A 3-year-old boy from rural Maharashtra presents with recurrent episodes of vomiting, lethargy, and developmental delay. His parents report that symptoms worsen after high-protein meals. On examination, he has hepatomegaly and mild intellectual disability. Plasma ammonia is elevated at 180 µmol/L (normal <50). Which investigation is most appropriate to confirm a urea cycle disorder?

Explanation

## Investigation of Choice in Urea Cycle Disorders ### Diagnostic Approach **Key Point:** Plasma amino acid profiling is the first-line confirmatory investigation for suspected urea cycle defects because it reveals the characteristic pattern of amino acid accumulation upstream of the enzymatic block. ### Why Plasma Amino Acid Profile is Diagnostic Each urea cycle enzyme deficiency produces a distinctive plasma amino acid signature: | Enzyme Defect | Elevated Amino Acids | Decreased Amino Acids | Urine Marker | |---|---|---|---| | **Carbamoyl phosphate synthetase I (CPS-I)** | Glutamine, alanine | Citrulline, arginine | Orotic acid (normal) | | **Ornithine transcarbamylase (OTC)** | Glutamine, alanine, aspartate | Citrulline, arginine | Orotic acid (↑↑) | | **Argininosuccinate synthetase (ASS)** | Glutamine, citrulline | Arginine | Argininosuccinate (↑↑) | | **Argininosuccinate lyase (ASL)** | Glutamine, argininosuccinate | Arginine | Argininosuccinate (↑↑) | | **Arginase (ARG1)** | Arginine (↑↑) | — | Arginine (↑) | **High-Yield:** Citrulline and argininosuccinate levels are particularly diagnostic: - **Low citrulline** suggests CPS-I or OTC deficiency - **High citrulline** with high argininosuccinate suggests ASS deficiency - **Argininosuccinate accumulation** is pathognomonic for ASL deficiency ### Clinical Pearl In this case, the combination of **elevated ammonia + developmental delay + hepatomegaly** in a young child with protein intolerance strongly suggests **OTC deficiency** (most common urea cycle disorder, X-linked). Plasma amino acid profiling will show: - ↑ Glutamine, alanine, aspartate - ↓ Citrulline (nearly absent) - ↑ Orotic acid in urine (secondary to carbamoyl phosphate shunting to pyrimidine synthesis) ### Diagnostic Algorithm ```mermaid flowchart TD A[Hyperammonemia + neurological signs]:::outcome --> B{Plasma amino acids?}:::decision B -->|Low citrulline| C[CPS-I or OTC deficiency]:::outcome B -->|High citrulline + argininosuccinate| D[ASS deficiency]:::outcome B -->|High argininosuccinate| E[ASL deficiency]:::outcome B -->|High arginine| F[Arginase deficiency]:::outcome C --> G[Urine orotic acid confirms OTC]:::action D --> H[Genetic testing for ASS1]:::action ``` **Tip:** Plasma amino acid profiling is non-invasive, rapid (results in 24–48 hours), and requires only a small blood sample — ideal for pediatric patients.