Ornithine transcarbamylase (OTC) deficiency is a rare genetic disorder that impacts the body’s ability to remove ammonia, a toxic waste product. It is considered the most common type of urea cycle disorder. If not managed, this condition can lead to severe health problems, including neurological damage. The severity of OTC deficiency can vary widely, from a life-threatening form in newborns to milder presentations later in life.
The Role of OTC and Its Deficiency
The human body continuously breaks down proteins, generating ammonia as a byproduct that must be converted into a less harmful substance for excretion. This conversion primarily occurs in the liver through the urea cycle. The ornithine transcarbamylase (OTC) enzyme plays a central role within this cycle, converting carbamoyl phosphate and ornithine into citrulline, a key step in processing nitrogen waste into urea.
When the OTC enzyme is deficient, the urea cycle cannot properly convert ammonia into urea. This leads to a dangerous accumulation of ammonia in the bloodstream (hyperammonemia), which is particularly harmful to the brain. The body buffers excess ammonia by converting it into glutamine, leading to elevated glutamine levels.
OTC deficiency is a genetic disorder caused by mutations in the OTC gene. Located on the X chromosome, the OTC gene makes the condition an X-linked recessive disorder. Males, with only one X chromosome, are typically more severely affected than females. Females have two X chromosomes; if one carries the mutation, the other can often compensate, leading to a spectrum of symptoms from asymptomatic to severe.
Recognizing Signs and Symptoms
OTC deficiency symptoms vary significantly depending on enzyme deficiency severity. In severe cases, particularly in male infants, symptoms often appear within the first few days of life. These early signs can include increased sleeping, lethargy, poor feeding, and vomiting. Without prompt intervention, these symptoms can rapidly progress to seizures and coma.
Individuals with milder forms of OTC deficiency, or those with late-onset disease, may not experience symptoms until later in childhood or adulthood. These cases can be triggered by metabolic stress, such as illness, fasting, or high protein intake. Symptoms in this group can include headaches, behavioral changes, and an aversion to protein-rich foods. Episodes of confusion, delirium, or hyperammonemic crises may also occur.
Diagnosing OTC Deficiency
Diagnosing OTC deficiency typically begins with evaluating clinical symptoms and measuring blood ammonia levels. Elevated ammonia in the blood is a primary indicator, often exceeding 200 µmol/L when encephalopathy is present. Further laboratory tests are then performed to confirm the diagnosis and distinguish it from other urea cycle disorders.
Plasma amino acid analysis is a key diagnostic tool, revealing specific patterns. In OTC deficiency, there are typically high levels of glutamine and alanine, while citrulline and arginine levels are low. Additionally, urine organic acid analysis usually shows elevated levels of orotic acid, which results from the buildup of carbamoyl phosphate due to the enzyme block. Genetic testing, which identifies mutations in the OTC gene, provides definitive confirmation of the diagnosis. In some regions, newborn screening programs may also help detect the condition early.
Treatment and Management Approaches
The primary goals of managing OTC deficiency are to reduce ammonia levels in the blood and prevent hyperammonemic crises. Dietary management is a cornerstone of treatment, involving strict protein restriction to limit ammonia production. Special formulas and foods are often used, especially for infants, to ensure adequate nutrition while controlling protein intake.
Medications known as ammonia scavengers play a significant role in long-term management. These drugs, such as sodium phenylacetate and sodium benzoate, help the body excrete nitrogen by binding to ammonia and forming compounds that can be eliminated in the urine. Carglumic acid may also be used in some cases. For acute, severe hyperammonemia, emergency treatment often involves hemodialysis to rapidly remove excess ammonia from the blood.
Liver transplantation is considered a definitive treatment option for OTC deficiency. A transplant can replace the deficient liver enzyme, allowing the body to process ammonia effectively and potentially eliminating the need for dietary restrictions and scavenger medications. While it does not reverse prior neurological damage, early transplantation is recommended for severe cases to improve long-term outcomes.