A Role of Aging in the Progression of Cortical Excitability in Benign Adult Familial Myoclonus Epilepsy type 1 Patients
A Role of Aging in the Progression of Cortical Excitability in Benign Adult Familial Myoclonus Epilepsy type 1 Patients
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衰老在良性成人家族性肌阵挛癫痫 1 型患者皮层兴奋性进展中的作用
DOI：
10.1002/mds.28718
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发表时间：
2021
影响因子：
8.6
通讯作者：
Ikeda Akio
中科院分区：
文献类型：
--
作者：
Neshige Shuichiro;Hitomi Takefumi;Tojima Maya;Oi Kazuki;Kobayashi Katsuya;Matsuhashi Masao;Shimotake Akihiro;Matsumoto Riki;Kanda Masutaro;Maruyama Hirofumi;Ishiura Hiroyuki;Tsuji Shoji;Takahashi Ryosuke;Ikeda Akio
最近的分子遗传学研究表明，不育α基序结构域12 （SAMD12）中TTTTA和TTTCA重复扩增异常是成人良性家族性肌阵挛性癫痫（BAFME） 1型的病因。这提供了扩大的重复大小与癫痫发作年龄之间呈负相关的证据。然而，在生命后期，非编码扩展重复序列长度对症状进展的影响尚不清楚。考虑到皮层兴奋性在BAFME晚期逐渐恶化，这一知识差距令人感兴趣。2我们评估了18例遗传诊断为BAFME 1型的患者，先前发现TTTTA和TTTCA重复长度异常1（表S1）。对皮层兴奋性（皮层体感诱发电位[SEP]的早期成分，即N20、P25和N33的振幅）、3龄（SEP检查时的当前年龄）和基因型（扩大的TTTTA和TTTCA重复大小之和）之间的内在相关性进行偏相关分析。我们还研究了患者年龄、基因型和增强的长环反射（c反射）之间的关系。扩增的TTTTA/TTTCA重复序列平均大小为5.9 Æ 2.0 kb。两种皮质性震颤的发病年龄（r= À0）。54， P= 0.037)和癫痫发作（r= À0）。62， P= 0.016)与扩展TTTTA/TTTCA重复序列的重复长度呈负相关（图1A）。患者年龄与N20或N33 SEP振幅无显著相关性（图1B）；年龄与P25振幅呈正相关（r= 0.51， P= 0.038）。此外，偏相关分析（排除扩增重复片段大小的影响）显示P25与年龄相关（r= 0.47， P= 0.057）。扩增重复序列大小与SEP振幅值之间的相关性不显著，但与P25和N33呈负相关（图1C）。c反射患者的平均检查年龄往往高于无c反射患者（57.3 Æ 4.2 vs. 32.0 Æ 2.8岁）。S1)。本研究表明：(1)癫痫发作的发病年龄与最近报道的TTTTA/TTTCA重复大小显著相关，(2)皮层震颤（BAFME的前驱症状）的发病年龄与重复大小存在潜在的相关性。此外，经偏相关分析，SEP检查皮层兴奋性与年龄显著相关，年龄的影响比基因型的影响更显著。这种相关性在SEP P25中强于N20，因为它增强了初级感觉运动区产生的突触后皮层电位。此外，c反射在老年患者中的高发生率可能支持皮层兴奋性与衰老之间的关联。因此，我们推测BAFME表型进展（通过SEP振幅增加反映）受到SAMD12和年龄扩大的TTTTA/TTTCA重复大小的共同影响；此外，至少在后期，老化的影响可能比重复膨胀的影响更大。此外，本研究中没有患者使用可能影响振幅的新型抗癫痫药物（如perampanel或左乙拉西坦）。bafme是一种独特的疾病，最初被认为是“良性”的，因为它的临床进展至少在中年之前是没有或边缘性的。内含子扩增可通过诱导细胞核内异常RNA聚集（病灶）的形成而引起疾病。在BAFME中观察到的时间依赖性神经元功能障碍可能是由于以下两个因素造成的：(1)重复扩张导致…
Recent molecular genetic studies have revealed that abnormal intronic TTTTA and TTTCA repeat expansion in sterile alpha motif domain containing 12 (SAMD12) causes benign adult familial myoclonus epilepsy (BAFME) type 1. 1 This provides evidence of an inverse correlation between the expanded repeat sizes and seizure onset age. However, the effect of noncoding expanded repeat length on symptom progression during the late lifetime stage remains obscure. This knowledge gap is of interest given that cortical excitability gradually worsens during late-stage BAFME. 2 We evaluated 18 patients with genetically diagnosed BAFME type 1 and previously identified abnormal TTTTA and TTTCA repeat lengths1 (Table S1). Partial correlation analyses were conducted for internal correlations among cortical excitability (amplitudes of early components of cortical somatosensory-evoked potential [SEP], ie, N20, P25, and N33), 3 aging (current age at SEP examination), and genotype (sum of the expanded TTTTA and TTTCA repeat sizes). 1 We also investigated the associations among patients’ age, genotype, and an enhanced long-loop reflex (C-reflex). The mean size of the expanded TTTTA/TTTCA repeats was 5.9 Æ 2.0 kb. The onset age of both cortical tremor (r= À0. 54, P= 0.037) and seizures (r= À0. 62, P= 0.016) was inversely correlated with the repeat size of expanded TTTTA/TTTCA repeats (Fig. 1A). There was no significant correlation between patient age and N20 or N33 SEP amplitude (Fig. 1B); in contrast, age was positively correlated with P25 amplitude (r= 0.51, P= 0.038). Furthermore, partial correlation analysis (which eliminated the effect of expanded repeat size) revealed an association between P25 and age (r= 0.47, P= 0.057). The correlations between expanded repeat size and any of the SEP amplitude values were not significant, although it tended to be negatively correlated with P25 and N33 (Fig. 1C). The mean age at examination tended to be higher in patients with C-reflex than in those without (57.3 Æ 4.2 vs. 32.0 Æ 2.8 years)(Fig. S1). This study demonstrates that (1) the onset age of seizure is significantly correlated with the combined TTTTA/TTTCA repeat size as recently reported1 and (2) there is a potential correlation between the onset age of cortical tremor (which is a prodromal symptom of BAFME) and the repeat size. Moreover, cortical excitability was significantly correlated with age at SEP examination based on the partial correlation analysis, which showed that age had a more significant effect than genotype. This correlation was stronger for the SEP P25 than N20 as it enhanced postsynaptic cortical potentials resulting from the primary sensorimotor area. Furthermore, the high occurrence of C-reflex in aged patients presumably supported the association between cortical excitability and aging. Therefore, we speculate that BAFME phenotypic progression (reflected by increased SEP amplitudes) is affected by the combination of the expanded TTTTA/TTTCA repeat size in SAMD12 and age; in addition, the influence of aging might be stronger than that of repeat expansion, at least in the late stage. Besides, no patient in this study used new antiepileptic drugs (eg, perampanel or levetiracetam) that could potentially affect the amplitude. 3BAFME is a unique disease initially considered “benign” as its clinical progression is absent or marginal at least until middle age. Intronic expansions would cause disease by inducing the formation of abnormal RNA aggregations (foci) in the cell nucleus. 4 Time-dependent neuronal dysfunction observed in BAFME could be due to these two contributing factors:(1) repeat expansion causing …
DOI：
10.1007/978-1-4939-9124-2_4
发表时间：
2019-01-01
期刊：
ALPHA-SYNUCLEIN
影响因子：
--
作者：
Concha-Marambio, Luis;Shahnawaz, Mohammad;Soto, Claudio
通讯作者：
Soto, Claudio
影响因子：
30.8
作者：
Ishiura, Hiroyuki;Doi, Koichiro;Tsuji, Shoji
通讯作者：
Tsuji, Shoji