Institute of Neuroscience and the Second Affiliated Hospital of Guangzhou Medical College, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, Guangzhou, China.
Epilepsia. 2010 Sep;51(9):1669-78. doi: 10.1111/j.1528-1167.2010.02645.x. Epub 2010 Jun 7.
Generalized epilepsy with febrile seizures plus (GEFS+) and severe myoclonic epilepsy in infancy (SMEI) are associated with sodium channel α-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.
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.
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.
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.
热性惊厥附加症（GEFS+）和婴儿严重肌阵挛性癫痫（SMEI）与钠离子通道α亚单位 1 型基因（SCN1A）突变有关。GEFS+和 SMEI 均伴有热性惊厥和部分性发作；SMEI 的特征为散发性发病和抗癫痫药物（AED）加重发作。因此，我们在表现为 AED 加重发作的局灶性癫痫伴热性惊厥前驱史（PEFS+）的孤立病例中，寻找基因突变。
使用变性高效液相色谱法（dHPLC）和测序对 SCN1A、SCN2A、SCN1B 和 GABRG2 中的基因突变，对 4 例患者的基因组 DNA 进行筛选。在 tsA201 细胞中，使用全细胞膜片钳分析来对两个新定义的 Na(v)1.1 突变体的生物物理特性进行表征。
检测到 SCN1A 中的两个杂合性新生突变（R946H 和 F1765L），证实这些突变导致 Na(v)1.1 功能丧失。当比较先前报道的突变体的功能缺陷时，发现所有来自 PEFS+的突变体均具有功能丧失的特征，而 GEFS+ 表现出轻度功能障碍，除了功能丧失之外，这与轻度临床表现一致。PEFS+ 在临床上与 SMEI 相似，可能存在 AED 诱导的发作加重，在生物学上与功能丧失有关，与 SMEI 不同的是，其突变不改变残基的疏水性或极性。
孤立性较轻的 PEFS+可能与 SCN1A 突变和 Na(v)1.1 功能丧失有关，这可能是钠离子通道阻断 AED 加重发作的基础。本研究从生物学角度对表型进行了特征描述，这可能有助于理解病理生理基础，并进一步对疾病进行管理。
