Correct Answer: D. Ornithine transcarbamoylase
Ornithine transcarbamoylase (OTC) catalyzes the second step of the urea cycle, converting carbamoyl phosphate and ornithine into citrulline. When OTC is deficient, carbamoyl phosphate accumulates and is shunted into alternative pathways. Specifically, accumulated carbamoyl phosphate drives increased pyrimidine synthesis, but more importantly, the block in the urea cycle prevents efficient ammonia disposal. Ammonia accumulates and is preferentially incorporated into glutamine via glutamine synthetase (glutamate + ammonia + ATP → glutamine + ADP + Pi). This is the body's primary mechanism for ammonia detoxification when the urea cycle is impaired. OTC deficiency is the most common urea cycle disorder in India and presents with hyperammonemia, elevated blood glutamine, and neurological symptoms. The elevated glutamine reflects the shunting of excess ammonia into glutamine synthesis as a compensatory mechanism for failed ammonia excretion via the urea cycle.
Why the other options are wrong
A. Arginosuccinate lyase — Arginosuccinate lyase deficiency (step 4 of urea cycle) causes argininosuccinic aciduria with elevated argininosuccinic acid in blood and urine, not glutamine. While ammonia may accumulate, the primary biochemical marker is argininosuccinic acid, not glutamine elevation. This is a rare urea cycle disorder in India. B. Alpha-galactosidase-A — Alpha-galactosidase-A deficiency causes Fabry disease (X-linked lysosomal storage disorder), characterized by accumulation of globotriaosylceramide. This has no direct relationship to ammonia metabolism, glutamine synthesis, or the urea cycle. This is a distractor unrelated to amino acid metabolism. C. Arginase — Arginase deficiency (step 6 of urea cycle) causes argininemia with elevated plasma arginine, not glutamine. Although ammonia may accumulate, the primary marker is hyperargininemia. Arginase deficiency is extremely rare and presents with spasticity and developmental delay, not the glutamine-centric metabolic derangement seen in OTC deficiency.
High-Yield Facts
- OTC deficiency is the most common urea cycle disorder (40% of cases) and X-linked; presents with hyperammonemia and elevated blood glutamine.
- Glutamine is the primary ammonia carrier and detoxification product when the urea cycle is blocked; synthesized by glutamine synthetase from glutamate + ammonia.
- Carbamoyl phosphate synthetase I deficiency (step 1) also causes hyperammonemia and elevated glutamine, but OTC deficiency is more common in India.
- Hyperammonemia from any urea cycle defect triggers glutamine synthesis as a compensatory ammonia disposal mechanism.
- Argininosuccinic acid accumulates in arginosuccinate lyase deficiency; arginine accumulates in arginase deficiency—not glutamine.
Mnemonics
Urea Cycle Defects → Glutamine Any block in the urea cycle (especially OTC) → ammonia ↑ → glutamine ↑ (via glutamine synthetase). Remember: ammonia has nowhere to go, so it gets trapped in glutamine. OTC = Ornithine + Carbamoyl → Citrulline OTC is step 2 of urea cycle. Deficiency → no citrulline, carbamoyl phosphate backs up, ammonia accumulates → glutamine ↑. Use when you see 'urea cycle' + 'glutamine'.
NBE Trap
NBE pairs urea cycle defects with enzyme names that sound similar (arginosuccinate lyase, arginase, OTC) to trap students who don't recall which step produces which metabolite. The key discriminator is that only OTC deficiency causes the ammonia → glutamine shunt because it blocks the entire cycle early; other defects accumulate their specific substrates (argininosuccinic acid, arginine) instead.
Clinical Pearl
In Indian pediatric practice, OTC deficiency presents as neonatal hyperammonemia with poor feeding, lethargy, and seizures. Elevated blood glutamine (>1000 µmol/L) alongside ammonia >200 µmol/L is pathognomonic. Dietary protein restriction and lactulose/rifaxomicin are standard management in Indian tertiary centers.
_Reference: KD Tripathi Ch. 12 (Amino Acid Metabolism); Robbins Ch. 7 (Genetic Disorders); Harrison Ch. 356 (Urea Cycle Disorders)_