疑似儿童神经元蜡样脂褐质沉积症5例诊断分析

Analysis of diagnosis of 5 children with suspected neuronal ceroid lipofuscinosis

目的探讨儿童神经元蜡样脂褐质沉积症(NCL)的诊断方式,特别是基因诊断的意义。方法回顾性分析2013年1月至2017年1月在首都医科大学宣武医院就诊的5例临床疑诊NCL的患儿资料,其中男3例、女2例,有2例为兄妹关系。患儿发病年龄3岁4个月至8岁11个月,来院首诊年龄3岁6个月至14岁。对脑影像表现异常的4例患儿及其父母、兄弟提取外周血DNA,检测相关基因。结果 4例确诊为NCL,1例为儿童癔症。基因检测:例1 TPP1基因c.887-17A>G为剪切变异;c.646G>A为错义变异。例2 TPP1基因c.1015_1016 del为移码变异;c.640C>T为无义变异。例3 CLN6基因核苷酸改变为c.158T>C(p.L53P)及c.889C>T(p.P297S)。3例父母均只携带其中1个杂合变异,例3受检者哥哥未携带突变。例4 CLN3基因c.1160_1169 delCAGCCTACGTinsGC杂合突变,母亲未检测到该突变,缺失父亲样本;CLN3基因外显子E3-E8杂合缺失,为真实缺失,母源。随访15～60个月,无死亡病例。结论对于怀疑NCL的患儿应及时检查头颅磁共振成像、脑电图及基因检测,导致NCL的基因突变TPP1(c.887-17A>G,c.1015_1016 del),CLN3(c.1160_1169 delCAGCCTACGTinsGC),CLN6[(c.158T>C(p.L53P),c.889C>T(p.P297S)]位点均为首次报告,基因型对于NCL的分型、判断预后十分重要。

Objective To investigate diagnosis of children’s neuronal ceroid lipofuscinosis(NCL),especially the significance of gene diagnosis. Methods The clinical data of 5 cases of suspected NCL in our hospital from January 2013 to January 2017 were retrospectively analyzed. There were 3 boys and 2 girls,2 of whom were sister and brother. The age of onset ranged from 3 years and 4 months to 8 years and 1 month,averaged 5 years and 9 months. The first visit to our hospital ranged from 3 years and 6 months to 14 years,with an average of 8 years and 1 month. DNA of peripheral blood was extracted from 4 children with abnormal imaging and their parents and brothers,and the related genes were detected.Results Four cases of children were diagnosed with NCL,and 1 case was diagnosed with hysteria;gene detection showed:case 1:TPP1 gene c.887-17 A>G was a shearing variant,and c.646 G>A was a missense mutation;case 2:TPP1 gene c.10151016 del was frameshift mutation,and c.640 C>T was nonsense mutation;the nucleotide of case 3:CLN6 gene changed to c.158 T>C(p.L53 P)and c.889 C>T(p.P297 S). The parents of the 3 cases only carried one of the heterozygous variants,and the brother of case 3 had no mutation. Heterozygous mutation existed in case 4:CLN3 gene,c.11601169 delCAGCCTACGTinsGC,which was not detected in the mother,and there was the deletion of the paternal sample;there was loss of heterozygosity in the exon E3-E8 of the CLN3 gene,which was the true missing from mother.Five cases were followed up for 15-60 months and there was no death. Conclusion Suspected NCL patients should be checked head MRI,electroencephalogram and gene. The gene mutation leads to NCL,such as TPP1(c.887-17 A>G,c.10151016 del),CLN3(c.11601169 delCAGCCTACGTinsGC),CLN6[(c.158 T>C(p.L53 P) and c.889 C>T(p.P297 S)],are reported for the first time. Genotype is very important for NCL classification and prognosis.