CAJ | 학술논문

目的探讨儿童交替性偏瘫(AHC) ATP1 A3基因突变特点及其对临床不典型病例的诊断价值.方法前瞻性收集2005年8月至2014年11月在北京大学第一医院儿科就诊的AHC患儿及家系成员的临床资料和外周血DNA,采用PCR扩增和Sanger测序的方法筛查ATP1 A3基因突变.结果共收集78例AHC患儿,其中男50例、女28例,仅3例有AHC家族史,1例为母女同患,1例为单卵双胎共患而父母表型正常,1例为兄妹同患而父母表型正常.发病年龄为生后6h至8岁6个月(中位4个月).根据Aicardi制定的临床诊断标准,72例符合典型AHC,6例为不典型AHC.基因突变筛查发现71例携带ATP1 A3基因突变,突变率为91.0％,3例有家族史者均发现该基因突变.除5例未获得父或母方基因组DNA外,95.5％(63/66)已证实为新生突变.共发现27种ATP1 A3基因突变类型,均为错义突变,其中11种突变为未报道的新突变,突变D801N和E815K分别占28.2％(20例)和16.9％(12例).6例不典型病例中,5例发现ATP1 A3基因突变.结论 ATP1A3基因为AHC的主要致病基因,且多数为新生突变,该基因有热点突变,较常见的2种为D801N和E815K.ATP1A3基因突变筛查有助于遗传咨询和不典型AHC病例的确诊.
목적 탐토인동교체성편탄(AHC) ATP1 A3기인돌변특점급기대림상불전형병례적진단개치.방법 전첨성수집2005년8월지2014년11월재북경대학제일의원인과취진적AHC환인급가계성원적림상자료화외주혈DNA,채용PCR확증화Sanger측서적방법사사ATP1 A3기인돌변.결과 공수집78례AHC환인,기중남50례、녀28례,부3례유AHC가족사,1례위모녀동환,1례위단란쌍태공환이부모표형정상,1례위형매동환이부모표형정상.발병년령위생후6h지8세6개월(중위4개월).근거Aicardi제정적림상진단표준,72례부합전형AHC,6례위불전형AHC.기인돌변사사발현71례휴대ATP1 A3기인돌변,돌변솔위91.0％,3례유가족사자균발현해기인돌변.제5례미획득부혹모방기인조DNA외,95.5％(63/66)이증실위신생돌변.공발현27충ATP1 A3기인돌변류형,균위착의돌변,기중11충돌변위미보도적신돌변,돌변D801N화E815K분별점28.2％(20례)화16.9％(12례).6례불전형병례중,5례발현ATP1 A3기인돌변.결론 ATP1A3기인위AHC적주요치병기인,차다수위신생돌변,해기인유열점돌변,교상견적2충위D801N화E815K.ATP1A3기인돌변사사유조우유전자순화불전형AHC병례적학진.
Objective To analyze the ATP1A3 mutations in patients with alternating hemiplegia of childhood (AHC) and recognize its value in diagnosing atypical cases.Method Data of all AHC patients seen at Peking University First Hospital from August 2005 to November 2014 were prospectively collected.Clinical information of the AHC patients and their family members were collected and analyzed.Genomic DNAs were extracted from their peripheral blood.Mutations in ATP1 A3 were screened by Sanger sequencing after PCR.Result A total of 78 AHC patients were recruited, including 50 males and 28 females.Only three patients had family history of AHC.The first family case had affected mother with AHC;the second family case was the older one of a monozygotic male twins with AHC but their parents were normal;the third family case had a sister with AHC but their parents were normal.The age of onset ranged from six hours to eight years and six months (median: 4 months).According to the Aicardi's clinical diagnostic criteria, 72 patients were considered as typical AHC cases and the other six patients were considered as atypical AHC cases for their age of onset was older than 18 months.Twenty-seven different missense ATP1A3 mutations were detected in 71 (91.0％, 71/78) patients with AHC, including 66 typical and 5 atypical cases.11 novel ATP1 A3 mutations were first reported.ATP1 A3 mutations were identified in the three AHC cases with family history.Parental analysis verified that the ATP1 A3 mutation of 63 patients (95.5 ％, 63/66) were de novo origin except lack of five unavailable maternal or paternal genomic DNA.Mutation D801N was found in 20 cases(28.2％), and E815K in 12 cases(16.9％).In the six atypical AHC patients, ATP1A3 mutations were detected in five of them.Conclusion ATP1 A3 was the major causative gene of AHC, and mutations were identified as de novo mostly.ATP1 A3 mutations in AHC had mutational hotspot, and the most common mutations were D801N and E815K.ATP1A3 mutation screening is helpful for the genetic and definite diagnosis of the atypical AHC cases.