A 3-day-old male neonate born to non-consanguineous parents presents with poor feeding, lethargy, and seizures. The mother reports the infant was normal at birth. Serum ammonia is 380 µmol/L (normal: 15–45), and plasma amino acid analysis shows elevated glutamine and alanine. Urine orotic acid is markedly elevated. Liver function tests are normal. What is the most likely diagnosis?

Explanation

## Clinical Presentation and Diagnosis **Key Point:** OTC deficiency is the most common urea cycle disorder (40% of cases) and presents with acute hyperammonemia in the neonatal period, typically 24–72 hours after birth. ### Why OTC Deficiency? 1. **Elevated urinary orotic acid** is the pathognomonic finding in OTC deficiency - Carbamoyl phosphate accumulates and is shunted to the pyrimidine synthesis pathway - Orotic acid is a pyrimidine precursor; its excretion is dramatically elevated (100–1000× normal) - This finding is **specific** to OTC deficiency among urea cycle disorders 2. **Hyperammonemia with normal liver function** - Ammonia cannot be incorporated into the urea cycle due to blocked ornithine utilization - Glutamine and alanine rise as ammonia scavenging pathways are activated 3. **Neonatal presentation (day 3)** - OTC deficiency typically manifests within the first 72 hours of life - Protein feeding triggers the hyperammonemic crisis ### Urea Cycle Defect Comparison | Enzyme Defect | Urinary Orotic Acid | Plasma Glutamine | Plasma Citrulline | Plasma Arginine | |---|---|---|---|---| | **OTC deficiency** | **↑↑↑ (markedly)** | ↑↑ | Low–normal | Low | | CPS I deficiency | Normal | ↑↑ | Very low | Low | | Argininosuccinate synthetase | Normal | ↑↑ | ↑↑ | Low | | Argininosuccinate lyase | Normal | ↑↑ | ↑↑ | ↑↑ | **High-Yield:** Elevated urinary orotic acid = OTC deficiency until proven otherwise. ### Mechanism of Orotic Acid Elevation ```mermaid flowchart TD A[Glutamine + CO₂ + NH₃]:::action --> B[Carbamoyl Phosphate Synthetase I]:::action B --> C[Carbamoyl Phosphate]:::outcome C --> D{OTC present?}:::decision D -->|Yes| E[Citrulline synthesis]:::action D -->|No - OTC deficiency| F[Carbamoyl phosphate accumulates]:::urgent F --> G[Shunted to pyrimidine synthesis]:::action G --> H[Orotic Acid ↑↑↑]:::outcome E --> I[Normal urea cycle]:::action ``` **Clinical Pearl:** X-linked inheritance of OTC deficiency means hemizygous males present severely in infancy; heterozygous females may present later or remain asymptomatic. ### Management Implications **Key Point:** OTC deficiency is treated with: - Protein restriction - Nitrogen scavenging agents (sodium benzoate, sodium phenylbutyrate) - Arginine supplementation (bypasses the enzymatic block) - Dialysis for acute hyperammonemic crisis [cite:Robbins 10e Ch 3] [cite:Harrison 21e Ch 297]