Clinical Scenario:
A 6-month-old male infant is brought to the emergency department with recurrent episodes of vomiting, lethargy, and altered consciousness. His parents report that these episodes are often triggered by high-protein meals or minor infections. On examination, the child is irritable initially and later becomes drowsy. Laboratory investigations reveal plasma ammonia of 320 µmol/L, normal blood glucose and lactate levels, markedly elevated plasma glutamine, low plasma citrulline, and increased urinary orotic acid. Which of the following is the most likely diagnosis?
A. Argininosuccinate lyase deficiency
B. Carbamoyl phosphate synthetase I deficiency
C. Ornithine transcarbamylase deficiency
D. Arginase deficiency
E. N-acetylglutamate synthase deficiency
Correct answer & Explanation:
Correct Answer: C. Ornithine transcarbamylase deficiency
Explanation:
This infant has hyperammonemia with low citrulline and increased urinary orotic acid, which is the classic biochemical pattern of ornithine transcarbamylase (OTC) deficiency.
OTC deficiency is the most common urea cycle disorder and is inherited as an X-linked recessive condition. The defect occurs in the mitochondrial conversion of carbamoyl phosphate and ornithine into citrulline. Accumulated carbamoyl phosphate is diverted into the pyrimidine synthesis pathway, resulting in increased orotic acid production.
Key differentiation:
- OTC deficiency: ↓ Citrulline + ↑ Orotic acid
- CPS I deficiency: ↓ Citrulline + Normal orotic acid
- NAGS deficiency: ↓ Citrulline + Normal orotic acid
- Argininosuccinate synthetase deficiency: ↑ Citrulline
- Argininosuccinate lyase deficiency: ↑ Argininosuccinate
Why other options are incorrect:
- Argininosuccinate lyase deficiency: Causes elevated argininosuccinate and usually increased citrulline.
- Carbamoyl phosphate synthetase I deficiency: Produces low citrulline but does not increase urinary orotic acid because carbamoyl phosphate formation is impaired.
- Arginase deficiency: Characterized by elevated arginine and progressive neurological symptoms rather than acute hyperammonemic episodes.
- N-acetylglutamate synthase deficiency: Mimics CPS I deficiency with low citrulline and normal orotic acid.
High-yield exam pearl:
Hyperammonemia + low citrulline + high urinary orotic acid = Ornithine transcarbamylase deficiency
