Association of TPH2 polymorphisms with valproic acid efficacy and neurological adverse events in pediatric epilepsy
Jiahao Zhu1, Xixuan Wang1,2, Xianhuan Shen1
1Department of Pharmacy, Shenzhen Baoan Women's and Children's Hospital, Shenzhen, China.
Objective:
Valproic acid (VPA) response in pediatric epilepsy shows high variability. This study investigated the association of tryptophan hydroxylase-2 (TPH2) polymorphisms with VPA efficacy and adverse drug reactions (ADRs) in children.
Methods:
In a retrospective cohort of 199 children with epilepsy receiving VPA treatment, TPH2 rs4570625 and rs1386494 were genotyped using Sequenom MassArray. Efficacy was categorized as uncontrolled seizure vs. seizure-free. ADRs were systemically recorded, and steady-state VPA concentrations were measured. Network pharmacology integrated protein-protein interactions, and functional enrichment to elucidate TPH2's role in VPA-related neurotoxicity.
Results:
The rs4570625 polymorphism was significantly associated with VPA treatment outcomes. GG homozygotes exhibited higher seizure-free rates (p = 0.031) and lower incidence of neurological ADRs (p = 0.036). GG carriers also displayed significantly higher VPA serum concentrations. Network pharmacology analyses identified the serotonergic synapse as the dominant enriched pathway linking TPH2 to VPA neurotoxicity, with MAOA and SLC6A4 as key regulatory hubs. No significant associations were observed between rs1386494 polymorphism and VPA treatment outcomes.
Conclusion:
TPH2 rs4570625 may serve as a potential exploratory biomarker for predicting VPA efficacy and neurological toxicity in pediatric epilepsy, mediated through serotonergic pathway dysregulation. Genotype-guided personalization could optimize VPA therapy.
Related Concept Videos
Antiepileptic Drugs: Modulators of Neurotransmitter Release Mediated by SV2A Protein
SV2A is a transmembrane glycoprotein located predominantly in the brain, modulating the release of neurotransmitters for neuronal communication. Both levetiracetam and brivaracetam exhibit a high affinity for...
Pharmacogenetic Phenotypes: Alterations in Pharmacokinetics, Drug Targets and Biologic Milieu
Pharmacokinetics in Pediatric Patients: Drug Metabolism
Antiepileptic Drugs: GABAergic Pathway Potentiators
The key GABA pathway potentiators used in epilepsy management are as follows.
Benzodiazepines are a well-known class of drugs used for their...
Pharmacogenetics of Drug Targets: β₂-Adrenergic Receptors, Apo E, Thymidylate Synthase
Pharmacokinetics in Pediatric Patients: Overview and Drug Absorption

