Clinical Scenario:
A 7-day-old exclusively breastfed male neonate is brought with poor feeding, lethargy, and recurrent vomiting. He was well until the fifth day of life. Examination reveals hypotonia and depressed neonatal reflexes. Laboratory investigations show:
Blood glucose: 92 mg/dL
Serum ammonia: 850 µmol/L
Arterial blood gas: pH 7.42
Serum lactate: Normal
Urine ketones: Negative
What is the most likely diagnosis?
A. Fatty acid oxidation defect
B. Organic acidemia
C. Urea cycle defect
D. Galactosemia
E. Maple syrup urine disease
Correct answer & Explanation:
Correct answer: C. Urea cycle defect
The presentation is classic for a neonatal urea cycle disorder causing severe hyperammonemia.
Explanation
Urea cycle defects should be strongly suspected in a neonate who is initially well but develops poor feeding, vomiting, lethargy, hypotonia, and encephalopathy after the first few days of life. Severe defects can produce very high ammonia concentrations soon after protein feeding begins.
The key biochemical clue is:
- Ammonia 850 µmol/L: profound hyperammonemia
- Normal glucose: argues against a typical hypoglycemic metabolic crisis
- Normal lactate: makes primary lactic acidosis less likely
- Negative urine ketones: argues against a significant ketotic metabolic crisis
- pH 7.42: importantly, there is no metabolic acidosis
In urea cycle defects, hyperammonemia commonly occurs without an increased-anion-gap metabolic acidosis. Respiratory alkalosis from hyperventilation is a classic finding, although the provided pH is essentially normal and therefore does not exclude the diagnosis.
The timing is also highly characteristic: affected neonates may appear normal initially and then deteriorate during the first several days of life, with vomiting, feeding difficulty, lethargy, hypotonia, and progressive encephalopathy.
Why the other options are less likely
| Option | Why less likely |
|---|---|
| A. Fatty acid oxidation defect | Often associated with hypoketotic hypoglycemia, particularly during fasting or illness. Here glucose is normal and ketones are absent. |
| B. Organic acidemia | Usually produces high-anion-gap metabolic acidosis, often with ketosis and elevated lactate. |
| C. Urea cycle defect | Severe isolated hyperammonemia with normal glucose and no metabolic acidosis is highly characteristic. |
| D. Galactosemia | Usually becomes apparent after milk feeding with jaundice, hepatocellular dysfunction, hypoglycemia, and/or E. coli sepsis, rather than isolated extreme hyperammonemia. |
| E. Maple syrup urine disease | Typically causes poor feeding, vomiting, lethargy, hypotonia and later neurologic abnormalities, but marked isolated hyperammonemia is not the characteristic biochemical abnormality. |
Exam pearl: In a sick neonate, think “hyperammonemia + respiratory alkalosis/no metabolic acidosis → urea cycle disorder.” In contrast, hyperammonemia + high-anion-gap metabolic acidosis ± ketosis → organic acidemia.
Because the patient is a male neonate, severe ornithine transcarbamylase (OTC) deficiency would be an important specific possibility: OTC deficiency is X-linked and can present as severe neonatal hyperammonemia in males. However, the information given is insufficient to identify the specific urea-cycle enzyme, so C. Urea cycle defect is the appropriate answer.
You can also practice another MCQ on another metabolic disorder.
References
- Simpson KL, MacLeod E, Kakajiwala A, Gropman A, Ah Mew N. Urea Cycle Disorders Overview. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2026. Updated 2025 Jul 3.
- Nagamani SCS, Burrage LC, Lee B. Argininosuccinate Lyase Deficiency. In: GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; updated 2025 Aug 14.
| Neonatal Hyperammonemia: Clinical Approach | |
|---|---|
| Case Summary | |
| Patient | 7-day-old male neonate, exclusively breastfed |
| Symptoms | Poor feeding, recurrent vomiting and lethargy beginning around day 5 of life |
| Examination | Hypotonia with depressed neonatal reflexes |
| Laboratory Investigations | |
| Blood glucose | 92 mg/dL — normal |
| Serum ammonia | 850 µmol/L — markedly elevated |
| Arterial blood gas | pH 7.42 — no metabolic acidosis |
| Serum lactate | Normal |
| Urine ketones | Negative |
| Why Consider a Urea Cycle Defect? | |
| Typical presentation | Neonates may initially appear well and then deteriorate after several days with feeding difficulty, vomiting, lethargy, hypotonia and encephalopathy. |
| Ammonia | Severe hyperammonemia, often >500 µmol/L |
| Acid-base pattern | Normal pH or respiratory alkalosis; metabolic acidosis is typically absent |
| Key clue | Onset after protein feeding begins, together with severe hyperammonemia and absence of significant metabolic acidosis |
| Pathophysiology — Simplified | |
| Normal process | Protein breakdown → ammonia production → urea cycle → urea formation → renal excretion |
| Urea cycle defect | A defect in one of the urea-cycle enzymes impairs conversion of ammonia into urea. |
| Result | ↓ Urea production/excretion → ↑ ammonia → hyperammonemia |
| Most Likely Diagnosis | |
| Diagnosis | Urea cycle defect |
| Why the Other Options Are Less Likely | |
| Fatty acid oxidation defect | Usually causes hypoketotic hypoglycemia. Here, glucose is normal and urine ketones are negative. |
| Organic acidemia | Typically associated with high-anion-gap metabolic acidosis, often with ketosis and elevated lactate. |
| Galactosemia | Classically causes jaundice, hepatocellular dysfunction, hypoglycemia and risk of E. coli sepsis. |
| Maple syrup urine disease | Causes neurologic deterioration, but marked isolated hyperammonemia is not typical. |
| Key Exam Pearls | |
| Pattern 1 | Hyperammonemia + respiratory alkalosis (or no metabolic acidosis) → think urea cycle disorder. |
| Pattern 2 | Hyperammonemia + high-anion-gap metabolic acidosis ± ketosis → think organic acidemia. |
| Male neonate | Severe neonatal hyperammonemia in a male infant should raise consideration of ornithine transcarbamylase (OTC) deficiency, an X-linked urea-cycle disorder. |
| External Link | |
| Further reading | GeneReviews: Urea Cycle Disorders Overview |
| References | |
|
1. Simpson KL, MacLeod E, Kakajawala A, Gro pman A, Ah Mew N. Urea Cycle Disorders Overview. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2026. 2. Nagamani SCS, Borrage LC, Lee B. Argininosuccinate Lyase Deficiency. In: GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; updated 2025. 3. Urea Cycle Disorders. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; updated 2026. |
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