by 
Introduction
Ornithine transcarbamylase (OTC) deficiency is an inherited disorder that affects the body’s ability to remove ammonia from the bloodstream. Ammonia is produced as a byproduct of protein metabolism. In people with OTC deficiency, a missing or reduced amount of the OTC enzyme prevents ammonia from being converted to urea in the liver. This causes a buildup of ammonia in the blood, which can damage the brain and other organs. OTC deficiency primarily affects males and symptoms can range from mild to severe depending on the level of residual enzyme activity. There is currently no cure for OTC deficiency, but treatment aims to control ammonia levels and symptoms.
Causes and Genetics
OTC deficiency is an X-linked genetic disorder caused by variants in the OTC gene located on the X chromosome. Females have two X chromosomes and males have one X and one Y chromosome. Females can be carriers of OTC deficiency but generally do not experience symptoms as long as one of their X chromosomes contains a normal OTC gene. Males only need one altered copy on their single X chromosome to develop OTC deficiency since they do not have a second normal copy to compensate. Variants in the OTC gene disrupt the body’s ability to produce functional ornithine transcarbamylase enzyme. Over 200 different variants have been identified as causing OTC deficiency.
Symptoms
The signs and symptoms of OTC deficiency typically appear during the newborn period or early childhood when ammonia levels peak. In newborns, symptoms often include lethargy, vomiting, seizures, and coma. If left untreated, it can cause permanent brain damage or be life-threatening. In older children and adolescents with partial OTC deficiency, symptoms may only appear during times of increased protein intake or stress such as infection. Common symptoms include headaches, nausea/vomiting, confusion, poor appetite, mood changes, and erratic behavior. Symptoms can progress to seizures, coma, and death without appropriate treatment.
Diagnosis and Testing
OTC deficiency is usually suspected based on symptoms, family history, and newborn screening results. Diagnosis is confirmed through blood and urine tests. Blood tests measure ammonia and plasma amino acid levels. Elevated ammonia and glutamine levels combined with low arginine and ornithine levels suggest OTC deficiency. Urine orotherm test can detect excess orotic acid, which is produced during the urea cycle when OTC enzyme function is compromised. Genetic testing is also available to identify variants in the OTC gene. Identification of the specific genetic variant helps predict severity and recurrence risk.
Dietary Treatment
Dietary protein restriction is central to managing OTC deficiency. Protein intake must be carefully monitored and limited because protein metabolism produces ammonia. Individualized diet plans calculate daily protein intake based on age, weight, and disease severity. Very low protein diets may provide 0.5-1 gram of protein per kilogram of body weight per day. Essential amino acids and calories are supplemented without additional protein. During times of illness or stress, protein intake must be temporarily and significantly reduced. Dietary treatment aims to control ammonia levels and avoid potential complications while still meeting growth and nutritional needs.
Medication
L-arginine supplements are commonly used in treating OTC deficiency. Arginine helps remove ammonia by stimulating the urea cycle. Supplements are started under medical guidance. Sodium benzoate and sodium phenylbutyrate are also prescribed medications that help bind ammonia and remove it from the body through alternative pathways. L-carnitine supports fat breakdown and energy production during times of increased protein restrictions. Medications work alongside dietary treatment to safely manage ammonia levels. Antiseizure drugs may be used if seizures occur. Supportive care is also provided during metabolic crises to prevent complications.
Liver Transplantation
In severe cases that do not respond well to conventional treatment, liver transplantation may be considered. The new liver can take over the urea cycle function, allowing affected individuals to eat a normal protein diet. Transplantation carries surgical risks but offers a potential cure by correcting the enzymatic defect. However, transplanted livers have a limited lifespan so patients require lifelong immunosuppressant medications. Transplant timing must balance severity of symptoms against risks. It is generally reserved for those with frequent acute metabolic decompensations despite standard treatment.
Long-Term Outlook and Follow Up Care
With early diagnosis and aggressive treatment, most individuals with OTC deficiency can live relatively normal lives. Diet therapy aims to control symptoms while supporting physical and cognitive development. Quality of life is highly dependent on level of residual enzyme activity. Those with partial enzyme function have fewer long-term complications if ammonia levels are well-managed through diet and medications. Severely affected individuals have poorer outcomes and require closer medical management. Patients benefit from lifelong screening of ammonia and amino acid levels under a metabolic specialist. Adherence to dietary protein restrictions and medications allows optimum management into adulthood.
Conclusion
OTC deficiency disrupts the body’s ability to break down protein and remove toxic ammonia from the blood. While it primarily affects males due to X-linked inheritance, females can be carriers. Early diagnosis and prompt control of ammonia levels through an individualized low protein diet, medications, and other supportive treatment minimize complications. With careful medical management and monitoring, most affected individuals can expect near-normal development and avoid severe outcomes. Treatment throughout life aims to balance controlling symptoms and risks against meeting nutritional needs. Advanced liver transplantation is an option for select severe cases.
*Note:
1. Source: Coherent Market Insights, Public sources, Desk research
2. We have leveraged AI tools to mine information and compile it
