What is the treatment approach for a pediatric or young adult patient with citrulinemia and a history of neurological symptoms?

Treatment of Citrulinemia with Neurological Symptoms

For pediatric or young adult patients with citrulinemia and neurological symptoms, liver transplantation should be strongly considered as it is the only curative treatment that prevents progressive neurological injury and reverses the metabolic defect, particularly when standard dietary and pharmacological interventions fail to control hyperammonemic episodes. 1

Immediate Medical Management

Acute Hyperammonemia Control

• Stop all protein intake immediately and administer intravenous glucose at 8-10 mg/kg/min to prevent catabolism 2
• Provide intravenous lipids starting at 0.5 g/kg daily to ensure adequate caloric intake (target ≥100 kcal/kg daily) 2
• Initiate lactulose at 15-30 mL orally every 1-2 hours until bowel movements occur, then titrate to 2-3 soft stools daily 2
• Check plasma ammonia levels every 3-4 hours until normalized (target <80-100 μmol/L) 2

Nitrogen Scavenger Therapy

• Administer sodium phenylbutyrate as the primary ammonia scavenger at weight-based dosing 3
• Add intravenous sodium benzoate and sodium phenylacetate for acute hyperammonemic crises 2, 4
• These medications help eliminate nitrogen-containing compounds that would otherwise produce ammonia 3

Amino Acid Supplementation

• Citrulline supplementation is NOT appropriate for citrulinemia (argininosuccinate synthetase deficiency), as citrulline itself accumulates in this disorder 3
• Arginine (free base) supplementation is required at 0.4 to 0.7 g/kg/day or 8.8 to 15.4 g/m²/day 3
• Arginine bypasses the enzymatic defect and allows for continued urea cycle function 3

Long-Term Dietary Management

Protein Restriction Protocol

• Limit daily protein intake based on age and tolerance, typically starting at 1.2-1.7 g/kg/day for children 3
• Divide protein intake equally between natural protein and supplemental essential amino acids for optimal growth 3
• Monitor plasma glutamine levels (maintain <1,000 mcmol/L), arginine, branched-chain amino acids, and serum protein 3
• Protein tolerance decreases as growth rate decreases, requiring ongoing adjustment 3

Caloric Supplementation

• Use protein-free caloric products when additional calories are needed 3
• Base total caloric intake on age-appropriate recommended dietary allowances 3

Escalation to Dialysis

Consider kidney replacement therapy (specifically CVVHD) if:

• Ammonia level rises above 150 μmol/L despite medical management 2
• Rapidly deteriorating neurological status develops 2
• Patient progresses to coma or cerebral edema 2

Definitive Treatment: Liver Transplantation

Indications for Transplant Referral

Liver transplantation is indicated when:

• Aggressive disease is not satisfactorily controlled with dietary and pharmacological interventions 1
• Recurrent hyperammonemic crises occur despite optimal medical management 1
• Progressive neurological injury is evident or anticipated 1

Timing Considerations

• The critical decision point is the degree of neurological injury before transplantation 1
• Transplantation prevents progression of neurological damage but does not reverse existing injury 1
• Early referral is essential, as proteinaceous meals or catabolism from normal childhood illnesses can trigger profound hyperammonemia causing progressive and additive CNS insult with intellectual decline 1
• Living related liver transplantation may be considered for optimal timing, though donor enzyme activity must be confirmed adequate (parents often have reduced enzyme activity as carriers) 1

Transplant Outcomes

• Liver transplantation essentially serves as "enzyme replacement therapy" and appears curative 1
• Post-transplant, patients can resume a normal diet and eliminate hyperammonemic crises 1
• However, a high rate of neurological complications after transplantation has been observed in some urea cycle disorders 1
• Behavioral improvements and reversal of neuro-behavioral changes have been documented even with late transplantation 5

Critical Pitfalls to Avoid

Common Management Errors

• Do NOT use citrulline supplementation in citrulinemia - this is only for CPS or OTC deficiency 3
• Do NOT delay transplant evaluation - waiting until severe neurological damage occurs limits potential for functional recovery 1
• Do NOT underestimate infection risk - fever can trigger metabolic decompensation and requires immediate medical attention 3
• Patients should wear a Medic Alert tag stating the diagnosis for emergency situations 3

Monitoring for Non-Compliance

• Noncompliance with diet or sodium phenylbutyrate is an emerging problem in early-treated patients who remain asymptomatic 1
• Brief periods of noncompliance are typically asymptomatic but carry long-term risks 1
• Periods of noncompliance with high succinylacetone levels increase somatic mutations that may promote hepatocarcinoma (though this is specific to tyrosinemia, similar concerns exist for other metabolic disorders) 1

Prognosis Considerations

Neurological Outcomes

• Patients with neonatal-onset disease have a high incidence of mental retardation despite treatment 3, 6
• The general neurological outcome is often unsatisfactory even with appropriate therapy 6
• Mortality remains significant, particularly in neonatal-onset cases (11/13 neonatal-onset patients died in one series) 6
• However, prognosis and quality of life can be improved with early diagnosis and appropriate therapy 6

Asymptomatic or Mild Cases

• Some patients with mild citrullinemia (identified through newborn screening) remain asymptomatic for extended periods (6-156 months) 7
• These cases are typically associated with missense mutations allowing residual enzyme activity 7
• Even asymptomatic patients require ongoing monitoring and dietary management 7