC results in the buildup of carbamyl phosphate, which enters the cytoplasm and is available for de novo pyrimidine biosynthesis. As a result, orotic acid and uracil will be elevated and excreted into the urine.

Pathway involving ornithine transcarbamylase (OTC)

🏥 What Are the Signs and Symptoms of OTC Deficiency?

The buildup of ammonia in the blood, caused by OTC deficiency can lead to:

  1. Elevated ammonia levels lead to hyperammonemia, which is toxic to the brain.

  2. Neurological symptoms include lethargy, irritability, and changes in behavior or mental status.

  3. Poor feeding and vomiting are common in infants.

  4. Developmental delays are seen in children due to the effect on the central nervous system.

  5. In severe cases, it also includes altered mental status and coma, especially when OTC is undiagnosed or untreated.

🧬 What Causes OTC Deficiency? Genetics of OTC Deficiency?

  • ⚠️OTC deficiency is an X-linked genetic disorder, meaning it predominantly affects males.

  • The enzyme is a homotrimer encoded by the gene OTC located on the X chromosome at position Xp11.4. As already mentioned, males tend to have a more severe presentation and worse prognosis, and male infants are at risk of acute metabolic decompensation.

  • Female carriers of the defect may be more or less symptomatic because of skewed X-chromosome inactivation.

👨🏾‍🤝‍👨🏽 What Are Disorders With Similar Symptoms to OTC Deficiency?

Other disorders with symptoms similar to OTC deficiency, affecting the urea cycle, include:

  1. Argininosuccinic aciduria leads to the buildup of ammonia and argininosuccinic acid in the blood.

  2. Citrullinemia causes elevated blood ammonia and citrulline levels.

  3. Carbamoyl phosphate synthetase I deficiency results in hyperammonemia due to impaired urea cycle functioning.

  4. N-acetylglutamate synthase deficiency is characterized by elevated ammonia levels due to reduced activation of the urea cycle.

  5. Argininemia: Causes high blood arginine levels, along with symptoms of hyperammonemia.

All these disorders share common symptoms like lethargy, vomiting, irritability, and potential neurological impairment due to the accumulation of ammonia and other toxic substances in the blood. 

📊 How Common Is OTC Deficiency?

  • ⚠️ A study specific to Japan estimated that OTC deficiency has a frequency of 1 in 80,000 births [citation].

  • The total frequency of this and the other urea cycle enzymopathies, carbamoyl phosphate synthetase deficiency, argininosuccinate synthetase deficiency, argininosuccinate lyase deficiency, and arginase deficiency, in Japan, was 1 in 46,000.

  • ⚠️ The other study estimated the prevalence of OTC to range from 1 in 40,000 to 1 in 80,000 [citation]. 

🧪 How To Test for OTC Deficiency?

The following compounds can be used to determine the indication for OTC deficiency:

  1. Elevated concentrations of orotic acid and uracil in urine. This can be assessed from the urine organic acid profile.

  2. Ammonia concentrations are really important in monitoring OTC deficiency.

  3. Diagnosis can be confirmed by molecular genetic testing for pathogenic mutations in the OTC gene.


👨🏽‍⚕️ How Is OTC Deficiency Treated?

  • Treatment often includes dietary restrictions, medications to remove ammonia from the body, and, in some cases, liver transplantation.


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