以婴儿癫痫性痉挛综合征为表型的吡哆醇依赖性癫痫

Phenotype of infantile epileptic spasm syndrome in pyridoxin-dependent epilepsy

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。

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.