中国早期儿童型白质消融性白质脑病患儿17例自然病程随访及其基因型-表型分析

目的 通过观察和分析17例中国早期儿童型白质消融性白质脑病(VWM)患儿的自然病程发展,了解其主要神经系统表型的进展特点,初步进行基因型-表型分析.方法 选择2006年9月-2010年10月北京大学第一医院临床诊断的17例VWM中国患儿为研究对象,提取其外周血白细胞DNA,PCR扩增致病基因真核细胞翻译启动因子2B(EIF2B1～5)的外显子及外显子与内含子交界区进行分子诊断.对其神经系统障碍的进展进行随访分析.结果 1.基本情况:17例患儿中男12例,女5例.13例起病前发育正常.2.起病特点:起病年龄平均2.7岁(0.4～6.4岁),70%(12/17例)为感染或头部外伤后急性起病,30%(5/17例)无诱因亚急性起病,均以运动障碍起病.3.病程特点:末次随访平均病程4.30 a(0.30～8.70 a),均呈进行性加重,3例死亡.64%(11/17例)病程中伴发作性加重.已获得独走技能的患儿最早于起病后0.17 a不能独走,发病2.00 a后均不能独走.发病4.50 a后患儿均丧失行走能力,最早丧失行走能力的年龄为起病后0.42 a,丧失行走能力的平均年龄为5.2岁(2.0～11.0岁),起病年龄越小,丧失行走能力的年龄越早.认知功能障碍进展缓慢.6例(35%)伴惊厥.重型患儿中女童明显少于男童.4.基因型-表型关系:重型患儿中eIF2Bγ突变者多于eIF2Bε突变者,相同基因型(eIF2Bγ:I346T)患儿表型存在明显差异.结论 早期儿童型VWM中国患儿运动功能退化进展最为突出,进展速度快.目前尚缺乏明确的基因型-表型相关性.

Follow-Up of Natural History of 17 Chinese Patients with Early Childhood-Onset Leukoencephalopathy with Vanishing White Matter and Analysis of Their Genotype-Phenotype

Objective To understand the progressive process of neurological phenotype in 17 Chinese patients with early childhood onset leukoencephalopathy with vanishing white matter(VWM),and preliminarily elucidate the genotype-phenotype correlation.Methods A follow-up study was performed in 17 Chinese children with early childhood onset VWM.These cases were molecularly confirmed by amplification eukaryotic translation initiation factor(EIF2B1-5) gene sequencing in DNA of peripheral leukocyte with polymerase chain reaction(PCR).Their neurological phenotype developments were followed up.Results 1.Basical characteristics:Seventeen patients consisted of 12 male and 5 female.Thirteen cases had normal development before the oneset of disease.2.Disease onset:The average age of disease onset was 2.7 years(aged 0.4-6.4 years),with acute onset precipitated by infection and mild head trauma in 70%(12/17 cases) and subacute onset in 30%(5/17 cases).The initial symptom was movement disturbance exclusively.3.Course of disease:Until the last follow-up,with the average course of disease being 4.30 years(0.30-8.70 years),all patients showed progressive regression,and 3 patients died.Episodic aggravation occurred in 64% patients(11/17 cases).The earliest time of losing walking ability was 0.17 year after disease onset.None of the patients could walk independently 2 years after disease onset.All the patients lost the ability of walking after 4.50 years of disease onset,with the earliest being 0.42 years after the disease onset and with the average age of 5.2 years old(2.0-11.0 years old).The earlier the disease onset,the sooner the patients lost the ability to walk.Compared with the motor function,cognition was relatively preserved.Six patients(35%) had infrequent seizures during the course.More male had severer phenotype than female.4.Genotype-phenotype correlations:Patients with severe phenotype tend to carry more eIF2Bγ mutation.The phenotype differed significantly in 2 patients with the same genotype(eIF2Bγ:I346T).Conclusions The development of motor functions is rapid and prominent in the Chinese VWM patients with early childhood onset.No definite genotype-phenotype correlation is identified.