Pre-emptive treatment in later-onset urea cycle disorders: a clinical perspective on glycerol phenylbutyrate

Later-onset urea cycle disorders (UCD) are characterized by variable clinical presentation and unpredictable metabolic decompensation. Current management often relies on a reactive approach, with treatment initiated after clinical manifestations. Glycerol phenylbutyrate (GPB) is widely used for ammonia control in UCD. However, its role in later-onset forms remains incompletely defined, particularly regarding timing of initiation. Available evidence suggests that hyperammonemia-related neurological injury may occur even in apparently stable patients, raising concerns about the adequacy of a wait-and-see strategy. This work provides a clinical perspective integrating current evidence together with personal experience to explore the potential role of pre-emptive GPB therapy in later-onset UCD. The limitations of current approaches are discussed, highlighting the discrepancy between apparent biochemical stability and ongoing neurological risk.

We suggest that a proactive treatment strategy may reduce the risk of neurological complications in selected patients with later-onset UCD. We propose a shift from reactive to pre-emptive management, positioning GPB as a potential tool in this context.