Unravelling the genetic complexity of drug-resistant epilepsy: a critical narrative review.

IF 3 3区医学 Q2 PHARMACOLOGY & PHARMACY

Expert Review of Clinical Pharmacology Pub Date : 2025-07-01 Epub Date: 2025-08-08 DOI:10.1080/17512433.2025.2545403

Martina Giacon, Salvatore Terrazzino

{"title":"Unravelling the genetic complexity of drug-resistant epilepsy: a critical narrative review.","authors":"Martina Giacon, Salvatore Terrazzino","doi":"10.1080/17512433.2025.2545403","DOIUrl":null,"url":null,"abstract":"Introduction: Drug-resistant epilepsy (DRE) affects 30% of epilepsy patients and represents a major therapeutic challenge. Understanding its genetic determinants is crucial for the development of effective precision medicine strategies.Areas covered: This review comprehensively evaluates genetic factors in DRE, including polymorphisms in pharmacokinetic (e.g. ABCB1) and pharmacodynamic (e.g. SCN1A), findings from genome-wide association studies (GWAS) that recently identified a significant locus at 1q42.11-q42.12 (CNIH3/WDR26) for focal DRE, the critical role of rare variants (e.g. in SCN1A, KCNQ2) and copy number variations (CNVs) in severe epileptic encephalopathies, and the emerging fields of epigenetics and polygenic risk scores (PRS).Expert opinion: Methodological limitations, including modest sample sizes and phenotypic heterogeneity, hamper genetic research on DRE. While common variants show little impact, rare variants, including CNVs, and epigenetic alterations offer promising opportunities. Future priorities include functional studies to clarify the impact of gene variants, the integration of multi-omics data and the development of advanced analytical techniques, such as machine learning and network approaches, to translate genetic discoveries into clinically actionable precision medicine and ultimately improve outcomes for DRE patients.","PeriodicalId":12207,"journal":{"name":"Expert Review of Clinical Pharmacology","volume":" ","pages":"503-517"},"PeriodicalIF":3.0000,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Expert Review of Clinical Pharmacology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1080/17512433.2025.2545403","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/8/8 0:00:00","PubModel":"Epub","JCR":"Q2","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":0}

引用次数: 0

Abstract

Introduction: Drug-resistant epilepsy (DRE) affects 30% of epilepsy patients and represents a major therapeutic challenge. Understanding its genetic determinants is crucial for the development of effective precision medicine strategies.

Areas covered: This review comprehensively evaluates genetic factors in DRE, including polymorphisms in pharmacokinetic (e.g. ABCB1) and pharmacodynamic (e.g. SCN1A), findings from genome-wide association studies (GWAS) that recently identified a significant locus at 1q42.11-q42.12 (CNIH3/WDR26) for focal DRE, the critical role of rare variants (e.g. in SCN1A, KCNQ2) and copy number variations (CNVs) in severe epileptic encephalopathies, and the emerging fields of epigenetics and polygenic risk scores (PRS).

Expert opinion: Methodological limitations, including modest sample sizes and phenotypic heterogeneity, hamper genetic research on DRE. While common variants show little impact, rare variants, including CNVs, and epigenetic alterations offer promising opportunities. Future priorities include functional studies to clarify the impact of gene variants, the integration of multi-omics data and the development of advanced analytical techniques, such as machine learning and network approaches, to translate genetic discoveries into clinically actionable precision medicine and ultimately improve outcomes for DRE patients.

查看原文本刊更多论文

揭示耐药癫痫的遗传复杂性：一项批判性的叙事回顾。

导言：耐药癫痫（DRE）影响30%的癫痫患者，是一项重大的治疗挑战。了解其遗传决定因素对于开发有效的精准医疗策略至关重要。覆盖区域:本综述全面评估了DRE的遗传因素，包括药代动力学（如ABCB1）和药效学（如SCN1A）的多态性，全基因组关联研究（GWAS）最近发现的局灶性DRE的重要位点1q42.11-q42.12 （CNIH3/WDR26）的发现，罕见变异（如SCN1A， KCNQ2）和拷贝数变异（cnv）在严重癫痫性脑病中的关键作用，以及表观遗传学和多基因风险评分（PRS）的新兴领域。专家意见：方法上的限制，包括适度的样本量和表型异质性，阻碍了DRE的遗传研究。虽然常见变异影响不大，但包括CNVs在内的罕见变异和表观遗传改变提供了有希望的机会。未来的重点包括功能研究，以阐明基因变异的影响，多组学数据的整合和先进分析技术的发展，如机器学习和网络方法，将基因发现转化为临床可操作的精准医学，并最终改善DRE患者的预后。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Expert Review of Clinical Pharmacology PHARMACOLOGY & PHARMACY-

CiteScore

7.30

自引率

2.30%

发文量

127

期刊介绍： Advances in drug development technologies are yielding innovative new therapies, from potentially lifesaving medicines to lifestyle products. In recent years, however, the cost of developing new drugs has soared, and concerns over drug resistance and pharmacoeconomics have come to the fore. Adverse reactions experienced at the clinical trial level serve as a constant reminder of the importance of rigorous safety and toxicity testing. Furthermore the advent of pharmacogenomics and ‘individualized’ approaches to therapy will demand a fresh approach to drug evaluation and healthcare delivery. Clinical Pharmacology provides an essential role in integrating the expertise of all of the specialists and players who are active in meeting such challenges in modern biomedical practice.