Recent advances in benign adult familial myoclonus epilepsy
Recent advances in benign adult familial myoclonus epilepsy
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DOI：
10.1111/ncn3.12685
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发表时间：
2022-11
影响因子：
0.4
通讯作者：
M. Matsukawa;H. Ishiura;S. Tsuji;Tatsushi Toda
中科院分区：
文献类型：
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作者：
M. Matsukawa;H. Ishiura;S. Tsuji;Tatsushi Toda
良性成人家族性肌阵挛癫痫（BAFME），也称为家族性皮质肌阵挛性震颤和癫痫（FCMTE），常染色体显性皮质震颤、肌阵挛和癫痫（ADCME）和家族性成人肌阵挛癫痫（FAME），是一种以罕见的全身性癫痫发作和震颤性肌阵挛为特征的常染色体显性遗传疾病。BAFME的诊断以前是基于临床特征和电生理学发现，但遗传分析现在在识别重复扩增后的诊断中变得越来越重要; BAFME是由SAMD 12（BAFME 1）、STARD 7（BAFME 2）、MARCHF 6（BAFME 3）、YEATS 2（BAFME 4）、TNRC 6A（BAFME 6）或RAPGEF 2（BAFME 7）中的TTTCA和TTTTA重复扩增引起的。这些发现有力地支持了我们先前提出的“重复基序-表型相关性”的概念。病理学上，携带TTTCA和TTTTA重复杂合扩增的BAFME 1患者在中枢神经系统中未显示任何明显的异常神经病理学发现。除了电生理学研究外，这些病理学发现表明神经元回路功能障碍，导致感觉运动皮层的兴奋性增强。BAFME 1患者的尸检大脑显示，在皮质神经元和小脑浦肯野细胞中存在由UUUCA重复序列组成的RNA灶。这些结果表明，RNA毒性引起的UUUCA重复扩增参与BAFME的发病机制。自从我们发现了BAFME 1的致病基因以来，对每种类型的BAFME的遗传学研究以及TTTCA和TTTTA扩增引起的BAFME的发病机制的研究都取得了进展。在这里，我们提出了一个全面的审查最近的进展，重点是扩大TTTCA和TTTTA重复在BAFME。
Benign adult familial myoclonus epilepsy (BAFME), also called familial cortical myoclonic tremor and epilepsy (FCMTE), autosomal dominant cortical tremor, myoclonus, and epilepsy (ADCME), and familial adult myoclonic epilepsy (FAME) is a disorder characterized by infrequent generalized seizures and tremulous myoclonus with an autosomal dominant mode of inheritance. The diagnosis of BAFME was previously based on clinical features and electrophysiological findings, but genetic analysis is now increasingly becoming important in the diagnosis after identification of repeat expansions; BAFME is caused by expansions of TTTCA and TTTTA repeats in SAMD12 (BAFME1), STARD7 (BAFME2), MARCHF6 (BAFME3), YEATS2 (BAFME4), TNRC6A (BAFME6), or RAPGEF2 (BAFME7). The findings strongly support a concept of “repeat motif–phenotype correlation” which we have proposed previously. Pathologically, BAFME1 patients carrying heterozygous expansions of TTTCA and TTTTA repeats do not show any obvious abnormal neuropathological findings in the central nervous system. These pathological findings, in addition to electrophysiological studies, suggest a dysfunctional neuronal circuit that causes enhanced excitability of the sensorimotor cortex. Autopsied brains of BAFME1 patients showed RNA foci consisting of UUUCA repeats in cortical neurons and cerebellar Purkinje cells. These findings suggest that RNA toxicity caused by UUUCA repeat expansions is involved in the pathogenesis of BAFME. Since our discovery of the causative gene for BAFME1, progress has been made in genetic studies of each type of BAFME, as well as in pathogenetic mechanisms of BAFME caused by TTTCA and TTTTA expansions. Here, we present a comprehensive review on recent advances focusing on expanded TTTCA and TTTTA repeats in BAFME.