Partial epilepsy with antecedent febrile seizures and seizure aggravation by antiepileptic drugs: Associated with loss of function of Nav1.1
Partial epilepsy with antecedent febrile seizures and seizure aggravation by antiepileptic drugs: Associated with loss of function of Nav1.1
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DOI：
10.1111/j.1528-1167.2010.02645.x
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发表时间：
2010-09-01
期刊：
影响因子：
5.6
通讯作者：
Duan, Shumin
中科院分区：
文献类型：
--
作者：
Liao, Wei-Ping;Shi, Yi-Wu;Duan, Shumin
目的：全身性癫痫伴热性惊厥加重（GEFS+）和婴儿期严重肌阵挛性癫痫（SMEI）与钠通道α亚单位1型基因（SCN 1A）突变有关。GEFS+和SMEI均发生热性惊厥和部分性惊厥;散发性发作和抗癫痫药物（AED）导致的惊厥加重是SMEI的特征。因此，我们搜索基因突变孤立的情况下，部分癫痫与前驱FS（PEFS+），表现出癫痫加重AEDs.Methods：基因组DNA从4例患者进行了筛选突变SCN 1A，SCN 2A，SCN 1B，和GABRG 2使用变性高效液相色谱（dHPLC）和测序。结果：在tsA 201细胞中检测到两个新定义的Na（v）1.1突变体（R946 H和F1765 L），它们被证实是Na（v）1.1功能丧失的原因。当比较以前报道的突变体的功能缺陷时，发现PEFS+的所有突变体都具有功能丧失的特征，而GEFS+显示出除功能丧失之外的轻度功能障碍，与轻度临床表现一致。结论：PEFS+与SMEI在临床上相似，可能与AED诱发的癫痫发作加重有关，在生物生理学上具有功能丧失的特征，而与SMEI不同的是发生了错义突变，但氨基酸残基的疏水性和极性没有改变。本研究的特点表型生物学，这可能有助于了解的病理生理基础，并进一步在疾病的管理。
P>Purpose:Generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy in infancy (SMEI) are associated with sodium channel alpha-subunit type-1 gene (SCN1A) mutations. Febrile seizures and partial seizures occur in both GEFS+ and SMEI; sporadic onset and seizure aggravation by antiepileptic drugs (AEDs) are features of SMEI. We thus searched gene mutations in isolated cases of partial epilepsy with antecedent FS (PEFS+) that showed seizure aggravations by AEDs.Methods:Genomic DNA from four patients was screened for mutations in SCN1A, SCN2A, SCN1B, and GABRG2 using denaturing high-performance liquid chromatography (dHPLC) and sequencing. Whole-cell patch clamp analysis was used to characterize biophysical properties of two newly defined mutants of Na(v)1.1 in tsA201 cells.Results:Two heterozygous de novo mutations of SCN1A (R946H and F1765L) were detected, which were proven to cause loss of function of Na(v)1.1. When the functional defects of mutants reported previously are compared, it is found that all mutants from PEFS+ have features of loss of function, whereas GEFS+ shows mild dysfunction excluding loss of function, coincident with mild clinical manifestations. PEFS+ is similar to SMEI clinically with possible AED-induced seizure aggravation and biophysiologically with features of loss of function, and different from SMEI by missense mutation without changes in hydrophobicity or polarity of the residues.Conclusions:Isolated milder PEFS+ may associate with SCN1A mutations and loss of function of Na(v)1.1, which may be the basis of seizure aggravation by sodium channel-blocking AEDs. This study characterized phenotypes biologically, which may be helpful in understanding the pathophysiologic basis, and further in management of the disease.