遗传性痉挛性截瘫三家系临床特点和基因突变分析

Clinical and genetic analyses of 3 pedigrees with hereditary spastic paraplegia

目的研究3个遗传性痉挛性截瘫（HSP）家系的临床表现特点及致病基因。方法收集自2014年1月至2015年11月就诊于郑州大学第一附属医院神经内科的3个HSP家系，分析3个家系内患者的临床表现、电生理及影像学检查结果，并采集外周静脉血提取基因组DNA，应用目标序列捕获测序技术对家系成员进行HSP相关基因检测。结果家系1为家族性HSP，患者主要表现为缓慢进行性发展的双下肢无力、步态异常，但并无认知功能障碍：家系2为家族性HSP，患者主要表现为早发、逐渐进展的双下肢痉挛性截瘫、智力下降；家系3内患者无家族史，临床表现部分与家系2内患者相同，同时还出现双下肢肌肉萎缩伴有胼胝体发育不良，而无其他类型症状。基因检测结果示：家系l基因突变类型为ATL1基因第7号外显子c．715C〉T（p．R239C），该突变与该家系共分离；家系2基因突变类型为SPG11基因第17号外显子：c．30993103delGTTTG（p．1033fs）及第22号外显子：c38173818insTGA（p．12721273insMe0：家系3基因突变类型为SPG11基因第32号外显子：c．6194C〉G（p．S2056X）及第29号内含子c．5121＋lC〉T剪接突变。结论应用目标序列捕获测序技术发现了与HSP相关致病基因ATLl的1个已知突变、SPGJJ基因的4个新发复合杂合突变。进一步丰富了HSP的突变数据库，为HSP的诊断提供了更多依据。

Objective To analyze the clinical manifestations and genetic mutations in 3 pedigrees with hereditary spastic paraplegia （HSP）. Methods Three pedigrees diagnosed as having HSP in our hospital from January 2014 to November 2015, were chosen; the clinical manifestations, electrophysiology and imaging features of the patients in these three families were analyzed. Genomic DNA was extracted from peripheral venous blood, and the targeted gene capturing was employed to identify the disease-causing genes of these patients. Results The patients from the first family was familiar HSP, and the main clinical features were progressive lower limbs weakness and abnormal gait without cognitive impairment; the patients from the second family were familiar HSP and those from the third family were HSP without family history, and the main clinical features of the two pedigrees were slowly progressive spastic paraplegia and cognitive impairment. In addition, thin corpus callosum was visible in MR imaging of family three. Genetic testing showed the first family presented with a known mutation c.715C〉T ofA TL1 exon 7 and the loci co-segregated in the family. The second family presented with novel compound heterozygous mutations in the SPGll gene： c.3099_3103delGTTTG mutation of exon 17and c3817_3818insTGA mutation of exon 22; novel compound heterozygous mutations in the SPGll gene in the third family were detected as follows： c.6194C 〉G mutation of exon 32 and c. 5121＋lC〉T splicing mutation ofintro 29. Conclusions Four novel mutations in SPGll gene and one known mutation in A TL1 gene are found, which enriches the known HSP mutation types. Targeted gene capture is an efficient and rapid tool for identifying the causation of some complex and genetically heterogeneous neurodegenerative diseases.