A 6-month-old female infant from a consanguineous family presents with recurrent vomiting, poor growth, and developmental delay. She has an aversion to protein-containing foods. Serum ammonia is 250 µmol/L. Plasma amino acid analysis shows markedly elevated citrulline (450 µmol/L; normal: 15–45) and low arginine. Urinary orotic acid is normal. What is the most likely diagnosis?

Explanation

## Clinical Presentation and Diagnosis **Key Point:** Citrullinemia type I (argininosuccinate synthetase deficiency) is characterized by markedly elevated plasma citrulline with low arginine and normal urinary orotic acid. ### Why Argininosuccinate Synthetase Deficiency? 1. **Markedly elevated plasma citrulline (450 µmol/L)** - Citrulline accumulates because it cannot be condensed with aspartate to form argininosuccinate - This is the hallmark biochemical finding - Citrulline is normally present in very low concentrations; marked elevation is diagnostic 2. **Low arginine** - Arginine synthesis is blocked downstream of the enzymatic defect - Arginine becomes deficient, contributing to hyperammonemia (arginine is essential for urea cycle function) - Arginine supplementation is therapeutic 3. **Normal urinary orotic acid** - The enzymatic block is AFTER carbamoyl phosphate formation - Carbamoyl phosphate does not accumulate and is not shunted to pyrimidine synthesis - Contrast with OTC deficiency, where orotic acid is markedly elevated 4. **Consanguineous family and infantile presentation** - Autosomal recessive inheritance - Typically presents in infancy with feeding difficulties and developmental delay ### Biochemical Comparison: Urea Cycle Defects | Defect | Plasma Citrulline | Plasma Arginine | Urinary Orotic Acid | Plasma Glutamine | |---|---|---|---|---| | **Argininosuccinate synthetase** | **↑↑↑ (markedly)** | **↓ (low)** | Normal | ↑↑ | | OTC deficiency | Low–normal | Low | ↑↑↑ (markedly) | ↑↑ | | Argininosuccinate lyase | ↑↑ (moderate) | ↑↑ (elevated) | Normal | ↑↑ | | CPS I deficiency | Very low | Low | Normal | ↑↑ | **High-Yield:** Markedly elevated citrulline + low arginine + normal orotic acid = Citrullinemia type I (argininosuccinate synthetase deficiency). ### Metabolic Block in Citrullinemia Type I ```mermaid flowchart TD A[Carbamoyl Phosphate + Ornithine]:::action --> B[Citrulline]:::outcome B --> C[Citrulline + Aspartate]:::action C --> D{Argininosuccinate Synthetase?}:::decision D -->|Yes| E[Argininosuccinate]:::action D -->|No - Deficiency| F[Citrulline accumulates ↑↑↑]:::urgent F --> G[Hyperammonemia]:::urgent E --> H[Argininosuccinate Lyase]:::action H --> I[Arginine + Fumarate]:::outcome I --> J[Urea Cycle Completion]:::action ``` **Clinical Pearl:** Patients with citrullinemia type I often have protein aversion and growth failure due to recurrent hyperammonemic episodes triggered by protein intake. Dietary protein restriction and arginine supplementation are cornerstones of management. ### Management **Key Point:** Treatment includes: - Protein restriction (typically 0.5–1.5 g/kg/day) - Arginine supplementation (100–200 mg/kg/day) — bypasses the enzymatic block and provides the missing end product - Nitrogen scavenging agents (sodium benzoate, sodium phenylbutyrate) — reduce ammonia load - Monitoring of plasma ammonia and amino acids **Mnemonic:** **CITRULLINE** = Citrullinemia; elevated Citrulline + low Arginine = Argininosuccinate Synthetase deficiency. [cite:Robbins 10e Ch 3] [cite:Harrison 21e Ch 297]