A 3-day-old male neonate born to non-consanguineous parents presents with poor feeding, lethargy, and seizures. Delivery was uneventful. On examination, he is hypotonic with a weak cry. Laboratory investigations show: blood ammonia 320 µmol/L (normal <50), arterial pH 7.32, HCO₃⁻ 18 mEq/L, normal liver function tests, and normal blood glucose. Plasma amino acid analysis shows elevated glutamine and alanine with low citrulline. Urine orotic acid is normal. What is the most likely diagnosis?

Explanation

## Clinical Presentation and Diagnosis This neonatal presentation with hyperammonemia, neurological symptoms (seizures, lethargy, hypotonia), and characteristic plasma amino acid pattern points to **CPS I deficiency**. ### Key Biochemical Findings **Key Point:** CPS I deficiency presents with: - Severe hyperammonemia (often >200 µmol/L) - **Normal or low urine orotic acid** (distinguishes from OTC deficiency) - Elevated glutamine and alanine (ammonia scavenging pathways) - **Low citrulline** (first urea cycle product cannot be formed) - Respiratory alkalosis followed by metabolic acidosis ### Differential Diagnosis of Urea Cycle Defects | Enzyme Defect | Blood NH₃ | Plasma Citrulline | Urine Orotic Acid | Urine Orotic Acid Pattern | | --- | --- | --- | --- | --- | | **CPS I deficiency** | ↑↑↑ (>200) | ↓ (very low) | Normal/low | Normal | | **OTC deficiency** | ↑↑↑ (>200) | ↓ (low) | ↑↑↑ (markedly elevated) | Crystal-like appearance | | **Argininosuccinate lyase** | ↑↑ (100–200) | ↑ (elevated) | ↑ | Elevated | | **Arginase deficiency** | ↑ (mild–moderate) | ↑↑ (very high) | Normal | Normal | ### Pathophysiology 1. CPS I catalyzes: **Ammonia + HCO₃⁻ + 2 ATP → Carbamoyl phosphate + ADP + Pi** 2. Without CPS I, carbamoyl phosphate cannot form → ammonia accumulates 3. Citrulline is the first urea cycle product; it cannot be synthesized → **very low plasma citrulline** 4. Ammonia is shunted into glutamine synthesis (glutaminase pathway) → **elevated glutamine and alanine** 5. Orotic acid synthesis is blocked at the step requiring carbamoyl phosphate, so urine orotic acid remains **normal** (unlike OTC deficiency) ### Clinical Pearl **Clinical Pearl:** The **combination of low citrulline + normal urine orotic acid** is pathognomonic for CPS I deficiency. This distinguishes it from OTC deficiency, which presents with low citrulline but **markedly elevated urine orotic acid** (because carbamoyl phosphate accumulates and is shunted to pyrimidine synthesis). ### Management **High-Yield:** Acute management includes: - Protein restriction - Nitrogen scavenging agents (sodium benzoate, sodium phenylbutyrate) - Arginine supplementation (bypasses the block, provides nitrogen disposal) - Hemodialysis for severe hyperammonemia (>400 µmol/L) [cite:Robbins 10e Ch 7]