Khurana Ishant, Khoury Jean, Busch Robyn M, Blümcke Ingmar, Najm Imad, El-Osta Assam
Baker Heart and Diabetes Institute, Epigenetics in Human Health and Disease Program, Melbourne, Victoria 3004, Australia.
Epilepsy Center, Neurological Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
Brain Commun. 2025 Aug 22;7(4):fcaf277. doi: 10.1093/braincomms/fcaf277. eCollection 2025.
Focal Cortical Dysplasia (FCD) is a common cause of drug-resistant epilepsy. These abnormalities arise during embryonic development and are challenging to classify due to their complex nature. The most recent classification update of FCD incorporates genetic and epigenetic results with other clinical data for the management of epilepsy associated with these lesions. Mutations in the mechanistic target of rapamycin pathway have been described in subtypes IIa and IIb of FCD. In this study, we aimed to study brain DNA methylation in human FCD samples and determine whether blood DNA methylation reflects epigenetic changes observed in brain tissue. We studied genome-wide methylation in 21 brain tissue samples (FCD; 13 and other pathologies; 8) resected from patients with medically intractable epilepsy along with matched blood samples from the same patients. These results were validated with 32 brain-blood matched samples. This study identified both unique and shared methylation signatures in brain and blood for FCD subty pes IIa and IIb and validated three methylation biomarkers (, , and ) that differentiate these subtypes. Methyl-Binding Domain capture sequencing identified 676 551 methylated regions, covering 70% of cytosine-guanine dinucleotide sites in the genome. Adjustments for factors like age, gender, and disease duration were made before analysis. A total of 13 methylation biomarkers were identified for improved classification of FCD IIb from IIa. The three biomarkers showed high specificity and sensitivity, with an area under the curve score of 0.98 and -value = 0.01. The study highlights the potential use of DNA methylation biomarkers as a non-invasive diagnostic tool for distinguishing between FCD subtypes, which could lead to more accurate treatment decisions for patients with epilepsy. The findings also underscore the importance of methylation patterns in understanding the pathophysiology of FCD.
局灶性皮质发育不良（FCD）是药物难治性癫痫的常见病因。这些异常在胚胎发育过程中出现，由于其性质复杂，难以进行分类。FCD的最新分类更新将遗传和表观遗传结果与其他临床数据相结合，用于管理与这些病变相关的癫痫。雷帕霉素机制靶点通路的突变已在FCD的IIa和IIb亚型中被描述。在本研究中，我们旨在研究人类FCD样本中的脑DNA甲基化，并确定血液DNA甲基化是否反映了在脑组织中观察到的表观遗传变化。我们研究了从药物难治性癫痫患者切除的21个脑组织样本（FCD；13个和其他病理；8个）中的全基因组甲基化，以及来自同一患者的匹配血液样本。这些结果在32个脑血匹配样本中得到了验证。本研究确定了FCD IIa和IIb亚型在脑和血液中独特和共同的甲基化特征，并验证了三种区分这些亚型的甲基化生物标志物（、和）。甲基结合域捕获测序鉴定出676551个甲基化区域，覆盖了基因组中70%的胞嘧啶-鸟嘌呤二核苷酸位点。在分析之前对年龄、性别和病程等因素进行了调整。共鉴定出13种甲基化生物标志物，用于改善FCD IIb与IIa的分类。这三种生物标志物显示出高特异性和敏感性，曲线下面积得分为0.98，-值=0.01。该研究强调了DNA甲基化生物标志物作为区分FCD亚型的非侵入性诊断工具的潜在用途，这可能会为癫痫患者带来更准确的治疗决策。这些发现还强调了甲基化模式在理解FCD病理生理学中的重要性。
