儿童白质消融性白质脑病54例的临床特点分析

Clinical features of 54 cases of leukoencephalopathy with vanishing white matter disease in children

目的总结儿童白质消融性白质脑病(VWM)的临床特点。方法对2007年1月至2019年3月北京大学第一医院儿科基因确诊的54例VWM患儿进行回顾性队列研究。用纸质登记表和电子病历系统对纳入患儿的既往病例资料进行回顾性收集,并将患儿按起病年龄分<1岁、1~<2岁、2~<4岁、4~<8岁、8~<18岁组5组。对各组患儿的运动功能进展、发作性加重及癫痫发作、生存状况、头颅磁共振成像(MRI)特征和基因型特点等进行对比分析。采用非参数检验、χ2检验或Fisher精确检验进行组间比较;采用Kaplan-Meier生存曲线对患儿的生存状况进行分析。结果54例VWM患儿中男34例、女20例,起病年龄为2岁8月龄(6月龄~9岁7月龄),其中<1岁组5例、1~<2岁组12例、2~<4岁组25例、4~<8岁组10例、8~18岁组2例。94%(51/54)的患儿以运动倒退为首发症状就诊。87%(47/54)的患儿在病程中出现发作性加重的现象。43%(23/54)的患儿在病程中出现癫痫发作。病程1~<3年,38%(9/24)存活患儿的运动功能为脑瘫粗大运动功能分级系统(GMFCS)Ⅳ~Ⅴ级。1~<2岁组,3例病程1~<3年的患儿中1例为GMFCSⅣ级;2~<4岁组,15例病程1~<3年患儿中6例为GMFCSⅣ~Ⅴ级;4~<8岁组4例病程1~<3年患儿中1例为GMFCSⅣ~Ⅴ级。对不同组别患儿头颅MRI病灶、液化及弥散受限范围进行对比分析,发现起病年龄越早,越容易出现皮层下白质(额叶P<0.01,颞叶及顶枕叶P均=0.002),内囊(前肢P<0.01,后肢P=0.001)以及脑干(中脑P=0.001,脑桥P<0.01)受累。此外,更容易出现内囊(前肢P=0.002,后肢P=0.005),脑干(中脑P=0.001,脑桥P=0.003)弥散受限以及皮层下白质液化(额叶及顶枕叶P<0.01,颞叶P=0.005)。总体VWM患儿的1年生存率为81%,2年生存率为75%,15年生存率为45%。EIF2B5基因变异最常见,占43%(23/54),其次为EIF2B3基因(22%,12/54)。结论VWM患儿主要以运动倒退为首发症状就诊,发作性加重和癫痫发作在病程中较常见。起病年龄越早,病情进展越迅速,运动功能倒退越严重,存活时间越短,并且头颅MRI病灶、液化和弥散受限范围越广泛。在VWM患儿中最常见的为EIF2B5基因变异,其次为EIF2B3基因变异。

Objective To summarize the clinical features of leukoencephalopathy with vanishing white matter disease(VWM)in children.Methods A retrospective cohort study was performed on 54 genetically diagnosed VWM patients in Peking University First Hospital from January 2007 to March 2019.Paper registration form and electronic medical record system were used to collect the data,and the children were divided into five groups according to the age of disease onset:<1 year,1-<2 years,2-<4 years,4-<8 years and 8-<18 years respectively.The progression of motor function,episodic aggravation,epileptic seizures,survival time,brain magnetic resonance imaging(MRI)and genotype features were analyzed and compared.Non-parametric test,χ2 test or Fisher′s exact test were used for comparison among groups;Kaplan-Meier survival curve was adopted to delineate the survival status of the children.ResultsFifty-four VWM patients were included in the study,including 34 males and 20 females.The age of disease onset was 2 years and 8 months(ranged from 6 months to 9 years and 7 months).Onset age was less than 1 year in 5 cases;onset age was 1-<2 years in 12 cases;onset age was 2-<4 years in 25 cases;onset age was 4-<8 years,in 10 cases;onset age was 8-<18 years in 2 cases;94%(51/54)of patients had complaint of motor regression at the first visit;87%(47/54)of patients suffered from episodic aggravation.Episodic seizures occurred in 43%(23/54)patients.In survivors with disease durations of 1-3 years,in 38%(9/24)patients the disease was classified as gradesⅣ-Ⅴby gross motor function classification system(GMFCS).For the onset age 1-<2 years group,1 patient was classified as GMFCSⅣamong 3 survivors with disease durations of 1-3 years.As for the 2-<4 years group,6 patients were classified as GMFCSⅣ-Ⅴamong 15 patients with disease durations of 1-3 years,whereas 1 patient was classified as GMFCSⅣ-Ⅴamong 4 patients with disease durations of 1-3 years in the 4-<8 years group.Lesions,liquefaction and diffusion restriction in brain MRI were compared among different groups,and it was revealed that the earlier the age of disease onset was,the more likely the subcortical white matter(frontal lobe P<0.01,temporal and parieto-occipital lobe both P=0.002),internal capsule(anterior limb P<0.01,posterior limb P=0.00)and brain stem(midbrain P=0.001,pons P<0.01)were to be involved.In addition,internal capsule(anterior limb P=0.002,posterior limb P=0.005)and brain stem(midbrain P=0.001,pons P=0.003)showed more diffuse restricted diffusion.Moreover,the subcortical white matter(frontal and parieto-occipital lobe both P<0.01,temporal lobe P=0.005)showed earlier rarefaction.The 1-year and 2-year survival rates of the overall patients were 81%and 75%respectively,while the 15-year survival rate was 45%.EIF2B5 gene variation was the most common,which accounts for 43%(23/54),followed by EIF2B3(22%,12/54).Conclusions The majority of VWM patients complained of motor regression at the first visit,episodic aggravation and epileptic seizures are common in the course.Earlier age at onset is associated with more rapid clinical progression,shorter survival time as well as more extensive lesions,liquefaction and diffusion restriction in brain MRI.The most common variant gene is EIF2B5,followed by EIF2B3.