CAJ | 학술논문

目的肌萎缩侧索硬化(ALS)是上、下运动神经元退变引起的一种进行性致死性疾病,家族性ALS占10%～20%,铜锌SOD1基因突变存在于20%的家族性患者和少数散发性患者,某些突变还具有地域分布和特殊临床表型的规律性.我们旨在分析我国3个家族性ALS家系SOD1基因突变特点,并与不同国家和地区SOD1突变比较,分析其临床表型的特征性.方法提取患者外周血基因组DNA,采用SOD1基因的5对引物对其5个外显子进行PCR扩增,产物直接测序.归纳整理患者临床表型资料,进行表型-基因型关联分析.结果家系1中SOD1基因外显子2的H46R杂合突变,即CAT→CGT,使得46位由编码组氨酸变为编码精氨酸.先证者48岁,女性,43岁起病,主要表现为肢体无力和萎缩.家系中其他3例患者首发症状与先证者相似,病情进展均较缓慢,生存期较长.家系2中先证者20岁,男性,临床表现为延髓性麻痹,病程进展快速,生存期1年,位于3号外显子的杂合突变,即G72C突变.其父亲也出现同样的突变,但无ALS临床表现,其姑姑也有类似病史.家系3中5例患者5号外显子的E133V杂合突变,先证者中年起病,病程逐渐进展,生存期5年.结论 H46R的杂合突变国内未见报道,国外日本人曾多次报道及巴基斯坦有1个家系报道,欧美均未见报道,推测此突变可能为亚裔所特有.G72C突变的家系,临床表型为较早发病,病程进展迅速,生存期1年,突变外显率低导致家族成员不发病,常被诊断为散发病例,因此对于散发性患者及其家族成员同时检测SOD1基因突变十分必要.E133V突变的家系为国际首先报道.
목적 기위축측색경화(ALS)시상、하운동신경원퇴변인기적일충진행성치사성질병,가족성ALS점10%～20%,동자SOD1기인돌변존재우20%적가족성환자화소수산발성환자,모사돌변환구유지역분포화특수림상표형적규률성.아문지재분석아국3개가족성ALS가계SOD1기인돌변특점,병여불동국가화지구SOD1돌변비교,분석기림상표형적특정성.방법 제취환자외주혈기인조DNA,채용SOD1기인적5대인물대기5개외현자진행PCR확증,산물직접측서.귀납정리환자림상표형자료,진행표형-기인형관련분석.결과 가계1중SOD1기인외현자2적H46R잡합돌변,즉CAT→CGT,사득46위유편마조안산변위편마정안산.선증자48세,녀성,43세기병,주요표현위지체무력화위축.가계중기타3례환자수발증상여선증자상사,병정진전균교완만,생존기교장.가계2중선증자20세,남성,림상표현위연수성마비,병정진전쾌속,생존기1년,위우3호외현자적잡합돌변,즉G72C돌변.기부친야출현동양적돌변,단무ALS림상표현,기고고야유유사병사.가계3중5례환자5호외현자적E133V잡합돌변,선증자중년기병,병정축점진전,생존기5년.결론 H46R적잡합돌변국내미견보도,국외일본인증다차보도급파기사탄유1개가계보도,구미균미견보도,추측차돌변가능위아예소특유.G72C돌변적가계,림상표형위교조발병,병정진전신속,생존기1년,돌변외현솔저도치가족성원불발병,상피진단위산발병례,인차대우산발성환자급기가족성원동시검측SOD1기인돌변십분필요.E133V돌변적가계위국제수선보도.
Objective To identify the mutations in Cu/Zn superoxide dismutase ( SOD1 ) gene in three Chinese kindreds with amyotrophic lateral sclerosis ( ALS), compare the genotypes with those found in other ethnic groups and to analyze the clinical characteristics.Methods The diagnosis of ALS met El Escorial ALS diagnostic criteria.Genomic DNA was extracted from peripheral blood in ALS patients using standard procedure.PCR amplifications of five exons of SOD1 were performed using primers as described in the previous publication.The PCR products were directly sequenced.Results A heterozygous mutation H46R was found in four affected members in a family with middle age onset and slowly progressive ALS.A heterozygous mutation of G72C was identified in a 20-year-old male who died of respiratory failure after two years of ALS.His father carried the same mutation without clinical phenotype.In the third family with 20affected members with middle age onset and rapidly progress, a mutation of E13V was identified in 5 affected subjects.Conclusions This study is the first large screening of SOD1 mutation in Chinese familiar ALS patients.H46R has previously been found only in Japanese and Pakistanis; this is the first report in Chinese, suggesting H46R may be specific to Asians.The family with mutation G72C presented decreased penetrance, therefore screening SOD1 mutation in sporadic cases and unaffected family members is necessary.E133V is the first reported mutation and needs more study to investigate its effect on the disease.