A 6-month-old girl, born to consanguineous parents in Delhi, presents with poor feeding, developmental delay, and recurrent vomiting after milk feeds. She has mild intellectual disability and a musty odour to her urine. Serum ammonia is 210 μmol/L (normal <50). Plasma amino acid profile shows markedly elevated arginine (450 μmol/L; normal 40–130) and elevated lysine. Urine shows elevated arginine and lysine. Liver function tests are normal. Genetic testing confirms a homozygous mutation in the AGXT2 gene. Which urea cycle intermediate is most likely elevated in this patient's plasma?

Explanation

## Clinical Presentation and Genetic Diagnosis This infant presents with **hyperammonaemia, developmental delay, elevated plasma arginine and lysine**, and a confirmed **AGXT2 gene mutation**. AGXT2 encodes **alanine-glyoxylate aminotransferase 2 (AGXT2)**, which is a mitochondrial enzyme involved in ornithine metabolism — NOT argininosuccinate lyase (ASL). The correct disease context here is **Hyperornithinemia-Hyperammonemia-Homocitrullinuria (HHH) syndrome**, caused by defective mitochondrial ornithine transport (ORNT1/SLC25A15), but AGXT2 mutations also impair mitochondrial ornithine handling, leading to ornithine accumulation. ## Pathophysiology: Why Ornithine Accumulates ```mermaid flowchart TD A[Ornithine from cytoplasm]:::outcome -->|AGXT2/mitochondrial transport impaired| B[Ornithine ACCUMULATES in plasma]:::urgent B --> C[Reduced ornithine entry into urea cycle]:::outcome C --> D[Hyperammonaemia]:::outcome C --> E[Elevated arginine secondary]:::outcome ``` **Key Point:** When mitochondrial ornithine metabolism is impaired (AGXT2 mutation), ornithine cannot be efficiently utilized in the urea cycle. This leads to: - **Elevated plasma ornithine** (primary accumulation) - Secondary hyperammonaemia (urea cycle substrate deficiency) - Elevated arginine and lysine (cationic amino acid competition for renal reabsorption) $$\text{Ornithine} + \text{Carbamoyl phosphate} \xrightarrow{\text{OTC}} \text{Citrulline}$$ When ornithine transport into mitochondria is impaired, this step is substrate-limited, causing ornithine to back up in the cytoplasm/plasma. ## Why Ornithine Is the Most Elevated Intermediate | Condition | Ornithine | Ammonia | Arginine | Citrulline | Argininosuccinate | |---|---|---|---|---|---| | **AGXT2/HHH-like** | ↑↑↑ | ↑ | ↑ (secondary) | ↓/Normal | Normal | | ASL deficiency | Normal | ↑ | ↑ | ↑ | ↑↑↑ (urine) | | Argininosuccinate synthetase | Normal | ↑ | ↓ | ↑↑ | Normal | | OTC deficiency | ↑ | ↑↑ | ↓ | ↓ | Normal | **Clinical Pearl:** The combination of **elevated arginine + elevated lysine in urine** with **hyperammonaemia** and an **AGXT2 mutation** points to impaired mitochondrial ornithine catabolism. Ornithine is the primary accumulating metabolite because it cannot be properly channelled into the urea cycle. ## Why Other Options Are Incorrect - **B) Carbamoyl phosphate:** Accumulates in CPS-I or OTC deficiency, not in AGXT2 mutations. - **C) Argininosuccinate:** Accumulates in ASL deficiency (encoded by *ASL* gene, not AGXT2). AGXT2 is not ASL. - **D) Citrulline:** Markedly elevated in citrullinaemia (ASS deficiency); not the primary accumulating metabolite here. ## Management **Treatment:** Protein restriction, ornithine supplementation (to drive urea cycle), and ammonia scavengers (sodium benzoate/phenylbutyrate) as needed. Dietary management aims to reduce ornithine precursor load. **High-Yield:** AGXT2 encodes a mitochondrial aminotransferase involved in ornithine/amino acid metabolism. Its deficiency leads to **ornithine accumulation** as the primary biochemical finding, with secondary hyperammonaemia. [cite:OMIM #238970; Scriver's OMMBID; Harrison's Principles of Internal Medicine 21e]