Table_1_Neurophysiological and Genetic Findings in Patients With Juvenile Myoclonic Epilepsy.pdf

ObjectiveTranscranial magnetic stimulation (TMS), a non-invasive procedure, stimulates the cortex evaluating the central motor pathways. The response is called motor evoked potential (MEP). Polyphasia results when the response crosses the baseline more than twice (zero crossing). Recent research shows MEP polyphasia in patients with generalized genetic epilepsy (GGE) and their first-degree relatives compared with controls. Juvenile Myoclonic Epilepsy (JME), a GGE type, is not well studied regarding polyphasia. In our study, we assessed polyphasia appearance probability with TMS in JME patients, their healthy first-degree relatives and controls. Two genetic approaches were applied to uncover genetic association with polyphasia.Methods20 JME patients, 23 first-degree relatives and 30 controls underwent TMS, obtaining 10–15 MEPs per participant. We evaluated MEP mean number of phases, proportion of MEP trials displaying polyphasia for each subject and variability between groups. Participants underwent whole exome sequencing (WES) via trio-based analysis and two-case scenario. Extensive bioinformatics analysis was applied.ResultsWe identified increased polyphasia in patients (85%) and relatives (70%) compared to controls (47%) and significantly higher mean number of zero crossings (i.e., occurrence of phases) (patients 1.49, relatives 1.46, controls 1.22; p < 0.05). Trio-based analysis revealed a candidate polymorphism, p.Glu270del,in SYT14 (Synaptotagmin 14), in JME patients and their relatives presenting polyphasia. Sanger sequencing analysis in remaining participants showed no significant association. In two-case scenario, a machine learning approach was applied in variants identified from odds ratio analysis and risk prediction scores were obtained for polyphasia. The results revealed 61 variants of which none was associated with polyphasia. Risk prediction scores indeed showed lower probability for non-polyphasic subjects on having polyphasia and higher probability for polyphasic subjects on having polyphasia.ConclusionPolyphasia was present in JME patients and relatives in contrast to controls. Although no known clinical symptoms are linked to polyphasia this neurophysiological phenomenon is likely due to common cerebral electrophysiological abnormality. We did not discover direct association between genetic variants obtained and polyphasia. It is likely these genetic traits alone cannot provoke polyphasia, however, this predisposition combined with disturbed brain-electrical activity and tendency to generate seizures may increase the risk of developing polyphasia, mainly in patients and relatives.

本项研究旨在探究经颅磁刺激（TMS）技术激发大脑皮层以评估中枢运动通路时的反应，即运动诱发电位（MEP）。当MEP的响应超过基线两次以上（零交叉）时，称之为多相性。近期的研究表明，在泛发性遗传性癫痫（GGE）患者及其一级亲属中，MEP的多相性表现与对照者相比具有显著差异。青少年肌阵挛癫痫（JME）作为一种GGE亚型，其多相性的研究尚不充分。本研究通过TMS技术对JME患者、其健康的一级亲属以及对照组进行评估，以研究多相性出现的概率。针对多相性与遗传的关联，本研究采用了两种遗传学方法。方法上，20名JME患者、23名一级亲属和30名对照者接受了TMS检查，每位参与者获得了10-15个MEP。我们评估了每位受试者的MEP平均相位数、显示多相性的MEP试验比例以及组间差异。受试者接受了基于三联体的全外显子测序（WES）以及两种案例情景分析。在深入的生物信息学分析中，我们发现了在JME患者及其亲属中，出现多相性的个体（患者为85%，亲属为70%）与对照组（47%）相比，其平均零交叉次数（即相位出现次数）显著增加（患者1.49，亲属1.46，对照组1.22；p < 0.05）。基于三联体的分析揭示了SYT14（突触结合蛋白14）基因中的一个候选多态性变异p.Glu270del，该变异在JME患者及其亲属中呈现多相性。在剩余参与者的Sanger测序分析中，未发现显著关联。在两种案例情景中，对优势比分析中确定的变异应用机器学习方法，获得了多相性的风险预测分数。结果显示61个变异，其中无一与多相性相关。风险预测分数确实表明非多相性受试者发生多相性的可能性较低，而多相性受试者发生多相性的可能性较高。结论上，与对照者相比，JME患者及其亲属中存在多相性。尽管尚无已知临床症状与多相性相关，但这一神经生理现象很可能源于共同的脑电图异常。本研究未发现遗传变异与多相性之间的直接关联。可能这些遗传特征本身不能引起多相性，然而，这种易感性结合脑电活动的紊乱和癫痫发作的倾向，可能增加发展多相性的风险，尤其是在患者及其亲属中。