SACS基因新发纯合突变致Charlevoix-Saguenay型常染色体隐性痉挛性共济失调一家系研究  

A novel homozygous mutation in the SACS gene causing autosomal recessive spastic ataxia of Charlevoix-Saguenay:study of a family

作　　者：李海江[1] 庞爱兰[1] 张艳兰[1] 韩雁冰[1] Li Haijiang;Pang Ailan;Zhang Yanlan;Han Yanbing(Department of Neurology,the First Affiliated Hospital of Kunming Medical University,Yunnan Provincial Clinical Research Center for Neurological Diseases,Kunming 650032,China)

机构地区：[1]昆明医科大学第一附属医院神经内科,云南省神经系统疾病临床医学研究中心,昆明650032

出　　处：《中华神经科杂志》2024年第6期593-599,共7页Chinese Journal of Neurology

基　　金：云南省重大科技专项计划(202102AA100061);云南省基础研究计划-昆医联合专项(202201AY070001-090);云南省教育厅科学研究基金(2021J0233);云南省高层次卫生计生技术人才培养项目(L-2019019)。

摘　　要：目的:报道 SACS基因新发纯合突变致Charlevoix-Saguenay型常染色体隐性痉挛性共济失调(ARSACS)患者的临床及遗传学特点,提高临床医师对该病的认识。 方法:对2022年3月就诊于昆明医科大学第一附属医院神经内科遗传代谢专病门诊的1个近亲结婚家系中的患者和父母进行详细的神经系统体格检查,提取患者及其父母外周血DNA,应用二代测序技术对患者及其父母进行全外显子测序(WES),变异位点经Sanger测序验证,并应用软件对突变位点进行分析。结果:患者为18岁汉族男性,3岁起病,表现为进行性双下肢发僵、行走不稳,体检发现双下肢锥体束征、小脑性共济失调、高足弓和锤状趾。其头颅磁共振成像(MRI)T 2WI和T 2液体衰减反转恢复序列(FLAIR)示双侧脑桥对称性低信号,小脑萎缩,胼胝体变薄。神经电生理检查结果显示感觉运动性周围神经病。眼科检查发现患者双眼共同性外斜视、双眼屈光不正。WES结果显示患者 SACS基因第10号外显子c.6958T>C(p.Tyr2320His)纯合变异,父母为杂合变异,并经Sanger测序验证。根据美国医学遗传学与基因组学学会指南该变异评级为疑似致病变异(PM1+PM2+PP3+PP4)。故该患者明确诊断为 SACS基因纯合突变c.6958T>C导致的ARSACS。 结论:本研究发现 SACS基因1个新的致病变异(c.6958T>C),导致了ARSACS,其主要临床特征为小脑性共济失调、锥体束征和感觉运动性周围神经病,头颅MRI检查T 2WI和T 2FLAIR双侧脑桥对称性低信号有助于缩小鉴别诊断范围。Objective To report the clinical and genetic characteristics of autosomal recessive spastic ataxia of Charlevoix-Saguenay(ARSACS)induced by a new homozygous mutation in the SACS gene,and to improve the clinicians′recognition of the disease.Methods Detailed nervous system physical examination was performed on the patient and his parents from a consanguineous family admitted to the Genetics and Metabolism Clinic of the Department of Neurology,the First Affiliated Hospital of Kunming Medical University in March 2022.The peripheral blood DNA of the patient and his parents was extracted,and whole exon sequencing(WES)was performed on the patient and his parents using second-generation sequencing technology.The mutation sites were verified by Sanger sequencing,and the mutation sites were analyzed by software.Results The 18-year-old Han ethnic male patient developed a progressive stiffness of his bilateral lower limbs and gait unsteadiness since the age of 3.He had pyramidal tract sign in his bilateral lower limbs,cerebellar ataxia,pes cavus and hammer toes.Brain magnetic resonance imaging(MRI)showed symmetrical low signal of bilateral pons,cerebellar atrophy and thinning of corpus callosum in T2WI and T2 fluid attenuated inversion recovery(FLAIR)sequences.Neuroelectrophysiological examination showed sensory motor peripheral neuropathy.Ophthalmic examination revealed concomitant exotropia and ametropia in both eyes.WES revealed a homozygous variant of c.6958T>C(p.Tyr2320His)in exon 10 of the SACS gene of the patient,and his parents were heterozygous variant carriers confirmed by Sanger sequencing.The variant was classified as possibly pathogenic(PM1+PM2+PP3+PP4)according to the American Society for Medical Genetics and Genomics.The patient was clearly diagnosed as ARSACS caused by homozygous mutation of c.6958T>C in the SACS gene.Conclusions A novel pathogenic variant(c.6958T>C)in the SACS gene identified in this study leads to the manifestation of ARSACS.The primary clinical manifestations include cerebellar ataxia,py

关 键 词：共济失调 SACS基因 突变 全外显子测序 

分 类 号：R744.7[医药卫生—神经病学与精神病学]