新生儿遗传性癫痫43例临床特征和基因型-表型关联分析

doi:10.12372/jcp.2026.25e1201

摘要/Abstract

摘要：

目的分析新生儿遗传性癫痫的临床与基因变异特征，探究基因变异特点与临床表现的相关性。方法回顾性收集2019年1月至2024年12月河北省儿童医院收治的新生儿遗传性癫痫病例，根据基因测序结果分为KCNQ2组和非KCNQ2组，比较两组临床特征，并分析KCNQ2基因型-表型相关性。结果共纳入新生儿遗传性癫痫43例，男26例、女17例，中位胎龄39.4（38.1~40.3）周，出生体重3 400（3 000~3 400）g，KCNQ2组24例、非KCNQ2组19例。癫痫起病时间为生后3.0（2.0~7.0）d，与非KCNQ2组相比，KCNQ2组癫痫起病时间更早，差异有统计学意义（P<0.05）。发作形式以阵挛（62.8%）、强直（53.5%）发作为主，头颅磁共振成像以脑实质信号异常（72.1%）为主，视频脑电图以多灶性放电（34.9%）多见，KCNQ2组和非KCNQ2组之间差异均无统计学意义（P>0.05）。KCNQ2组自限性新生儿癫痫（SeLNE）13例、发育性癫痫性脑病（DEE）11例，其中23例成功随访，19例发作控制、8例发育迟缓、2例死亡；非KCNQ2组SeLNE 1例、DEE10例、其他8例，其中13例随访成功，7例发作控制、7例发育迟缓、4例死亡。KCNQ2组SeLNE比例高于非KCNQ2组（54.2%对5.3%，P<0.01），死亡和发育迟缓比例低于非KCNQ2组（43.5%对84.6%，P=0.033）。KCNQ2核苷酸序列变异共19例，其中10例SeLNE，5例遗传性变异，4例错义变异，7例氨基酸改变位于C末端。9例DEE均为新发变异，其中7例错义变异，5例氨基酸改变位于S4、S6及邻近区域、B螺旋区。预测11例错义变异蛋白结构变化：4例SeLNE中2例蛋白二级结构改变，3例氢键改变，4例蛋白稳定性下降；7例DEE中6例蛋白二级结构改变，4例氢键改变，6例蛋白稳定性下降。结论新生儿遗传性癫痫中KCNQ2基因变异最多见。与其他基因变异相比，KCNQ2变异所致新生儿癫痫起病时间更早，不良预后比例较低，其中新发、错义和重要结构域的变异可能与DEE表型相关。

关键词: 新生儿癫痫, 基因变异, KCNQ2, 自限性新生儿癫痫, 发育性癫痫性脑病

Abstract:

Objective To analyze the clinical and genetic variation characteristics of hereditary epilepsy in neonates and explore the correlation between the characteristics of genetic variations and clinical manifestations. Methods A retrospective collection was made of neonatal hereditary epilepsy cases admitted to Hebei Children's Hospital from January 2019 to December 2024. The cases were divided into KCNQ2 group and non-KCNQ2 group based on the results of gene sequencing. The clinical features of the two groups were compared, and the genotype-phenotype correlation of KCNQ2 was analyzed. Results A total of 43 cases of neonatal hereditary epilepsy were included, including 26 boys and 17 girls, with a gestational age of 39.4 (38.1-40.3) weeks and a birth weight of 3400 (3000-3400) g. There were 24 cases in the KCNQ2 group and 19 cases in the non-KCNQ2 group. The onset time of epilepsy was 3.0 (2.0-7.0) days after birth, which was earlier in the KCNQ2 group than in the non-KCNQ2 group (P<0.05). The main seizure forms were clonic (62.8%) and tonic (53.5%) seizures. The main abnormality on head MRI was abnormal brain parenchymal signal (72.1%). The most common finding on video electroencephalogram was multifocal discharges (34.9%). There were no statistically significant differences between the two groups (P>0.05). In the KCNQ2 group, there were 13 cases of self-limiting neonatal epilepsy (SeLNE) and 11 cases of developmental and epileptic encephalopathy (DEE). Among the 23 cases successfully followed up, 19 cases had seizure control, 8 cases had significant developmental delay, and 2 cases died. In the non-KCNQ2 group, there was 1 case of SeLNE, 10 cases of DEE, and 8 other cases. Among the 13 cases successfully followed up, 7 cases had seizure control, 7 cases had significant developmental delay, and 4 cases died. The proportion of SeLNE in the KCNQ2 group was higher than that in the non-KCNQ2 group (54.2% vs. 5.3%, P<0.01), and the proportion of death and significant developmental delay was lower in the KCNQ2 group (43.5% vs. 84.6%, P=0.033). There were 19 cases of KCNQ2 nucleotide sequence variations, including 10 cases of SeLNE, 5 cases of hereditary variations, and 4 cases of missense variations. Seven amino acid changes were located at the C-terminal. All 9 cases of DEE were de novo variations, including 7 cases of missense variations, and 5 amino acid changes were located at the S4, S6 and adjacent regions, and the B-helix region. Prediction of protein structural changes induced by 11 missense variants: among 4 SeLNE cases, 2 showed alterations in protein secondary structure, 3 exhibited changes in hydrogen bonds, and 4 demonstrated decreased protein stability; among 7 DEE cases, 6 displayed alterations in protein secondary structure, 4 presented changes in hydrogen bonds, and 6 manifested decreased protein stability. Conclusions KCNQ2 gene variations are the most common in neonatal hereditary epilepsy. Compared with other gene variations, KCNQ2-induced neonatal epilepsy has an earlier onset time and a lower proportion of adverse outcomes. Among them, de novo, missense, and variations at important functional domain sites, may be associated with severe phenotypes of DEE.

Key words: neonatal epilepsy, genetic variant, KCNQ2, self-limited neonatal epilepsy, developmental and epileptic encephalopathy

中图分类号:

霍相孜, 冯丽娟, 孟灵芝, 张玉东, 孙玉丽, 马莉, 曹延延, 夏耀方. 新生儿遗传性癫痫43例临床特征和基因型-表型关联分析[J]. 临床儿科杂志, 2026, 44(3): 175-184.

HUO Xiangzi, FENG Lijuan, MENG Lingzhi, ZHANG Yudong, SUN Yuli, MA Li, CAO Yanyan, XIA Yaofang. Clinical characteristics and genotype-phenotype correlation analysis of 43 cases of neonatal hereditary epilepsy[J]. Journal of Clinical Pediatrics, 2026, 44(3): 175-184.

图/表 8

表1

表2

KCNQ2组患儿基因变异、诊断、治疗及预后情况"

患儿	基因变异	位点分布	合子状态	变异来源	既往报道	ACMG 评级	诊断	ASMs	末次发作时间	末次随访时间	发育迟缓
例1	c.1049delA(p.N350Tfs*39)	C端	杂合	新发	否	P	SeLNE	PB、LEV	2月龄	67月龄	否
例2	c.354T>A(p.Y118X)	S1~S2	杂合	新发	否	P	SeLNE	PB、LEV	3月龄	66月龄	否
例3	c.1742G>A(p.R581Q)	C端	杂合	新发	是	P	DEE	PB、LEV	－	死亡	－
例4	c.997C>T(p.R333W)	C端	杂合	新发	是	P	DEE	PB、LEV、OXC	4个月	64月龄	是
例5	c.601C>T(p.R201C)	S4	杂合	新发	是	P	DEE	PB、LEV	－	死亡	－
例6	c.671T>G(p.V224G)	S4~S5	杂合	新发	否	LP	DEE	PB、LEV、TPM、OXC	49月龄	54月龄	是
例7	c.341C>T(p.T114I)	S1~S2	杂合	新发	是	P	DEE	PB、LEV、TPM、CZP	48月龄	48月龄	是
例8	c.1154delT(p.I385Tfs*5)	C端	杂合	父源	是	P	SeLNE	PB、OXC	3月龄	42月龄	否
例9	c.1679G>A(p.R560Q)	C端	杂合	母源	是	LP	SeLNE	PB、OXC	4月龄	42月龄	否
例10	c.1657C>T(p.R553W)	C端	杂合	新发	是	P	DEE	PB、LEV	2月龄	39月龄	是
例11	c.807G>C(p.W269C)	H5	嵌合	新发	否	LP	SeLNE	PB、LEV、OXC	4月龄	38月龄	否
例12	c.640C>T(p.R214W)	S4	杂合	父源	是	P	SeLNE	PB	新生儿期	38月龄	否
例13	c.2165_2168del(p.S722Tfs*207)	C端	杂合	新发	否	P	SeLNE	PB	新生儿期	29月龄	否
例14	c.1658G>A(p.R553Q)	C端	杂合	新发	是	P	SeLNE	PB、LCM	6月龄	22月龄	否
例15	c.1900dup(p.E634Gfs*231)	C端	杂合	母源	否	LP	SeLNE	PB	新生儿期	12月龄	否
例16	c.2579del(p.G860Vfs*70)	C端	杂合	父源	否	LP	SeLNE	PB	新生儿期	12月龄	否
例17	c.850_852dup(p.T284dup)	S5~S6	杂合	新发	否	LP	DEE	PB、MDZ、LEV、OXC	10月龄	10月龄	是
例18	c.1867_1871dup(p.K625Sfs*19)	C端	杂合	新发	否	P	DEE	PB、LEV	2月龄	11月龄	是
例19	c.922C>G(p.P308A)	S6	杂合	新发	否	P	DEE	PB、LEV、TPM、OXC	－	失访	－
例20	chr20:g.61828040_62325861del			－	否	LP	SeLNE	PB、LEV、OXC	3月龄	64月龄	否
例21	chr20:g.61974661_62129119del			－	是	LP	SeLNE	PB、LEV	1月龄	58月龄	否
例22	chr20:g.62069957_62129207del			－	否	LP	DEE	PB、LEV、OXC	28月龄	52月龄	是
例23	chr20:g.62075991_62324656del			父源	否	LP	DEE	PB、VPA	4月龄	21月龄	是
例24	chr20:g.62044782_62078210del			父源	否	LP	SeLNE	PB、LEV	新生儿期	20月龄	否

表2

表3

非KCNQ2组患儿基因变异、诊断、治疗及预后情况"

患儿	致病基因	基因变异	遗传方式	合子状态	变异来源	既往报道	ACMG 评级	诊断	ASMs	末次发作时间	末次随访时间	发育迟缓
例25	GRIN2D	c.2021C>A(p.T674K)	AD	杂合	新发	是	LP	DEE	PB、MDZ、LEV、CZP	－	死亡	－
例26	SCN2A	c.4868C>A(p.T1623N)	AD	杂合	新发	是	LP	DEE	PB	－	死亡	－
例27	ALDH7A1	c.1547A>G(p.Y516C) c.1553G>C(p.R518T)	AR	杂合	父源母源	是	LP	PDE	PB	－	失访	－
例28	SCN3A	c.2624T>C(p.I875T)	AD	杂合	新发	是	P	微小脑回畸形	PB、LEV	－	失访	－
例29	PACS1	c.607C>T(p.R203W)	AD	杂合	新发	是	P	SHMS	PB	30月龄	44月龄	是
例30	FGF12	c.341G>A(p.R114H)	AD	杂合	新发	是	P	DEE	PB、LEV	24月龄	41月龄	是
例31	PACS1	c.607C>T(p.R203W)	AD	杂合	新发	是	P	SHMS	PB、LEV	16月龄	36月龄	是
例32	WWOX	c.172+1G>C(p.?)	AR	纯合	母源	是	P	DEE	PB、LEV、TPM、VGB	7月龄	35月龄	是
例33	SCN1A	c.4493T>C(p.I1498T)	AD	杂合	新发	否	LP	癫痫	PB、LEV	－	失访	－
例34	SCN2A	c.643G>A(p.A215T)	AD	杂合	新发	是	P	DEE	PB、OXC、LEV、TPM	2月龄	27月龄	是
例35	KCNT1	c.2987T>C(p.L996P)	AD	杂合	新发	否	LP	DEE	PB	－	失访	－
例36	GABRG2	c.928A>G(p.T310A)	AD	杂合	新发	否	P	DEE	PB、LEV	－	失访	－
例37	SCN2A	c.643G>A(p.A215T)	AD	杂合	新发	是	P	DEE	PB、LEV、LCM	－	死亡	－
例38	KCNT1	c.1283G>A(p.R428Q)	AD	杂合	新发	是	P	DEE	PB、LEV、TPM、PER	8月龄	8月龄	是
例39	ANK2	c.268del(p.V90Wfs*57)	AD	杂合	母源	否	LP	SeLNE	PB、LEV、OXC	2月龄	8月龄	否
例40	SCN8A	c.5401C>G(p.Q1801E)	AD	杂合	新发	是	LP	癫痫	PB、LEV、OXC	8月龄	8月龄	否
例41	HSD17B4	c.526A>G(p.N176D)	AR	纯合	父源	是	－	DBPD	－	－	死亡	－
例42	chr22:g.32121503_32253559del				母源	否	LP	微小脑回畸形	PB	－	失访	－
例43	chr2:g.164450242_179650868dup				新发	否	P	DEE	PB、LEV、TPM	2月龄	5月龄	是

表3

表4

表5

图1

图2

图3

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组别	例数	男性[n(%)]	胎龄[M(P₂₅~P₇₅)]/周	出生体重($\bar{x}\pm s$)/g	癫痫起病时间[M(P₂₅~P₇₅)]/d	癫痫家族史[n(%)]
KCNQ2组	24	13(54.2)	39.5(38.2~40.4)	3 320±431	2.0(1.3~3.8)	3(12.5)
非KCNQ2组	19	13(68.4)	39.2(37.8~40.1)	3 393±531	5.0(3.0~12.0)	1(5.3)
统计量		χ²=0.90	Z=0.71	t=0.27	Z=2.51	－
P		0.342	0.478	0.792	0.012	0.618¹⁾

组别	例数	自动症	强直	阵挛	肌阵挛	癫痫性痉挛	自主神经症状	序贯发作¹⁾
KCNQ2组	24	7(29.2)	12(50.0)	14(58.3)	3(12.5)	2(8.3)	20(83.3)	8(33.3)
非KCNQ2组	19	5(26.3)	11(57.9)	13(68.4)	3(15.8)	0(0.0)	12(63.2)	8(42.1)
χ²值		0.04	0.27	0.46	－	－	1.33	0.35
P		0.836	0.606	0.497	1.000²⁾	0.495²⁾	0.249	0.555

组别	例数	头颅MRI		vEEG
组别	例数	脑实质信号异常	无明显异常	高度失律/暴发-抑制	多灶性放电	局灶性放电	仅脑电发育延迟	无明显异常/ 界限性
KCNQ2组	24	18(75.0)	5(20.8)	7(29.2)	6(25.0)	5(20.8)	4(16.7)	2(8.3)
非KCNQ2组	19	13(68.4)	1(5.3)	4(21.1)	9(47.4)	4(21.1)	1(5.3)	1(5.3)
χ²值		0.23	－	0.06	2.36	0.00	－	－
P		0.738	0.205¹⁾	0.728	0.126	1.000	0.363¹⁾	1.000¹⁾