肢带型肌营养不良1B型2例临床及遗传学分析

Clinical and genetic analysis of limb girdle muscular dystrophy 1B in 2 cases

目的探讨肢带型肌营养不良1B型的临床特征及其致病基因LMNA特点。方法回顾分析2例肢带型肌营养不良1B患儿及家系成员临床资料,应用高通量测序、Sanger测序技术对可能致病突变位点进行筛查和验证;通过查阅文献、生物信息学分析、肌肉组织活检分析突变位点的致病性。结果患儿男、女各1例,分别为3岁6个月和4岁;均表现为走路困难,易疲劳,四肢肌力下降;肌酸激酶及其同工酶均上升,肌电图未见肌源性损害,肌肉活检示肌纤维大小不等,肌纤维内细胞核数量明显增加,符合肌营养不良表现。高通量测序结果显示2例患儿均存在LMNA基因突变,分别为c. 67 C>T(p.P 23 S)以及c. 1039 G>T(p.E 347 X)杂合突变,其中c. 67 C>T未见报道;生物信息学提示该位点致病,且在不同的物种间保守。结论基因检测有助肢带型肌营养不良1B型的诊断。

Objective To explore the clinical characteristics of limb girdle muscular dystrophy (LGMD) 1B and the mutation features of its pathogenic gene LMNA. Method The clinical data of 2 children with LGMD 1B and their family members were retrospectively analyzed. Screening and validation of possible pathogenic mutation sites were performed by high-throughput sequencing and Sanger sequencing. The pathogenicity of mutation sites was analyzed by literature review, bioinformatics analysis, and muscle tissue biopsy. Results In one boy aged 3 years and 6 months and one girl aged 4 years, both showed difficulty in walking, fatigue easily and muscle weakness of limbs. Creatine kinase and its isoenzymes were increased. No myogenic damage was found by electromyography. Muscle biopsy showed that the size of muscle fibers varied, and the number of nuclei in muscle fibers increased significantly, which are in accord with the manifestation of muscular dystrophy. The results of high throughput sequencing showed that there were heterozygous mutations in LMNA gene, c.67C>T (p.P23S) and c.1039G>T (p.E347X), in both children respectively, among which C.67C>T had not been reported before. Bioinformatics suggested that this site was pathogenic and conservative among different species. Conclusion Gene detection is helpful for the diagnosis of LGMD1B.