Understanding OTC Deficiency

Ornithine Transcarbamylase (OTC) Deficiency Overview

Ornithine transcarbamylase (OTC) deficiency is an X-linked partially dominant urea cycle disorder and is the most common form of all urea cycle defects, accounting for about 40% of cases. It primarily affects hemizygous males more severely, with heterozygous females often being asymptomatic or having mild symptoms.

Clinical Manifestations in the Neonatal Period:

• Male newborns with OTC deficiency typically present with severe hyperammonemia within the first few days of life.
• Symptoms in the neonatal period are related mostly to brain dysfunction and include refusal to eat, vomiting, tachypnea, lethargy, convulsions, progressing to coma.
• Physical findings may include hepatomegaly and signs of increased intracranial pressure (bulging fontanelle, dilated pupils).
• Hyperammonemia can cause cerebral edema and death if untreated.
• Mild forms occur in symptomatic females or some males with episodic hyperammonemia after protein ingestion or during catabolic states such as infections.
• Cognitive impairment, including mild to moderate intellectual disability, is a common sequela.

Laboratory Findings:

• Marked hyperammonemia is a key laboratory finding.
• Plasma amino acid profile usually shows increased glutamine and alanine, with low citrulline and arginine levels.
• High urinary excretion of orotic acid distinguishes OTC deficiency from other urea cycle disorders.
• Blood urea nitrogen is often low.
• Ammonia levels in healthy term newborns can be up to 100 μmol/L and up to 150 μmol/L in preterm infants. Levels above 200 μmol/L in an ill infant suggest pathological hyperammonemia.
• In OTC deficiency, hyperammonemia episodes may recur unless treated.

When to Check Ammonia Levels After Birth:

• It is imperative to measure plasma ammonia in any ill infant with unexplained illness or neurological symptoms, especially if infection, birth trauma or other common causes are ruled out.
• Ammonia levels should be checked urgently if the neonate develops symptoms such as poor feeding, vomiting, lethargy, or seizures after birth.
• Because severe hyperammonemia manifests mostly within the first few days of life in OTC deficiency, early ammonia measurement in symptomatic newborns is critical.
• Newborn screening may detect some urea cycle disorders, but OTC deficiency is often not included in screening panels.

Complications in the Neonatal Period:

• Severe hyperammonemia (>300 μmol/L) for more than 12 hours is associated with poor neurological outcomes, including cerebral edema, coma, and death.
• Early and aggressive treatment is essential to prevent permanent brain damage.
• Untreated neonatal hyperammonemia has very high mortality.

Summary of Management:

• Immediate measurement of ammonia in symptomatic newborns.
• Prompt treatment of hyperammonemia with nitrogen scavengers (sodium benzoate, phenylacetate), arginine supplementation (except in arginase deficiency), protein restriction, and supportive care.
• Dialysis if ammonia levels do not respond rapidly to medical treatment.
• Long-term management includes protein-restricted diets and prevention of catabolic states.

This information is comprehensively outlined in Nelson Textbook of Pediatrics 20th edition in the chapter on amino acid metabolism disorders, especially under sections on ornithine transcarbamylase deficiency and hyperammonemia in neonates.