肢带型肌营养不良1B型2例临床及遗传学分析
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摘要
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) 1 B and the mutation features of its pathogenic gene LMNA. Method The clinical data of 2 children with LGMD 1 B 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.67 C>T(p.P23 S) and c.1039 G>T(p.E347 X), in both children respectively, among which C.67 C>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 LGMD1 B.
Objective To explore the clinical characteristics of limb girdle muscular dystrophy(LGMD) 1 B and the mutation features of its pathogenic gene LMNA. Method The clinical data of 2 children with LGMD 1 B 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.67 C>T(p.P23 S) and c.1039 G>T(p.E347 X), in both children respectively, among which C.67 C>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 LGMD1 B.
引文
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[8]Menezes MP,Waddell LB,Evesson FJ,et al.Importance and challenge of making an early diagnosis in LMNA-related muscular dystrophy[J].Neurology,2012,78(16):1258-1263.
[9]Adadi N,Radi FZ,Lahrouchi N,et al.Inherited dilated cardiomyopathy in a large Moroccan family caused by LMNAmutation[J].Anatol J Cardiol,2018,20(1):65-68.
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[11]Maraldi NM,Capanni C,Cenni V,et al.Laminopathies and lamin-associated signaling pathways[J].J Cell Biochem,2011,112(4):979-992.
[12]Pasqualin LM,Reed UC,Costa TV,et al.Congenital muscular dystrophy with dropped head linked to the LMNA gene in a brazilian cohort[J].Pediatr Neurol,2014,50(4):400-406.
[2]Wicklund MP,Kissel JT.The limb-girdle muscular dystrophies[J].Neurol Clin,2014,32(3):729-749.
[3]杨钊,董继宏.常染色体显性遗传性肢带型肌营养不良症研究进展[J].中国临床神经科学,2016,24(1):84-88.
[4]Rodriguez BM,Khouzami L,Decostre V,et al.N-acetyl cysteine alleviates oxidative stress and protects mice from dilated cardiomyopathy caused by mutations in nuclear A-type lamins gene[J].Hum Mol Genet,2018,27(19):3353-3360.
[5]Maggi L,D'Amico A,Pini A,et al.LMNA-associated myopathies:the Italian experience in a large cohort of patients[J].Neurology,2014,83(18):1634-1644.
[6]Ahmadifard A,Jamshidi J,Tafakhori A,et al.Emery-dreifuss muscular dystrophy:a report of a large family with 11affected individuals[J].Int J Mol Cell Med,2016,5(3):196-198.
[7]Furuta M,Sumi-Akamaru H,Takahashi MP,et al.An elderlyonset limb girdle muscular dystrophy type 1B(LGMD1B)with pseudo-hypertrophy of paraspinal muscles[J].Neuromuscul Disord,2016,26(9):593-597.
[8]Menezes MP,Waddell LB,Evesson FJ,et al.Importance and challenge of making an early diagnosis in LMNA-related muscular dystrophy[J].Neurology,2012,78(16):1258-1263.
[9]Adadi N,Radi FZ,Lahrouchi N,et al.Inherited dilated cardiomyopathy in a large Moroccan family caused by LMNAmutation[J].Anatol J Cardiol,2018,20(1):65-68.
[10]Maggi L,Carboni N,Bernasconi P.Skeletal muscle laminopathies:a review of clinical and molecular features[J].Cells,2016,5(3).pii:E33.doi:10.3390/cells5030033.
[11]Maraldi NM,Capanni C,Cenni V,et al.Laminopathies and lamin-associated signaling pathways[J].J Cell Biochem,2011,112(4):979-992.
[12]Pasqualin LM,Reed UC,Costa TV,et al.Congenital muscular dystrophy with dropped head linked to the LMNA gene in a brazilian cohort[J].Pediatr Neurol,2014,50(4):400-406.