A 6-year-old boy from rural Maharashtra is brought to the emergency department with acute onset confusion, ataxia, and slurred speech following a viral upper respiratory infection 3 days ago. His mother reports he had been well until the illness. On examination: temperature 37.8°C, GCS 13/15, hyperreflexia, and tremor. Laboratory findings: blood ammonia 156 µmol/L (normal <50), normal liver function tests, normal blood glucose, CSF parameters normal. A urine sample shows elevated orotic acid. Which urea cycle enzyme defect would be most consistent with this presentation of acute hyperammonemia triggered by infection?

Explanation

## Acute Hyperammonemia in a School-Aged Child — Stress-Triggered Presentation This case represents a **stress-induced decompensation** of an underlying urea cycle disorder in a previously asymptomatic individual — a classic presentation of **heterozygous OTC deficiency in females** or **mild OTC deficiency in males**. ### Clinical Context: Why Infection Triggers Hyperammonemia **Key Point:** Viral infection increases: 1. Protein catabolism (fever, systemic inflammation) 2. Ammonia generation from amino acid breakdown 3. Demand on the urea cycle In a child with borderline urea cycle capacity (heterozygous OTC), this metabolic stress precipitates symptomatic hyperammonemia. ### Diagnostic Reasoning **High-Yield:** The combination of: - **Acute presentation** (not neonatal) triggered by infection - **Elevated orotic acid** in urine — pathognomonic for OTC deficiency - **Normal liver function** — excludes acquired hyperammonemia from hepatic disease - **Normal CSF** — excludes meningitis/encephalitis - **Age 6 years** — consistent with heterozygous female (males typically present in neonatal period) ```mermaid flowchart TD A[Viral Infection]:::outcome --> B[Increased Protein Catabolism]:::action B --> C[↑ Ammonia Production]:::urgent C --> D{Urea Cycle Capacity?}:::decision D -->|Normal| E[Ammonia Detoxified]:::outcome D -->|Heterozygous Defect| F[Partial Enzyme Activity]:::action F --> G[Hyperammonemia Develops]:::urgent G --> H[Neurological Symptoms]:::urgent H --> I[Encephalopathy]:::urgent C --> J[Elevated Ammonia 156 µmol/L]:::outcome ``` ### Why OTC Deficiency (Heterozygous Female) Is the Answer | Feature | OTC Heterozygous Female | CPS I Deficiency | Argininosuccinate Synthetase | |---|---|---|---| | **Age of onset** | School-age (stress-triggered) | Neonatal | Neonatal/early infancy | | **Trigger** | Infection, protein load, fasting | Present from birth | Present from birth | | **Urinary orotic acid** | ↑↑↑ (markedly elevated) | Normal/low | Normal | | **Plasma citrulline** | ↓ (low) | ↓↓ (very low) | ↑↑ (very high) | | **Inheritance** | X-linked (heterozygous females symptomatic) | Autosomal recessive | Autosomal recessive | **Clinical Pearl:** Heterozygous females with OTC deficiency have ~50% enzyme activity due to X-inactivation. They remain asymptomatic until a metabolic stress (infection, high protein intake, pregnancy, surgery) overwhelms their reduced urea cycle capacity. ### Why Not the Other Options? **CPS I deficiency:** Presents in neonatal period with severe hyperammonemia from birth; urinary orotic acid is normal or low (not elevated). Does not have stress-triggered presentation in older children. **Argininosuccinate synthetase deficiency:** Presents in neonatal period with severe hyperammonemia and hypercitrullinuria (markedly elevated plasma citrulline). Urinary orotic acid is normal. Stress-triggered presentation in school-age is not typical. **Glutaminase deficiency:** Extremely rare; not a recognized cause of primary hyperammonemia. Glutaminase is involved in ammonia release, not urea cycle function. ### Management 1. **Acute:** IV arginine (1–2 g/kg bolus), sodium benzoate (250 mg/kg/day), protein restriction 2. **Chronic:** Protein-restricted diet, arginine supplementation, avoid triggers 3. **Genetic:** Confirm OTC mutation; counsel on X-linked inheritance; screen siblings **High-Yield:** Any school-age or adult female presenting with acute hyperammonemia triggered by infection or stress should raise suspicion for heterozygous OTC deficiency. [cite:Harrison 21e Ch 297; KD Tripathi 8e Ch 12]