A 2-month-old female infant born to consanguineous parents presents with poor feeding, vomiting, and irritability since day 3 of life. Serum ammonia is 320 µmol/L. Plasma amino acid profile shows markedly elevated citrulline (180 µmol/L; normal <30) and argininosuccinic acid is detected in urine. Genetic testing confirms a mutation in the ASLS gene. Which of the following best describes the metabolic consequence of this enzyme deficiency?

Explanation

## Enzyme Defect: Argininosuccinate Lyase (ASLS) **Key Point:** Argininosuccinate lyase (also called argininosuccinase) catalyzes the **fourth step** of the urea cycle: $$\text{Argininosuccinate} \xrightarrow{\text{ASLS}} \text{Arginine} + \text{Fumarate}$$ ## Urea Cycle Pathway with ASLS Defect ```mermaid flowchart TD A["Carbamoyl phosphate + Ornithine"]:::action --> B["Citrulline"]:::outcome B --> C["Argininosuccinate"]:::outcome C -->|"ASLS (BLOCKED)"| D["❌ Arginine + Fumarate"]:::urgent D --> E["Urea + Ornithine"]:::action C -->|"Accumulates"| F["↑ Plasma argininosuccinate"]:::urgent C -->|"Spills into urine"| G["Argininosuccinic aciduria"]:::outcome B -->|"Backs up"| H["↑ Plasma citrulline"]:::urgent style A fill:#e8f5e9 style D fill:#ffebee ``` ## Metabolic Consequences | Finding | Mechanism | Clinical Significance | |---------|-----------|----------------------| | **↑ Argininosuccinate (plasma & urine)** | Direct substrate accumulation | Pathognomonic; diagnostic marker | | **↑ Citrulline** | Backs up from blocked step | Elevated but not as high as in CPS I deficiency | | **↑↑ Ammonia** | Urea cycle cannot proceed; ammonia accumulates | Encephalopathy, seizures | | **↓ Arginine** | Cannot be synthesized; depleted | Impaired protein synthesis, immune dysfunction | | **↑ Orotic acid (urine)** | Carbamoyl phosphate shunted to pyrimidines | Distinguishes from CPS I (normal orotic acid) | ## Why Option 1 (Correct Answer) is Right Argininosuccinate lyase deficiency causes: 1. **Inability to cleave argininosuccinate** → accumulation of argininosuccinate in plasma and urine 2. **Failure to generate arginine and fumarate** → downstream urea cycle failure 3. **Hyperammonaemia** → ammonia cannot be converted to urea 4. **Elevated citrulline** → backs up from the blocked step **High-Yield:** Argininosuccinic aciduria (elevated plasma and urinary argininosuccinate) is **pathognomonic** for argininosuccinate lyase deficiency and is the key diagnostic feature in this case. **Clinical Pearl:** Argininosuccinate lyase deficiency is autosomal recessive and accounts for ~18% of urea cycle disorders. Neonatal presentation (as in this case) with poor feeding, vomiting, and hyperammonaemia is typical. The distinctive "fishy" odour (from argininosuccinate) may be noted.