MCQ: Metabolic disorder | high-yield | diagnosis

Correct Answer:
B. Elevated plasma citrulline

Explanation: Urea Cycle Defect

This infant has a urea cycle disorder, suggested by the combination of:

• Neonatal presentation after initiation of protein feeding
• Severe hyperammonemia
• Respiratory alkalosis
• Normal glucose and lactate
• Absence of significant ketosis

The markedly elevated plasma citrulline points specifically toward Citrullinemia Type I, caused by deficiency of argininosuccinate synthetase (ASS1).

ASS1 normally combines citrulline with aspartate to form argininosuccinate in the urea cycle. When ASS1 is deficient, citrulline accumulates markedly in plasma, while the impaired urea cycle leads to accumulation of ammonia.

Therefore, the characteristic biochemical finding is:

Markedly elevated plasma citrulline.

Why the other options are incorrect

• A. Elevated argininosuccinic acid — Characteristic of argininosuccinate lyase (ASL) deficiency, also known as argininosuccinic aciduria. Plasma and urinary argininosuccinic acid are typically elevated.
• C. Elevated plasma leucine — Suggests maple syrup urine disease (MSUD), caused by impaired branched-chain amino acid metabolism. MSUD typically produces elevated branched-chain amino acids and their corresponding ketoacids rather than isolated hyperammonemia with respiratory alkalosis.
• D. Elevated urinary methylmalonic acid — Suggests methylmalonic acidemia. Organic acidemias such as methylmalonic and propionic acidemia commonly produce high-anion-gap metabolic acidosis, ketosis, and hyperammonemia, rather than the respiratory alkalosis classically associated with an acute urea cycle disorder.
• E. Elevated urinary orotic acid — Strongly suggests OTC deficiency when accompanied by hyperammonemia and low plasma citrulline. In contrast, CPS1 deficiency typically has low or normal urinary orotic acid. Although urinary orotic acid can increase in some other urea cycle disorders, it is not the hallmark finding of Citrullinemia Type I.

High-Yield Exam Pearl

Hyperammonemia + respiratory alkalosis → think urea cycle disorder.

Then use the plasma amino-acid and urinary orotic-acid pattern to identify the defect:

• ↑↑ Citrulline → Citrullinemia Type I (ASS1 deficiency)
• ↑ Argininosuccinic acid → Argininosuccinic aciduria (ASL deficiency)
• ↓ Citrulline + ↑ urinary orotic acid → OTC deficiency
• ↓/low-normal citrulline + normal/low urinary orotic acid → CPS1 deficiency
• Hyperammonemia + metabolic acidosis + ketosis → consider organic acidemia

These biochemical patterns are supported by international UCD guidelines, which describe high plasma citrulline without significant argininosuccinate as strongly suggestive of ASS deficiency, while low citrulline with increased urinary orotic acid suggests OTC deficiency and low orotic acid suggests CPS1/NAGS deficiency. Organic acidemias such as propionic acidemia typically present with high-anion-gap metabolic acidosis, ketosis, hyperammonemia, and elevated C3 acylcarnitine.

You can also practice another MCQ on Progeria.

References

1. Häberle J, Boddaert N, Burlina A, Chakrapani A, Dixon M, Huemer M, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis. 2012;7:32. doi:10.1186/1750-1172-7-32.
2. Baumgartner MR, Hörster F, Dionisi-Vici C, Haliloglu G, Karall D, Chapman KA, et al. Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia. Orphanet J Rare Dis. 2014;9:130. doi:10.1186/s13023-014-0130-8.