Clinical analysis of PAFAH1B1 gene variants in pediatric patients with epilepsy.

PURPOSE: PAFAH1B1, also known as LIS1, is associated with type I lissencephaly in humans, which is a severe developmental brain disorder believed to result from abnormal neuronal migration. Our objective was to characterize the genotypes and phenotypes of PAFAH1B1-related epilepsy. METHODS: We conducted a comprehensive analysis of the medical histories, magnetic resonance imaging findings, and video-electroencephalogram recordings of 11 patients with PAFAH1B1 variants at the Neurology Department of Beijing Children's Hospital from June 2017 to November 2022. RESULTS: The age of onset of epilepsy ranged from 2 months to 4 years, with a median onset age of 5 months. Among these 11 patients (comprising 6 boys and 5 girls), all were diagnosed with lissencephaly type 1. Predominantly, generalized tonic-clonic and spasm seizures characterized PAFAH1B1-related epilepsy. Additionally, 10 out of the 11 patients exhibited severe developmental disorders. All patients exhibited de novo variants, with three individuals displaying 17p13.3 deletions linked to haploinsufficiency of PAFAH1B1. Four variants were previously unreported. Notably, three patients with 17p13.3 deletions displayed developmental delay and drug resistant epilepsy, whereas the single patient with mild developmental delay, Intelligence Quotient (IQ) 57 and well-controlled seizures had a splicing-site variant. CONCLUSION: The severity of the phenotype in patients with PAFAH1B1 variants ranged from drug-responsive seizures to severe epileptic encephalopathy. These observations underscore the clinical heterogeneity of PAFAH1B1-related disorders, with most patients exhibiting developmental disorders. Moreover, the severity of epilepsy appears to be linked to genetic variations.

UGT1A polymorphism rs4148324 associated with topiramate plasma concentration to dose ratio in children with epilepsy.

PURPOSE: The objective of this study is to evaluate the association between genetic polymorphisms and the concentration to dose ratio of topiramate in children with epilepsy. METHODS: A cohort of 163 pediatric patients with epilepsy receiving topiramate therapy were enrolled. The ultra-performance liquid chromatography-tandem mass spectrometry method was employed to measure the trough plasma concentration of topiramate at steady-state. These concentrations were normalized by dividing them by the ratio of total daily dose to body weight, yielding the concentration to dose ratio (CDR) of topiramate. MassArray system identified 30 single nucleotide polymorphisms associated with the pharmacokinetics and pharmacodynamics of topiramate. The CDR values were logarithmic transformed (lnCDR) for normal distribution. The association between the identified genetic polymorphisms and lnCDR was assessed using the PLINK software, employing linear regression analysis with adjustments by epilepsy types, estimated glomerular filtration rate, alanine aminotransferase, valproic acid, phenobarbital, and oxcarbazepine. RESULTS: Variant rs4148324 (UGT1A1/3/4/5/6/7/8/9/10, BETA = 0.182, P = 0.010) was significantly associated with lnCDR of topiramate. Patients carrying the G allele exhibited higher normalized topiramate plasma concentrations. No other significant associations were found. CONCLUSIONS: In pediatric patients receiving topiramate therapy, rs4148324 was associated with normalized topiramate plasma concentration. Further studies are warranted to validate and confirm the findings.

Population pharmacokinetics of topiramate in Chinese children with epilepsy.

OBJECTIVE: Topiramate, a broad-spectrum antiepileptic drug, exhibits substantial inter-individual variability in both its pharmacokinetics and therapeutic response. The aim of this study was to investigate the influence of patient characteristics and genetic variants on topiramate clearance using population pharmacokinetic (PPK) models in a cohort of Chinese pediatric patients with epilepsy. METHOD: The PPK model was constructed using a nonlinear mixed-effects modeling approach, utilizing a dataset comprising 236 plasma concentrations of topiramate obtained from 181 pediatric patients with epilepsy. A one-compartment model combined with a proportional residual model was employed to characterize the pharmacokinetics of topiramate. Covariate analysis was performed using forward addition and backward elimination to assess the influence of covariates on the model parameters. The model was thoroughly evaluated through goodness-of-fit analysis, bootstrap, visual predictive checks, and normalized prediction distribution errors. Monte Carlo simulations were utilized to devise topiramate dosing strategies. RESULT: In the final PPK models of topiramate, body weight, co-administration with oxcarbazepine, and a combined genotype of GKIR1-UGT (GRIK1 rs2832407, UGT2B7 rs7439366, and UGT1A1 rs4148324) were identified as significant covariates affecting the clearance (CL). The clearance was estimated using the formulas CL (L/h) = 0.44 × (BW/11.7)0.82 × eOXC for the model without genetic variants and CL (L/h) = 0.49 × (BW/11.7)0.81 × eOXC × eGRIK1-UGT for the model incorporating genetic variants. The volume of distribution (Vd) was estimated using the formulas Vd (L) = 6.6 × (BW/11.7). The precision of all estimated parameters was acceptable. Furthermore, the model demonstrated good predictability, exhibiting stability and effectiveness in describing the pharmacokinetics of topiramate. CONCLUSION: The clearance of topiramate in pediatric patients with epilepsy may be subject to the influence of factors such as body weight, co-administration with oxcarbazepine, and genetic polymorphism. In this study, PPK models were developed to better understand and account for these factors, thereby improving the precision and individualization of topiramate therapy in children with epilepsy.

Population pharmacokinetics of oxcarbazepine active metabolite in Chinese children with epilepsy.

Oxcarbazepine (OXC) is an antiepileptic drug whose efficacy is largely attributed to its monohydroxy derivative metabolite (MHD). Nevertheless, there exists significant inter-individual variability in both the pharmacokinetics and therapeutic response of this drug. The objective of this study is to explore the impact of patients' characteristics and genetic variants on MHD clearance in a population pharmacokinetic (PPK) model of Chinese pediatric patients with epilepsy. The PPK model was developed using a nonlinear mixed effects modeling method based on 231 MHD plasma concentrations obtained from 185 children with epilepsy. The one-compartment model and combined residual model were established to describe the pharmacokinetics of MHD. Forward addition and backward elimination were employed to evaluate the impact of covariates on the model parameters. The model was evaluated using goodness-of-fit, bootstrap, visual predictive checks, and normalized prediction distribution errors. In the two final PPK models, age, estimated glomerular filtration rate (eGFR), and a combined genotype of six variants (rs1045642, rs2032582, rs7668282, rs2396185, rs2304016, rs1128503) were found to significantly reduce inter-individual variability for MHD clearance. The inter-individual clearance equals to 1.38 × (Age/4.74)0.29 × (eGFR/128.66)0.25 × eθABCB-UGT-SCN-INSR for genetic variants included model and 1.30 × (Age/4.74)0.30 × (eGFR/128.66)0.23 for model without genetic variants. The precision of all parameters was deemed acceptable, and the model exhibited good predictability while remaining stable and effective.    Conclusion: Age, eGFR, and genotype may play a significant role in MHD clearance in children with epilepsy. The developed PPK models hold potential utility in facilitating oxcarbazepine dose adjustment in pediatric patients. What is Known: • The adjustment of the oxcarbazepine regimen remains difficult due to the considerable inter- and intra-individual variability of oxcarbazepine pharmacokinetics. • Body weight and co-administration with enzyme-inducing antiepileptic drugs emerge as the most influential factors contributing to the pharmacokinetics of MHD. What is New: • A positive correlation was observed between eGFR and the clearance of MHD in pediatric patients with epilepsy. • We explored the influence of genetic polymorphisms on MHD clearance and identified a combined genotype (ABCB-UGT-SCN-INSR) that exhibited a significant association with MHD concentration.

Intramolecular Transamidation of Secondary Amides via Visible-Light-Induced Tandem Reaction.

Transformation of secondary amides to N-acylimines was used as an effective strategy to activate otherwise unreactive amide bonds. In this tandem reaction, the Rose Bengal-catalyzed photo-oxidative coupling of arylglycine esters and enamides generates N-acylimines, which undergo intramolecular transamidation and imine hydrolysis to afford bioactive acyl Mannich base derivatives under metal-free and mild conditions.