无脑回-巨脑回畸形患儿的临床特征及分子遗传学研究

Analysis on clinical and genetic characteristics of childhood lissencephaly-pachygyria

目的研究无脑回-巨脑回畸形患儿的临床特征及分子遗传学特征,分析基因型和表型的关联。方法收集2014年1月至2020年3月就诊的60例无脑回-巨脑回畸形患儿的临床资料,包括临床症状、头颅影像学、治疗随访等,其中45例患儿家系行全基因组二代测序分析。结果60例患儿中男30例、女30例,起病年龄2天至14岁,其中单纯巨脑回45例(75.0%),单纯无脑回4例(6.7%),巨脑回合并无脑回11例(18.3%);仅以运动或语言发育落后为首发症状就诊者10例(16.7%),伴癫痫者48例(80.0%),其中痉挛发作31例。50例合并惊厥的患儿随访1.5个月至5年,2例热性惊厥未用药无发作,12例经抗癫痫药物、4例经手术治疗后无癫痫发作,31例仍有反复癫痫发作,1例因重症肺炎病亡。60例患儿中59例存在不同程度的精神运动发育落后,1例14岁起病的局灶性巨脑回患儿发育正常。行全基因组分析的45例患儿家系中发现4例血小板激活因子乙酰水解酶lB亚单位1(PAFAH1B1/LIS 1)基因变异及1例α-微管蛋白1a(TUBA1A)基因变异,均为新发变异,美国医学遗传学与基因组学学会分类均为致病性变异。结论无脑回-巨脑回患儿临床上多有难治性癫痫和不同程度的发育迟缓,多数预后不良,痉挛发作的一线用药和癫痫手术治疗对部分患儿有益;仅少数患儿发现PAFAH1B1基因及TUBA1A基因致病性变异。

Objective To analyze the clinical and genetic characteristics of lissencephaly-pachygyria in children,and to perform genotype-phenotype analysis.Methods The clinical data of 60 children diagnosed with lissencephaly-pachygyria from January 2014 to March 2020 were collected,and next generation sequencing analysis was performed in 45 children and their parents.Results The onset age of 60 cases(30 males and 30 females)ranged from 2 days to 14 years old.Among 60 cases,45 cases(75%)were pachygyria,4 cases(6.7%)were lissencephaly,and 11 cases(18.3%)were pachygyria with lissencephaly.Ten patients(16.7%)had motor or language retardation as the onset symptom,and 48 patients(80%)had epilepsy.Among them,31 cases had spasm.During the follow-up period from 1.5 months to 5 years,among 50 patients with seizure,two cases of febrile seizure were seizure-free without treatment,12 cases were seizure-free by treatment with antiepileptic drugs and 4 cases were seizure-free after epilepsy operation;31 cases still had recurrent seizures;one case died of severe pneumonia.Among the 60 children,59 had different degrees of psychomotor retardation,and 1 child(with onset age of 14 years)had normal development with focal pachygyria.Four mutations in PAFAH1B1/LIS 1 gene and one mutation in TUBA1A gene were found in 45 pedigrees.All the mutations were de novo and classified as pathogenic according to the American College of Medical Genetics and Genomics classification.Conclusions Most lissencephaly-pachygyria patients had refractory epilepsy,developmental retardation and poor prognosis.The first-line medication of epileptic spasm and epilepsy surgery may be beneficial to some patients.PAFAH1B1/LIS 1 gene and TUBA1A gene mutations were found in a few patients.