遗传性痉挛性截瘫35型临床表型及基因型分析

Clinical phenotype and genotype analysis of hereditary spastic paraplegia type 35

目的报道8例遗传性痉挛性截瘫35型(SPG35)患者,总结SPG35的临床及遗传学特点。方法对2006年9月至2021年6月就诊于上海交通大学附属第六人民医院和上海交通大学医学院附属瑞金医院的8例SPG35患者进行临床资料采集、体格检查、影像学检查、全外显子测序、一代测序和家系共分离验证,并进一步对该疾病的临床、遗传学和发病机制作一总结。结果8例先证者中7例为幼年起病,1例为成年起病,临床均表现为进行性加重的行走困难。其中2例临床表现为单纯型痉挛型截瘫,余6例不仅有运动系统功能的损害,还伴有认知功能障碍和吞咽困难等其他表型。基因检测共发现了13个脂肪酸2-羟化酶(FA2H)基因(NM24306)突变,其中6个为已知突变,7个为本文新报道突变。结论SPG35是一种常染色体隐形遗传的神经系统退行性疾病,其致病基因为FA2H基因,临床表现存在一定的异质性,基因型与表型相关性尚不十分明确。

Objective To report 8 cases of hereditary spastic paraplegia type 35(SPG35)in Chinese mainland,summarize the clinical and genetic features of this disease.Methods Eight probands with SPG35,admitted in Shanghai Jiao Tong University Affiliated Sixth People′s Hospital and Ruijin Hospital,Shanghai Jiao Tong University School of Medicine from September 2006 to June 2021,were collected in detail.Physical examination,cranial imaging examination and whole exome sequencing were conducted,followed by Sanger sequencing and family co-segregation.In addition,the recent advances in clinical,genetic and pathogenesis studies of the disease were also reviewed.Results Among all of the 8 patients,7 had juvenile-onset and 1 was adult-onset.The clinical phenotype of 2 cases was pure spastic paraplegia.The other 6 cases presented with complicated form,which was characterized by not only motor dysfunction,but also cognitive impairment and dysphagia,etc.Genetic testing revealed a total of 13 fatty acid 2-hydroxylase(FA2H)gene(NM_024306)mutations,of which 6 were reported and 7 were newly reported in this study.Conclusions SPG35 is an autosomal recessive neurodegenerative disease with highly phenotypic heterogeneity,with the causative gene as FA2H.The genotype-phenotype correlations in SPG35 are not clear.