Email Alert | RSS

北京大学学报（医学版） ›› 2024, Vol. 56 ›› Issue (5): 781-787. doi: 10.19723/j.issn.1671-167X.2024.05.005

• 论著 • 上一篇    下一篇

以婴儿癫痫性痉挛综合征为表型的吡哆醇依赖性癫痫

焦莶如1,2, 龚潘2, 牛悦1, 徐兆1, 周宗朴1, 杨志仙1,*()   

  1. 1. 北京大学人民医院儿科，北京 100044
    2. 北京大学第一医院儿科，北京 100034
  • 收稿日期:2024-06-25 出版日期:2024-10-18 发布日期:2024-10-16
  • 通讯作者: 杨志仙 E-mail:zhixian.yang@163.com
  • 基金资助:
    国家自然科学基金(82171436);北京市健康促进与研究基金(2020-2-4077);北京市临床重点专科建设项目-儿科学基金(2199000726);北京大学医学青年科技创新基金(中央高校基本科研业务费资助BMU2024YFJHPY005);北京大学人民医院学院建设项目(BMU2023XY016);北京大学人民医院人才引进启动资金(2023-T-02);北京大学人民医院研究与发展基金揭榜挂帅项目(RDGS2023-10)

Phenotype of infantile epileptic spasm syndrome in pyridoxin-dependent epilepsy

Xianru JIAO1,2, Pan GONG2, Yue NIU1, Zhao XU1, Zongpu ZHOU1, Zhixian YANG1,*()   

  1. 1. Department of Pediatrics, Peking University People's Hospital, Beijing 100044, China
    2. Department of Pediatrics, Peking University First Hospital, Beijing 100034, China
  • Received:2024-06-25 Online:2024-10-18 Published:2024-10-16
  • Contact: Zhixian YANG E-mail:zhixian.yang@163.com
  • Supported by:
    the National Natural Science Foundation of China(82171436);Beijing Health Promotion Research Fund Project(2020-2-4077);Beijing Clinical Key Specialty Construction Project-Pediatrics Foundation(2199000726);Peking University Medicine Fund of Fostering Young Scholars' Scientific & Technological innovation(中央高校基本科研业务费资助BMU2024YFJHPY005);Peking University People's Hospital School Construction Project(BMU2023XY016);Peking University People's Hospital Talent Introduction Start-up Fund(2023-T-02);Peking University People's Hospital R&D Fund Unveiling Project(RDGS2023-10)

RICH HTML

   

PDF (PC)

摘要：

目的: 分析5例以婴儿癫痫性痉挛综合征(infantile epileptic spasm syndrome，IESS)为表型的吡哆醇依赖性癫痫(pyridoxine-dependent epilepsy，PDE)患儿的临床诊治过程及预后。方法: 收集携带ALDH7A1基因变异PDE患儿共75例，筛选出以IESS为表型的PDE患儿共5例，对其临床表现、诊治过程、血生化指标、代谢筛查指标、脑电图(electroencephalogram，EEG)、头颅磁共振成像(magnetic resonance imaging，MRI)及基因检测结果等进行分析。结果: 5例PDE中，女3例，男2例，末次随访年龄1岁3个月至11岁9个月，表型均符合IESS。5例均为足月产，2例出生时有缺氧窒息，3例出生时未见异常。癫痫发作起病年龄为出生后24 h内至4个月。1例仅表现为癫痫性痉挛(epileptic spasms，ES); 3例表现为局灶性发作和ES; 1例以ES起病，后期出现多种发作类型，包括局灶性发作和全面性强直-阵挛发作，且出现癫痫持续状态而造成继发性脑损伤。发作间期EEG结果3例提示高度失律，1例提示广泛性及多灶性放电，1例提示多灶性放电。3例头颅MRI未见异常，2例病程中分别继发脑萎缩及脑积水。5例均携带ALDH7A1基因复合杂合变异，其中2例携带外显子缺失变异。5例患儿开始大剂量维生素B6维持治疗时间分别为起病后第2天、第4年、第3年、第4天及第2个月。至末次随访，4例发作控制且EEG恢复正常，1例脑萎缩者发作未控制且EEG仍异常。3例发育重度落后，2例轻度落后。结论: IESS可为PDE的少见表型，大剂量维生素B6可控制或减少癫痫发作。延迟诊断及治疗、继发性脑损伤、基因型特别是缺失异常与不良预后相关。

关键词: 吡哆醇依赖性癫痫, 婴儿癫痫性痉挛综合征, 维生素B6, ALDH7A1基因

Abstract:

Objective: To analyze the clinical diagnosis, treatment, and prognosis of the patients with pyridoxine-dependent epilepsy (PDE) characterized by infantile epileptic spasm syndrome (IESS). Methods: A total of 75 PDE patients with ALDH7A1 variants were diagnosed at the Department of Pediatrics of Peking University First Hospital and Peking University People's Hospital from July 2012 to June 2024, and five PDE patients with the phenotype of IESS were selected. The clinical manifestations, treatment, blood biochemistry, metabolic screening, electroencephalogram (EEG), brain magnetic resonance imaging (MRI), and gene testing results of the five PDE patients were analyzed. Results: Among the five patients diagnosed with PDE, three were female and two were male, and the phenotype was consistent with IESS. The age at the last follow-up was from one year and 3 months to 11 years and 9 months. All the five cases were delivered at term. Two cases had anoxia and asphyxia at birth, and three cases had normal birth history. The onset age of seizure ranged from one day to 4 months after birth. One case presented with epileptic spasms (ES), and three cases presented with focal seizure and ES. The other patient was started with ES, followed by multiple seizure types, including focal seizure and generalized tonic-clonic seizure, and developed epileptic status which caused secondary brain injury. The interictal EEG results showed hypsarrhythmia in three cases, generalized and multifocal discharges in one cases, and multifocal discharges in one case. No abnormalities were found in brain MRI in three cases, and secondary cerebral atrophy and hydrocephalus were observed in two cases during the course of the disease. Gene analysis confirmed that the five patients carried compound heterozygous variants of ALDH7A1, and two of them carried exon deletion variants. High dose pyridoxine treatment started at the end of 2 days, 4 years, 3 years, 4 days. and 2 months after the onset of the disease. Up to the last follow-up, seizures of four cases were controlled, followed by normal EEG. One patient with brain atrophy had uncontrolled seizures and EEG remained abnormal. The neurodevelopment of the three patients were severely delayed, and two were mildly delayed. Conclusion: IESS could be a rare phenotype of PDE. High doses of pyridoxine can control or reduce the frequency of seizures. Delayed diagnosis and treatment, secondary brain injury, and the genotype, especially deletions variants, were associated with poor prognosis.

Key words: Pyridoxine-dependent epilepsy, Infantile epileptic spasm syndrome, Vitamin B6, ALDH7A1

中图分类号: 

  • R742.1

表1

5例表型为婴儿癫痫性痉挛综合征吡哆醇依赖性癫痫患儿的临床特征"

Case Current age/ Gender GA Birth history Age at seizure onset Age at the onset of ES Seizure type Age at which vitamin B6 treatment started Current medication Interictal EEG/Age Brain MRI Outcome
1 7y8m/F At term Normal 4m 4m ES 4m PN Hypsarrhythmia/4m Normal Severe ID/GDD
2 11y9m/F At term Normal 1m 7m FS, ES 4y PN Hypsarrhythmia/2y Normal Severe ID/GDD
3 7y4m/M At term Hypoxia 1m 1m ES, GTCS, FS, SE 3y PN, VPA, LEV, LTG Hypsarrhythmia/2y Brain atrophy Severe ID/GDD
4 1y6m/F At term Hypoxia < 24 h < 24 h ES, FS 4 d PN Generalized and multifocal discharges/4 d Abnormal white matter signal in both cerebral hemispheres, Intraventricular hemorrhage, bilateral ventricle fullness, subcutaneous hematoma/8 d; hydrocephalus/4m Mild ID/DD
5 1y3m/M At term Normal < 24 h 43 d FS, ES 2m PN Multifocal discharges/14 d Normal Mild ID/DD

图1

3例以婴儿癫痫性痉挛综合征为表型的吡哆醇依赖性癫痫患儿EEG"

图2

病例3头颅MRI"

表2

5例表型为婴儿癫痫性痉挛综合征吡哆醇依赖性癫痫患儿的遗传学特征"

Case ALDH7A1 variants (NM_001182.4) Source of variants Prediction resultsACMG
Polyphen2 SIFT Mutation taster
1c.563T>C p.(V188A) Paternal Probably damaging Deleterious Disease causing Variant of uncertain significance
Deletion exon 1 Maternal - - - Pathogenic
2c.1547A>G p.(Y516C) Paternal Probably damaging Deleterious Disease causing Likely pathogenic
c.1061A>G p.(Y354C) Maternal Probably damaging Deleterious Disease causing Pathogenic
3c.1553G>C p.(R518T) Paternal Probably damaging Deleterious Disease causing Likely pathogenic
c.1547A>G p.(Y516C) Maternal Probably damaging Deleterious Disease causing Likely pathogenic
4Deletion exons 8-13 Paternal - - - Pathogenic
c.871+5G>A Maternal - - - Pathogenic
5c.1061A>G p.(Y354C) Paternal Probably damaging Deleterious Disease causing Pathogenic
c.1112C>A p.(P371Q) Maternal Probably damaging Deleterious Disease causing Likely pathogenic
1 Hunt AD Jr , Stokes J Jr , McCrory WW , et al. Pyridoxine dependency: Report of a case of intractable convulsions in an infant controlled by pyridoxine[J]. Pediatrics, 1954, 13 (2): 140- 145.
doi: 10.1542/peds.13.2.140
2 Mills PB , Struys E , Jakobs C . Mutations in antiquitin in individuals with pyridoxine-dependent seizures[J]. Nat Med, 2006, 12 (3): 307- 309.
doi: 10.1038/nm1366
3 Zuberi SM , Wirrell E , Yozawitz E , et al. ILAE classification and definition of epilepsy syndromes with onset in neonates and infants: Position statement by the ILAE task force on nosology and definitions[J]. Epilepsia, 2022, 63 (6): 1349- 1397.
doi: 10.1111/epi.17239
4 Jiao X , Xue J , Gong P , et al. Clinical and genetic features in pyridoxine-dependent epilepsy: A Chinese cohort study[J]. Dev Med Child Neurol, 2020, 62 (3): 315- 321.
doi: 10.1111/dmcn.14385
5 Tseng LA , Abdenur JE , Andrews A , et al. Timing of therapy and neurodevelopmental outcomes in 18 families with pyridoxine-dependent epilepsy[J]. Mol Genet Metab, 2022, 135 (4): 350- 356.
doi: 10.1016/j.ymgme.2022.02.005
6 Strijker M , Tseng LA , van Avezaath LK , et al. Cognitive and neurological outcome of patients in the Dutch pyridoxine-dependent epilepsy (PDE-ALDH7A1) cohort, a cross-sectional study[J]. Eur J Paediatr Neurol, 2021, 33, 112- 120.
doi: 10.1016/j.ejpn.2021.06.001
7 Struys EA , Bok LA , Emal D , et al. The measurement of urinary Delta(1)-piperideine-6-carboxylate, the alter ego of alpha-aminoadipic semialdehyde, in Antiquitin deficiency[J]. J Inherit Metab Dis, 2012, 35 (5): 909- 916.
doi: 10.1007/s10545-011-9443-0
8 Struys EA , Jakobs C . Metabolism of lysine in alpha-aminoadipic semialdehyde dehydrogenase-deficient fibroblasts: Evidence for an alternative pathway of pipecolic acid formation[J]. FEBS Lett, 2010, 584 (1): 181- 186.
doi: 10.1016/j.febslet.2009.11.055
9 Jansen LA , Hevner RF , Roden WH , et al. Glial localization of antiquitin: Implications for pyridoxine-dependent epilepsy[J]. Ann Neurol, 2014, 75 (1): 22- 32.
doi: 10.1002/ana.24027
10 Lux AL , Osborne JP . A proposal for case definitions and outcome measures in studies of infantile spasms and West syndrome: Consensus statement of the West Delphi group[J]. Epilepsia, 2004, 45 (11): 1416- 1428.
doi: 10.1111/j.0013-9580.2004.02404.x
11 van Karnebeek CD , Tiebout SA , Niermeijer J , et al. Pyridoxine-dependent epilepsy: An expanding clinical spectrum[J]. Pediatr Neurol, 2016, 59, 6- 12.
doi: 10.1016/j.pediatrneurol.2015.12.013
12 Basura GJ , Hagland SP , Wiltse AM , et al. Clinical features and the management of pyridoxine-dependent and pyridoxine-responsive seizures: Review of 63 North American cases submitted to a patient registry[J]. Eur J Pediatr, 2009, 168 (6): 697- 704.
doi: 10.1007/s00431-008-0823-x
13 Mefford HC , Zemel M , Geraghty E , et al. Intragenic deletions of ALDH7A1 in pyridoxine-dependent epilepsy caused by Alu-Alu recombination[J]. Neurology, 2015, 85 (9): 756- 762.
doi: 10.1212/WNL.0000000000001883
14 Pérez B , Gutiérrez-Solana LG , Verdú A , et al. Clinical, biochemical, and molecular studies in pyridoxine-dependent epilepsy. Antisense therapy as possible new therapeutic option[J]. Epilepsia, 2013, 54 (2): 239- 248.
doi: 10.1111/epi.12083
15 Bennett CL , Chen Y , Hahn S , et al. Prevalence of ALDH7A1 mutations in 18 North American pyridoxine-dependent seizure (PDS) patients[J]. Epilepsia, 2009, 50 (5): 1167- 1175.
doi: 10.1111/j.1528-1167.2008.01816.x
16 Al Teneiji A , Bruun TU , Cordeiro D , et al. Phenotype, biochemical features, genotype, and treatment outcome of pyridoxine-dependent epilepsy[J]. Metab Brain Dis, 2017, 32 (2): 443- 451.
doi: 10.1007/s11011-016-9933-8
17 Falsaperla R , Vari MS , Toldo I , et al. Pyridoxine-dependent epilepsies: An observational study on clinical, diagnostic, therapeutic and prognostic features in a pediatric cohort[J]. Metab Brain Dis, 2018, 33 (1): 261- 269.
doi: 10.1007/s11011-017-0150-x
18 Scharer G , Brocker C , Vasiliou V , et al. The genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy due to mutations in ALDH7A1[J]. J Inherit Metab Dis, 2010, 33 (5): 571- 581.
doi: 10.1007/s10545-010-9187-2
19 Tlili A , Hamida Hentati N , Chaabane R , et al. Pyridoxine-dependent epilepsy in Tunisia is caused by a founder missense mutation of the ALDH7A1 gene[J]. Gene, 2013, 518 (2): 242- 245.
doi: 10.1016/j.gene.2013.01.041
20 Mills PB , Footitt EJ , Mills KA , et al. Genotypic and phenotypic spectrum of pyridoxine-dependent epilepsy (ALDH7A1 deficiency)[J]. Brain, 2010, 133 (Pt 7): 2148- 2159.
21 Gibaud M , Barth M , Lefranc J , et al. West syndrome is an exceptional presentation of pyridoxine- and pyridoxal phosphate-dependent epilepsy: Data from a French cohort and review of the literature[J]. Front Pediatr, 2021, 9, 621200.
doi: 10.3389/fped.2021.621200
22 Mastrangelo M , Gasparri V , Bernardi K , et al. Epilepsy phenotypes of vitamin B6-dependent diseases: An updated systematic review[J]. Children (Basel), 2023, 10 (3): 553.
23 Srinivasaraghavan R , Parameswaran N , Mathis D , et al. Antiquitin deficiency with adolescent onset epilepsy: Molecular diagnosis in a mother of affected offsprings[J]. Neuropediatrics, 2018, 49 (2): 154- 157.
doi: 10.1055/s-0037-1621721
24 Baxter P . Epidemiology of pyridoxine dependent and pyridoxine responsive seizures in the UK[J]. Arch Dis Child, 1999, 81, 431- 433.
doi: 10.1136/adc.81.5.431
25 Yeghiazaryan NS , Zara F , Capovilla G , et al. Pyridoxine-dependent epilepsy: An under-recognised cause of intractable seizures[J]. J Paediatr Child Health, 2012, 48 (3): E113- E115.
26 Haidar Z , Jalkh N , Corbani S , et al. Atypical pyridoxine dependent epilepsy resulting from a new homozygous missense mutation, in ALDH7A1[J]. Seizure, 2018, 57, 32- 33.
doi: 10.1016/j.seizure.2018.03.010
27 Marguet F , Barakizou H , Tebani A , et al. Pyridoxine-dependent epilepsy: Report on three families with neuropathology[J]. Metab Brain Dis, 2016, 31 (6): 1435- 1443.
doi: 10.1007/s11011-016-9869-z
28 Coughlin CR , Tseng LA , Abdenur JE , et al. Consensus guidelines for the diagnosis and management of pyridoxine-dependent epilepsy due to alpha-aminoadipic semialdehyde dehydrogenase deficiency[J]. J Inherit Metab Dis, 2021, 44 (1): 178- 192.
doi: 10.1002/jimd.12332
29 杨志仙, 秦炯. 吡哆醇依赖性癫痫的临床及分子遗传学研究进展[J]. 中华儿科杂志, 2013, 51 (11): 867- 870.
30 van Karnebeek CD , Jaggumantri S . Current treatment and management of pyridoxine-dependent epilepsy[J]. Curr Treat Options Neurol, 2015, 17 (2): 335.
31 Ohtsuka Y , Yamatogi Y , Yoshida H , et al. High-dose pyridoxal phosphate in the treatment of the West and the Lennox syndromes[J]. No To Hattatsu, 1983, 15 (3): 225- 233.
32 Ohtsuka Y , Matsuda M , Ogino T , et al. Treatment of the West syndrome with high-dose pyridoxal phosphate[J]. Brain Dev, 1987, 9 (4): 418- 421.
doi: 10.1016/S0387-7604(87)80116-X
33 Mytinger JR , Joshi S . The current evaluation and treatment of infantile spasms among members of the child neurology society[J]. J Child Neurol, 2012, 27 (10): 1289- 1294.
doi: 10.1177/0883073812455692
34 Pietz J , Benninger C , Schäfer H , et al. Treatment of infantile spasms with high-dosage vitamin B6[J]. Epilepsia, 1993, 34 (4): 757- 763.
doi: 10.1111/j.1528-1157.1993.tb00458.x
35 Xue J , Qian P , Li H , et al. Clinical characteristics of two cohorts of infantile spasms: Response to pyridoxine or topiramate monotherapy[J]. World J Pediatr, 2018, 14 (3): 290- 297.
doi: 10.1007/s12519-018-0127-9
[1] 朱莎,徐宗胜,夏晴,方筱静,赵丹华,刘献增. 伴杏仁核肥大的颞叶癫痫的临床及病理特征[J]. 北京大学学报（医学版）, 2019, 51(5): 824-828.
[2] 龚潘，杨志仙，薛姣，钱萍，杨海坡，刘晓燕，边凯归. 头皮脑电图中高频振荡在癫痫性脑病伴睡眠中持续棘慢波患儿中的应用[J]. 北京大学学报(医学版), 2018, 50(2): 213-220.
Viewed
Full text


Abstract

Cited
  Shared   
  Discussed   
No Suggested Reading articles found!
ISSN 1671-167X
CN 11-4691/R
主管单位：中华人民共和国教育部
主办单位：北京大学
地址： 北京市海淀区学院路38号 北京大学医学部 《北京大学学报（医学版）》
邮编：100191
电话：010-82801551
Email： xbbjb2@bjmu.edu.cn

《北京大学学报（医学版）》
微信公众号
版权所有 © 2018 《北京大学学报（医学版）》编辑部