Pediatrics · Year 3 · from Pediatrics

Case 3: Urea Cycle Disorder - Ornithine Transcarbamylase Deficiency

Patient Demographics

  • Age: 3-day-old male
  • Sex: Male

Chief Complaint

"The baby is lethargic and not feeding."

History of Present Illness

A 3-day-old full-term male infant is brought from home after becoming increasingly lethargic over the past 12 hours. He was born at home with a midwife and was breastfeeding well initially. Over the past day, he has become difficult to arouse, has stopped feeding, and has been breathing rapidly. His mother notes he has become "stiff" and has had some jerky movements of his arms. There is no fever. He is the first child of non-consanguineous parents. The maternal uncle died at 5 days of life from "unknown causes."

Physical Examination

  • Vital Signs: Temperature 36.0C (hypothermic), HR 170 bpm, RR 60/min (Kussmaul-type), BP 55/35 mmHg
  • General: Lethargic, intermittently irritable newborn with minimal response to stimulation
  • HEENT: Anterior fontanelle full
  • Respiratory: Tachypneic (central hyperventilation), clear breath sounds
  • Neurologic: Hypotonic with intermittent extensor posturing, poor suck, hyperreflexia

Laboratory Findings

  • Glucose: 65 mg/dL (normal)
  • ABG: pH 7.52, pCO2 22, HCO3 18 (respiratory alkalosis)
  • Ammonia: 1,850 umol/L (critically elevated; normal <50)
  • Lactate: 2.5 mmol/L (mildly elevated)
  • BUN: 2 mg/dL (low)
  • Plasma amino acids: Elevated glutamine, low citrulline, absent argininosuccinate
  • Urine orotic acid: Markedly elevated

Diagnosis

Ornithine transcarbamylase (OTC) deficiency with hyperammonemic crisis

Clinical Reasoning

This infant presents with hyperammonemic encephalopathy. The pattern of findings is diagnostic:

  • Severe hyperammonemia (>1,500 umol/L) causing encephalopathy
  • Respiratory alkalosis (from central hyperventilation - ammonia stimulates respiratory center; distinguishes from organic acidemias which cause metabolic acidosis)
  • Low BUN (cannot synthesize urea)
  • Elevated glutamine, low citrulline (amino acid pattern)
  • Elevated urine orotic acid (pathognomonic for OTC deficiency - carbamoyl phosphate is shunted to pyrimidine synthesis)
  • Symptom-free interval followed by deterioration (normal at birth, then decompensates as protein intake increases)
  • Family history of neonatal male death (X-linked inheritance - males severely affected)

OTC deficiency is the most common urea cycle disorder, with X-linked inheritance. Male infants with complete deficiency present in the first days of life with devastating hyperammonemia.

Management

EMERGENCY - Hyperammonemia is neurotoxic and requires immediate treatment:

  1. Stop all protein intake: NPO immediately
  1. Prevent catabolism:
  • D10W at 1.5-2x maintenance (10-12 mg/kg/min glucose)
  • Consider intralipids for calories (20% lipid at 2-3 g/kg/day)
  1. Nitrogen scavengers (Ammonul - sodium benzoate/sodium phenylacetate):
  • Loading dose: 250 mg/kg of each IV over 90-120 minutes
  • Maintenance: 250-500 mg/kg/day continuous infusion
  • Provides alternative pathways for nitrogen excretion
  1. Arginine supplementation:
  • Arginine HCl 200-600 mg/kg/day IV
  • Arginine becomes essential when urea cycle is blocked
  1. Hemodialysis:
  • Indicated for ammonia >500 umol/L or rising despite medical management
  • Most effective method for rapid ammonia removal
  1. Supportive care:
  • Correct hypothermia
  • Seizure management if needed
  • Prepare for possible intubation
  1. Genetics/Metabolic consultation: Immediate

Long-Term Management (if survives acute crisis):

  • Protein-restricted diet
  • Chronic nitrogen scavengers (sodium phenylbutyrate or glycerol phenylbutyrate)
  • Arginine or citrulline supplementation
  • Consider liver transplantation (curative)

Prognosis

Neonatal-onset OTC deficiency with severe hyperammonemia has high mortality and significant neurodevelopmental morbidity in survivors. Early hemodialysis may improve outcomes. Liver transplantation is curative but does not reverse existing brain injury.

Clinical Image

Image Description: Diagram of the urea cycle showing the location of the ornithine transcarbamylase (OTC) enzyme and the biochemical consequences of its deficiency, including accumulation of carbamoyl phosphate and orotic acid.

Source: Wikimedia Commons URL: https://commons.wikimedia.org/wiki/File:Urea_cycle.svg License: CC BY-SA 4.0

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