What is the diagnostic workup and treatment for a patient suspected of having citrullinemia?

Diagnostic Workup and Treatment for Citrullinemia

The diagnostic workup for suspected citrullinemia should include plasma amino acid analysis to detect elevated citrulline levels, genetic testing to confirm the diagnosis, and ammonia level measurement, followed by treatment with protein restriction, citrulline or arginine supplementation, and nitrogen scavengers such as sodium phenylbutyrate.

Diagnostic Workup

Initial Laboratory Assessment

• Blood tests:
  • Plasma amino acid analysis (elevated citrulline is the hallmark finding)
  • Ammonia level (often elevated during metabolic crisis)
  • Complete blood count
  • Comprehensive metabolic panel including liver function tests
  • Blood urea nitrogen (BUN) and creatinine

Confirmatory Testing

• Genetic testing:
  • Essential for confirming the diagnosis 1
  • Should be performed in all patients with clinical and biochemical suspicion of citrullinemia 1
  • Will identify mutations in the ASS1 gene (for type I citrullinemia) or SLC25A13 gene (for type II citrullinemia)

Additional Diagnostic Tests

• Cerebrospinal fluid (CSF) analysis:

  • May show elevated citrulline levels in CSF 2
  • Should be considered in patients with neurological symptoms mimicking encephalitis

• Urine studies:

  • Urine orotic acid levels (may be elevated)
  • Urine amino acid profile

Neuroimaging

• Brain MRI during acute crisis to assess for cerebral edema
• May be normal between episodes 2

Electroencephalography (EEG)

• May show bilateral slowing with some spike waves during acute episodes 2

Treatment Approach

Acute Management of Hyperammonemic Crisis

1. Immediate ammonia reduction:

   • Hemodialysis or continuous renal replacement therapy (CRRT) for severe hyperammonemia (>500 μmol/L) 1
   • CRRT is more effective than peritoneal dialysis for ammonia clearance 1

2. Pharmacological intervention:

   • Intravenous nitrogen scavengers (sodium benzoate, sodium phenylacetate)
   • Stop protein intake temporarily
   • Provide high-calorie, protein-free nutrition to prevent catabolism

Long-term Management

1. Dietary Management:

   • Protein restriction based on age and disease severity 3, 4
   • For infants with neonatal-onset disease: 1.6-1.9 g/kg/day protein for first 4 months
   • For ages 4-12 months: 1.4-1.7 g/kg/day protein
   • For ages 1-3 years: 1.2-1.4 g/kg/day protein
   • Caloric supplementation with protein-free products as needed

2. Amino Acid Supplementation:

   • Citrullinemia Type I:

     • L-arginine supplementation: 0.4-0.7 g/kg/day or 8.8-15.4 g/m²/day 3, 4

   • Citrullinemia Type II:

     • Low-carbohydrate diet may be beneficial 5
     • L-arginine supplementation

3. Nitrogen Scavenger Medications:

   • Sodium phenylbutyrate: 450-600 mg/kg/day in children, maximum 20g/day 3, 4
   • Sodium benzoate (alternative option)
   • Carglumic acid may be considered in some cases (100 mg/kg/day) 6

4. Monitoring:

   • Regular monitoring of plasma ammonia levels
   • Plasma amino acid profiles
   • Nutritional status assessment
   • Neurological evaluation

Special Considerations

• For Type II Citrullinemia (CTLN2):

  • Low-carbohydrate diet has shown effectiveness 5
  • May present later in life, even in elderly patients
  • Consider dietary habits in diagnosis (aversion to carbohydrates, preference for protein-rich foods)

• Liver Transplantation:

  • Consider for patients with recurrent hyperammonemic crises despite optimal medical therapy 1
  • Particularly effective for type II citrullinemia

Follow-up and Monitoring

• Regular monitoring of plasma amino acid levels every 3-6 months
• Ammonia levels during intercurrent illnesses
• Developmental assessment in children
• Neuropsychological evaluation as needed

Prevention of Metabolic Decompensation

• Avoid prolonged fasting
• Develop emergency protocol for intercurrent illnesses
• Patient/family education on early signs of hyperammonemia
• Medical alert bracelet
• Genetic counseling for family members 1

Common Pitfalls and Caveats

• Delayed diagnosis is common in late-onset cases, as symptoms may mimic encephalitis or psychiatric disorders 2
• Always measure ammonia in any patient with unexplained neurological symptoms or confusion
• Protein restriction must be carefully balanced to prevent malnutrition while controlling ammonia levels
• Intercurrent illnesses can trigger metabolic decompensation and require prompt intervention
• Medication adherence can be challenging, especially with sodium benzoate due to unpleasant taste 6