Monitoring the Treatment of Urea Cycle Disorders Using Phenylbutyrate Metabolite Analyses: Still Many Lessons To Learn

Authors

Kevin E Glinton
Charles G Minard
Ning Liu
Qin Sun
Sarah H Elsea
Lindsay C Burrage
Sandesh C S Nagamani

Publication Date

11-1-2023

Journal

Molecular Genetics and Metabolism

DOI

10.1016/j.ymgme.2023.107699

PMID

37717413

PMCID

PMC11162249

PubMedCentral® Posted Date

11-1-2024

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes

Keywords

Child, Humans, Phenylbutyrates, Retrospective Studies, Urea Cycle Disorders, Inborn, Glycerol phenylbutyrate, nitrogen-scavengers, phenylbutyrate, phenylacetate, PAA:PAGN, urea cycle disorders

Abstract

Medications that elicit an alternate pathway for nitrogen excretion such as oral sodium phenylbutyrate (NaPBA) and glycerol phenylbutyrate (GPB) and intravenous sodium phenylacetate (NaPAA) are important for the management of urea cycle disorders (UCDs). Plasma concentrations of their primary metabolite, phenylacetate (PAA), as well as the ratio of PAA to phenylacetylglutamine (PAGN) are useful for guiding dosing and detecting toxicity. However, the frequency of toxic elevations of metabolites and associated clinical covariates is relatively unknown. A retrospective analysis was conducted on 1255 plasma phenylbutyrate metabolite measurements from 387 individuals. An additional analysis was also conducted on a subset of 68 individuals in whom detailed clinical information was available. In the course of these analyses, abnormally elevated plasma PAA and PAA:PAGN were identified in 39 individuals (4.15% of samples) and 42 individuals (4.30% of samples), respectively. Abnormally elevated PAA and PAA:PAGN values were more likely to occur in younger individuals and associate positively with dose of NAPBA and negatively with plasma glutamine and glycine levels. These results demonstrate that during routine clinical management, the majority of patients have PAA levels that are deemed safe. As age is negatively associated with PAA levels however, children undergoing treatment with NaPBA may need close monitoring of their phenylbutyrate metabolite levels.

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