UBTF基因变异相关儿童期发病的神经退行性变的临床与基因特点分析

Clinical characteristics and genetic analysis of childhood onset neurodegeneration associated with UBTF gene variation

目的总结UBTF基因变异导致儿童期发病的神经退行性变患儿的临床表型及遗传学特点。方法回顾性分析2020年2月至2023年1月于郑州大学附属儿童医院神经内科确诊的3例儿童期发病的神经退行性变患儿的临床和遗传学资料。对3例先证者采用全外显子基因测序均发现存在UBTF基因变异,通过一代Sanger测序法对其家系成员的UBTF基因进行验证,分析UBTF基因的变异特点,同时对3例患儿的治疗及随访结果进行总结。结果3例儿童期发病的神经退行性变患儿中,男性2例,女性1例,就诊年龄分别为出生后9个月、4岁和6个月,临床表型主要包括运动发育迟缓、语言及智力发育障碍、肌张力障碍。其中例1和例2存在癫痫发作,例1伴有吞咽困难、喂养问题、体重不增、共济失调。头颅MRI平扫显示例1和例2存在不同程度的脑萎缩,例1胼胝体发育不全、脑室扩张和软化灶;例3影像学检查结果提示非特异性蛛网膜下腔增宽。3例患儿的染色体拷贝数变异及线粒体环基因检测未见异常;全外显子基因检测提示存在UBTF基因新生错义变异[NM_014233.4:c.1414(exon14)G>A(p.Gly472Ser)、c.1392(exon14)G>T(p.Lys464Asn)]及母源无义变异[NM_014233.4:c.520C>T(p.Arg174*)],均为未报道的变异位点。3例患儿均接受综合康复功能训练,取得了一定程度的语言和智力改善。例1通过单一抗癫痫药物治疗有效控制癫痫发作,例2应用4种以上抗癫痫发作药物才有效控制癫痫发作。结论UBTF基因变异导致儿童期发病的神经退行性变相对较罕见,部分病例可伴随脑萎缩。UBTF基因新生错义变异及母源无义变异为3例先证者的遗传学病因。

Objective To summarize the clinical phenotype and genetic characteristics of children with neurodegeneration caused by UBTF gene mutations in childhood.Methods The clinical and genetic data of 3 children with neurodegeneration in childhood diagnosed in the Department of Neurology,Children′s Hospital Affiliated to Zhengzhou University from February 2020 to January 2023 were retrospectively analyzed.All the 3 probands were found having UBTF gene mutations through the whole exome gene sequencing,and the first generation Sanger sequencing method was used to verify the UBTF gene in their family members.The variation characteristics of the UBTF gene were analyzed,and the treatment and follow-up results of the 3 children were summarized.Results Among the 3 children with childhood onset neurodegeneration,2 were male and 1 female,aged 9 months,4 years and 6 months after birth,respectively.The clinical phenotypes mainly included motor retardation,speech and mental retardation,and dystonia.Among them,case 1 and case 2 had seizures,case 1 had dysphagia,feeding problems,no weight gain and ataxia.Brain MRI plain scan showed that case 1 and case 2 had different degrees of cerebral atrophy,case 1 had hypoplasia of corpus callosum,ventricle expansion and softening focus,and case 3 showed non-specific widening of the subarachnoid space.There were no abnormalities in the chromosome copy number variation and mitochondrial ring gene testing in the 3 children;the whole exon gene testing suggested the de novo missense variant in the UBTF gene[NM_014233.4:c.1414(exon14)G>A(p.Gly472Ser),c.1392(exon14)G>T(p.Lys464Asn)]and the maternal nonsense variant[NM_014233.4:c.520C>T(p.Arg174*)],which were unreported site variants.In terms of treatment,the 3 children received comprehensive rehabilitation function training,and achieved a certain degree of language and intelligence improvement.Seizure control was effectively managed in case 1 with a single antiepileptic drug.Epileptic seizures were effectively treated and controlled in case 2 using more than 4 types of antiepileptic drugs.Conclusions Neurodegenerative changes caused by UBTF gene mutations in childhood are relatively rare,and some cases may be accompanied with brain atrophy.De novo missense variation and maternal nonsense variation of the UBTF gene are the genetic etiology of the 3 probands.