ATP1A2 / ATP1A3基因变异患儿10例遗传学及临床特征分析

doi:10.12372/jcp.2025.24e1372

临床儿科杂志 ›› 2025, Vol. 43 ›› Issue (8): 590-597.doi: 10.12372/jcp.2025.24e1372

ATP1A2 / ATP1A3基因变异患儿10例遗传学及临床特征分析

裴培¹, 李伟华², 淮婉³, 姚如恩³, 葛禾佳¹, 王纪文⁴, 王秀敏⁵, 吉炜⁶, 周昀箐⁴, 贺影忠⁴(), 韩凤⁴()

1.嘉兴大学附属第二医院儿童医学中心儿科（浙江嘉兴 314000）
2.上海交通大学医学院附属上海儿童医学中心儿科（上海 200127）
3.上海交通大学医学院附属上海儿童医学中心遗传分子诊断科（上海 200127）
4.上海交通大学医学院附属上海儿童医学中心神经内科（上海 200127）
5.上海交通大学医学院附属上海儿童医学中心内分泌代谢科（上海 200127）
6.上海交通大学医学院附属上海儿童医学中心心血管科（上海 200127）

收稿日期:2024-12-23 录用日期:2025-03-21 出版日期:2025-08-15 发布日期:2025-07-28
通讯作者: 贺影忠,韩凤 E-mail:heyingzhong@scmc.com.cn;hanfeng@scmc.com.cn
基金资助:
海南省自然科学基金项目(824MS167)

Genetic and clinical characteristics analysis of 10 children with ATP1A2/ATP1A3 gene variants

PEI Pei¹, LI Weihua², HUAI Wan³, YAO Ruen³, GE Hejia¹, WANG Jiwen⁴, WANG Xiumin⁵, JI Wei⁶, ZHOU Yunqing⁴, HE Yingzhong⁴(), HAN Feng⁴()

1. Department of Pediatrics, Jiaxing University Affiliated Second Hospital Children's Medical Center, Jiaxing 314000, Zhejiang, China
2. Department of Pediatrics, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
3. Department of Genetic and Molecular Diagnosis, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
4. Department of Neurology, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
5. Department of Endocrinology and Metabolism, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China
6. Department of Cardiovascular Medicine, Shanghai Children's Medical Center, Shanghai Jiao Tong University School of Medicine, Shanghai 200127, China

Received:2024-12-23 Accepted:2025-03-21 Published:2025-08-15 Online:2025-07-28
Contact: HE Yingzhong, HAN Feng E-mail:heyingzhong@scmc.com.cn;hanfeng@scmc.com.cn

摘要/Abstract

摘要：

目的总结10例ATP1A2及ATP1A3基因变异患儿的临床表现和基因变异类型，丰富对该疾病的基因型-表型关联认识，促进临床医师对该疾病的了解。方法回顾性收集2015年11月至2024年6月诊治的10例ATP1A2及ATP1A3基因变异患儿的临床资料，分析其遗传学及临床特征，结合文献检索，总结已报道的ATP1A2及ATP1A3基因变异类型与临床表现的关系。结果共纳入ATP1A2及ATP1A3基因变异患儿10例，女3例、男7例，起病年龄0至14岁；以惊厥起病3例，以肌无力起病2例，偏瘫起病1例，交替性偏瘫起病1例，注意力缺陷障碍伴遗尿起病1例，1例以惊厥合并肌无力起病，语言运动障碍起病1例。基因检测ATP1A2变异3例，ATP1A3变异7例，均为点突变。目前ATP1A2基因（NM_000702.3）变异c.587G>A（p.Arg196His）及c.2841-2A>C突变位点和ATP1A3基因（NM_152296.4）变异c.1013C>T（p.Ala338Val）及c.2426C>A（p.Ala809Asp）突变位点尚未见报道。结论新发现的变异丰富了ATP1A2及ATP1A3基因变异谱及临床表现谱，同时提示临床工作者对于以癫痫、肌无力及偏瘫等神经症状为首发表现的疾病，若疗效欠佳时应及时完善基因检测以明确诊断。

关键词: ATP1A2基因, ATP1A3基因, 儿童交替性偏瘫, 家族性偏瘫性偏头痛, 癫痫

Abstract:

Objective To summarize the genetic clinical manifestations and mutation typing of 10 pediatric patients with ATP1A2 and ATP1A3 gene mutations, enriching the understanding of the genotype-phenotype correlation of this disease and promoting the understanding of this disease by clinicians. Methods A retrospective collection of clinical data from 10 pediatric patients with ATP1A2 and ATP1A3 gene mutations treated at Hospital from November 2015 to June 2024 was conducted. The genetic and clinical characteristics were analyzed, and a literature search was performed to summarize the relationship between the reported types of ATP1A2 and ATP1A3 gene mutations and their clinical manifestations. Results This study included 10 pediatric patients (3 girls and 7 boys), and the age of onset ranged from birth to 14 years old. Three children had onset with convulsions, 2 with muscle weakness, 1 with hemiplegia, 1 with alternating hemiplegia, 1 with attention deficit disorder accompanied by enuresis, 1 with convulsions combined with muscle weakness, and 1 with language and motor disabilities. Genetic testing identified ATP1A2 mutations in 3 cases and ATP1A3 mutations in 7 cases, all of which were point mutations. The mutation sites c.587G>A(p.Arg196His) and c.2841-2A>C in the ATP1A2 gene (NM_000702.3), as well as c.1013C>T(p.Ala338Val) and c.2426C>A(p.Ala809Asp) in the ATP1A3 gene (NM_152296.4) have not been previously reported. Conclusions The newly discovered mutations enrich the mutation spectrum of ATP1A2 and ATP1A3 genes and their clinical manifestations. Meanwhile, it suggests to clinicians that for diseases presenting initially with neurological symptoms such as epilepsy, muscle weakness, and hemiplegia, if the treatment outcome is suboptimal, gene testing should be promptly carried out to establish a definite diagnosis.

Key words: ATP1A2 gene, ATP1A3 gene, alternating hemiplegia of childhood, familial hemiplegic migraine, epilepsy

中图分类号:

裴培, 李伟华, 淮婉, 姚如恩, 葛禾佳, 王纪文, 王秀敏, 吉炜, 周昀箐, 贺影忠, 韩凤. ATP1A2 / ATP1A3基因变异患儿10例遗传学及临床特征分析[J]. 临床儿科杂志, 2025, 43(8): 590-597.

PEI Pei, LI Weihua, HUAI Wan, YAO Ruen, GE Hejia, WANG Jiwen, WANG Xiumin, JI Wei, ZHOU Yunqing, HE Yingzhong, HAN Feng. Genetic and clinical characteristics analysis of 10 children with ATP1A2/ATP1A3 gene variants[J]. Journal of Clinical Pediatrics, 2025, 43(8): 590-597.

图/表 6

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参考文献 24

[1]	Friedrich T, Tavraz NN, Junghans C. ATP1A2 mutations in migraine: seeing through the facets of an ion pump onto the neurobiology of disease[J]. Front Physiol, 2016, 7:239. doi: 10.3389/fphys.2016.00239 pmid: 27445835
[2]	Pavone P, Pappalardo XG, Mustafa N, et al. Alternating hemiplegia of childhood: neurological comorbidities and intrafamilial variability[J]. Ital J Pediatr, 2022, 48(1): 29.
[3]	Ruan DD, Zou J, Liao LS, et al. In vitro study of ATP1A3 p.Ala275Pro mutant causing alternating hemiplegia of childhood and rapid-onset dystonia-parkinsonism[J]. Front Neurosci, 2024, 18: 1415576.
[4]	Salles PA, Mata IF, Brünger T, et al. ATP1A3-related disorders: an ever-expanding clinical spectrum[J]. Front Neurol, 2021, 12: 637890.
[5]	Wang P, Yang YR, Zhang HB, et al. Cognitive dysfunction in a patient with migraine and APT1A2 mutation: a case report[J]. Neurol Sci, 2021, 42(12): 5425-5431.
[6]	孙于林, 杨光, 万林, 等. ATP1A3基因相关发作性疾病的临床特征及基因变异分析[J]. 临床儿科杂志, 2020, 38(11): 817-820.
	Sun YL, Yang G, Wan L, et al. Clinical characteristics and mutation analysis of ATP1A3 gene associated paroxysmal diseases[J]. Linchuang Erke Zazhi, 2020, 38(11): 817-820.
[7]	Bondžić AM, Vasić Anićijević DD, Janjić GV, et al. Na, K-ATPase as a biological target for gold (Ⅲ) complexes: a theoretical and experimental approach[J]. Curr Med Chem, 2021, 28(23): 4742-4798.
[8]	Staehr C, Aalkjaer C, Matchkov VV. The vascular Na, K-ATPase: clinical implications in stroke, migraine, and hypertension[J]. Clin Sci (Lond), 2023, 137(20): 1595-1618.
[9]	Fedosova NU, Habeck M, Nissen P. Structure and function of Na,K-ATPase-the sodium-potassium pump[J]. Compr Physiol, 2021, 12(1): 2659-2679. doi: 10.1002/cphy.c200018 pmid: 34964112
[10]	Murata K, Kinoshita T, Ishikawa T, et al. Region- and neuronal-subtype-specific expression of Na,K-ATPase alpha and beta subunit isoforms in the mouse brain[J]. J Comp Neurol, 2020, 528(16): 2654-2678. doi: 10.1002/cne.24924 pmid: 32301109
[11]	Isaksen TJ, Lykke-Hartmann K. Insights into the pathology of the α2-Na(+)/K(+)-ATPase in neurological disorders; Lessons from animal models[J]. Front Physiol, 2016, 7: 161. doi: 10.3389/fphys.2016.00161 pmid: 27199775
[12]	Smith RS, Florio M, Akula SK, et al. Early role for a Na⁺, K⁺-ATPase (ATP1A3) in brain development[J]. Proc Natl Acad Sci U S A, 2021, 118(25): e2023333118.
[13]	Carreño O, Corominas R, Serra SA, et al. Screening of CACNA1A and ATP1A2 genes in hemiplegic migraine: clinical, genetic, and functional studies[J]. Mol Genet Genomic Med, 2013, 1(4): 206-22.
[14]	Tang W, Zhang M, Qiu E, et al. A Chinese family with familial hemiplegic migraine type 2 due to a novel missense mutation in ATP1A2[J]. Cephalalgia, 2019, 39(11): 1382-1395.
[15]	Zou S, Lan YL, Gong Y, et al. The role of ATP1A3 gene in epilepsy: We need to know more[J]. Front Cell Neurosci, 2023, 17: 1143956.
[16]	Alyamani SA, Aldhalaan HM, Almuhaizea MA, et al. Expanding the Allelic spectrum in ATP1A3-related disorders with 3 novel mutations and clinic features[J]. Neurosciences (Riyadh), 2023, 28(3): 195-198. doi: 10.17712/nsj.2023.3.20220131 pmid: 37482377
[17]	Vezyroglou A, Akilapa R, Barwick K, et al. The phenotypic continuum of ATP1A3-related disorders[J]. Neurology, 2022, 99(14): e1511-e1526.
[18]	Monteiro FP, Curry CJ, Hevner R, et al. Biallelic loss of function variants in ATP1A2 cause hydrops fetalis, microcephaly, arthrogryposis and extensive cortical malformations[J]. Eur J Med Genet, 2020, 63(1): 103624.
[19]	Dard R, Mignot C, Durr A, et al. Relapsing encephalopathy with cerebellar ataxia related to an ATP1A3 mutation[J]. Dev Med Child Neurol, 2015, 57(12): 1183-1186.
[20]	Vetro A, Nielsen HN, Holm R, et al. ATP1A2- and ATP1A3-associated early profound epileptic encephalopathy and polymicrogyria[J]. Brain, 2021, 144(5): 1435-1450. doi: 10.1093/brain/awab052 pmid: 33880529
[21]	Córdoba NM, Lince-Rivera I, Gómez JLR, et al. ATP1A2-related epileptic encephalopathy and movement disorder: Clinical features of three novel patients[J]. Epileptic Disord, 2024, 26(3): 332-340. doi: 10.1002/epd2.20220 pmid: 38512072
[22]	Xiang Y, Li F, Song Z, et al. Two pediatric patients with hemiplegic migraine presenting as acute encephalopathy: case reports and a literature review[J]. Front Pediatr, 2023, 11:1214837.
[23]	Du Y, Li C, Duan FJ, et al. Early treatment in acute severe encephalopathy caused by ATP1A2 mutation of familial hemiplegic migraine type 2: case report and literature review[J]. Neuropediatrics, 2020, 51(3): 215-220.
[24]	Li Y, Liu X, Wang C, et al. Molecular and clinical characteristics of ATP1A3-related diseases[J]. Front Neurol, 2022, 13: 924788.

患儿	性别	发病年龄 /岁	确诊年龄 /岁	基因类型	突变类型	ACMG 评级	证据	HGVS基因变异命名	REVEL
例1	女	1	2.2	ATP1A3	错义突变	致病性	PP3_strong+PM2_supporting+PP2+ PS2+PS4	NM_152296.5:c.2443G> A(p.Glu815Lys)	0.94
例2	男	2.4	2.4	ATP1A3	错义突变	致病性	PP3_moderate+PM2_supporting+ PP2+PM5+PS2+PS4	NM_152296.5:c.2266C> T(p.Arg756Cys)	0.98
例3	男	5	5	ATP1A3	错义突变	可能致病性	PP3_moderate+PM2_supporting+ PP2+PS2_moderate	NM_152296.5:c.1013C> T(p.Ala338Val)	0.89
例4	男	4.2	5	ATP1A3	错义突变	可能致病性	PP3_strong+PM2_supporting+ PP2+PS2_moderate	NM_152296.5:c.2426C> A(p.Ala809Asp)	0.97
例5	女	1.5	1.6	ATP1A3	错义突变	致病性	PP3_moderate+PM2_supporting +PP2+PM5+PS2+PS4	NM_152296.5:c.2266C> T(p.Arg756Cys)	0.98
例6	男	1.1	1.9	ATP1A3	错义突变	致病性	PP3_Moderate+PM2_supporting+ PP2+PP1+PS4+PS2+PS3_moderate	NM_152296.5:c.2767G> A(p.Asp923Asn)	0.78
例7	男	1.5	3.5	ATP1A3	错义突变	致病性	PP3_moderate+PM2_supporting+ PS4+PS3_moderate+PS2+PP2	NM_152296.5:c.2401G> A(p.Asp801Asn)	0.91
例8	女	14	14	ATP1A2	错义突变	可能致病性	PP3_moderate+PM2_supporting+ PP2+PP4_moderate	NM_000702.4:c.587G> A(p.Arg196His)	0.78
例9	男	0.1	8	ATP1A2	剪接位点突变	可能致病性	PVS1_moderate+PM2_supporting	NM_000702.4:c.2841-2A>C	-
例10	男	0.7	2.1	ATP1A2	错义突变	致病性	PP3_strong+PM2_supporting+PP2+ PS2_moderate+PS3_moderate+PS4_supporting	NM_000702.4:c.2936C> T(p.Pro979Leu)	0.95

患儿	家族情况	首发表现	脑电图	头颅MRI	发育
例1	父母未携带	惊厥	左侧半球波幅高，弥漫性慢波发放，左侧半球明显	正常	语言运动落后
例2	父亲、姐姐携带	语言运动障碍	背景活动变慢	双侧大脑半球脑池脑沟增宽	语言运动落后
例3	父母未携带	注意缺陷障碍，遗尿	未做	双侧侧脑室形态不对称	语言运动落后
例4	父母未携带	惊厥，肌无力	正常	正常	正常
例5	父母未携带	惊厥	两枕区见中等量阵发性高电位3~4c/s慢波	两侧脑室偏大，脑沟加深	语言运动落后
例6	父母未携带	肌无力	正常	正常	语言运动落后
例7	父母未携带	交替性偏瘫	两枕区见中等量短段中-高电位3c/sδ慢波	正常	语言运动落后
例8	父亲携带	偏瘫	未做	正常	语言运动落后
例9	父亲携带	肌无力	未做	正常	语言运动落后
例10	父母未携带	惊厥	高幅θ、δ活动明显增多	正常	语言运动落后

基因型	ATP1A2					ATP1A3
疾病	FHM		AHC	FARIMPD	EP	DYT		DEE	AHC	CAPOS	JOP
突变位点	c.188del	c.1453A>T	c.879C>G	c.2278del	c.3027T>A	c.281T>C	c.2264G>C	c.875T>G	c.821T>A	c.967C>T	c.385G>A
	c.524del	c.1570G>T	c.1133C>A	c.295_296dup		c.410C>A	c.2266C>T	c.947G>T	c.1079C>G	c.2267G>A
	c.571G>A	c.1639del	c.1148G>A	c.2869G>T		c.562C>T	c.2315G>A	c.1081T>C	c.1165G>A	c.2312C>T
	c.605G>A	c.1642C>T				c.821T>C	c.2338T>C	c.1807-2A>T	c.2407G>A	c.2839G>T
	c.720_721del	c.1743C>A				c.829G>A	c.2401G>T	c.2479A>T	c.2452G>A
	c.855dup	c.1778G>T				c.946G>A	c.2408G>A	c.2116G>A	c.2512_2516del
	c.869_872del	c.1843G>A				c.954C>G	c.2415C>G	c.2144T>C	c.2767G>A
	c.901G>A	c.2126_2127del				c.958G>C	c.2431T>C	c.2443G>A
	c.970G>A	c.2291T>C				c.1072G>A	c.2542+1G>C	c.2552A>C
	c.988G>A	c.2357C>T				c.1072G>T	c.2542+1G>A	c.2752GTCdel
	c.991C>G	c.2471dup				c.1073G>A	c.2652dup
	c.1033A>G	c.2501G>A				c.1088T>C	c.2673_2678del
	c.1097G>T	c.2708G>A				c.1299del	c.2677G>A
	c.1130G>T	c.2977CTCdel				c.1429A>T	c.2759A>C
	c.1234C>T	c.2983dup				c.1784_1792del	c.2763G>A
	c.1405A>T					c.1930C>T	c.2767G>C
						c.1959C>A	c.2768A>C
						c.2116G>C	c.2771T>C
						c.2153C>A	c.2839G>C
						c.2167G>C	c.2839G>A
						c.2224GACdel	c.2902del
						c.2225A>T	c.2966_2996del
						c.2263G>A	c.3013+1G>A
						c.2263G>T	c.3035ACTdup

项目	基因类型
项目	ATP1A2	ATP1A3
染色体位置	1q23	19q13
神经系统分布位置	神经元和星形胶质细胞	GABA能神经元
特征性核心临床表现	反复发作偏头痛，认知功能障碍、情绪波动等	显著运动障碍，认知和行为问题
癫痫持续状态	少见	多见
头颅MRI	脑皮层和小脑萎缩少见	脑皮层和小脑萎缩多见
治疗	非甾体类抗炎药缓解偏头痛，抗癫痫药物控制癫痫发作，抗偏头痛药物减轻急性严重脑病症状等	氟桂利嗪在部分病例中有效；消除诱因和促进睡眠控制急性发作，物理治疗，康复训练等

ATP1A2 / ATP1A3基因变异患儿10例遗传学及临床特征分析

Genetic and clinical characteristics analysis of 10 children with ATP1A2/ATP1A3 gene variants

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