ATP1A3基因突变相关疾病1个家系报道及文献复习

ATP1A3-related disorders:a family report and literature review

目的探讨ATP1A3基因突变相关疾病的临床表现及致病基因变异情况。方法选取2023年1月28日于济宁市第一人民医院儿童康复科就诊的ATP1A3基因突变相关疾病1个家系为研究对象。对先证者及其家庭成员进行全外显子组测序(WES),采用Sanger测序进行DNA测序验证。检索国内外数据库中对ATP1A3基因突变相关疾病研究相关文献,分析先证者临床特点和基因变异情况。本研究遵循的程序符合济宁市第一人民医院医学伦理委员会的规定,并通过该伦理委员会审查及批准(2022伦审研第094号),并且监护人对先证者的诊治均知情同意。结果①先证者为4岁3个月龄男童,临床特征包括左侧上下肢体偏瘫,左下肢远端肌力弱,左侧肢体肌张力障碍,左膝腱反射较对侧弱。颅脑MRI提示右顶叶异常信号,考虑为扩大的血管周围间隙,磁共振脑血管成像(MRA)检查结果未见明显异常。先证者胞姐4岁发病时首发症状为左侧肢体不灵活,病情进行性加重,10岁时已全身受累,四肢瘫痪。Sanger测序结果显示,先证者及胞姐存在ATP1A3基因c.2401G>T(p.Asp801Tyr)杂合变异,其父母和胞妹均未携带该变异基因。依据美国医学遗传学与基因组学学会(ACMG)相关指南,该基因变异评级为致病变异(PS2_verystrong+PM1+PM2_supporting+PP2+PP3)。②文献检索结果:按照本研究设定的检索策略进行检索,关于ATP1A3基因突变相关疾病研究文献共计39篇,涉及97例ATP1A3基因相关疾病患者,起病年龄为生后1 d至59岁,其中79.4%(77/97)在婴幼儿期发病;45.4%(44/97)存在偏瘫发作,37.1%(36/97)存在肌张力障碍,22.7%(22/97)合并癫痫发作。这97例患者(疾病诊断时年龄为生后1 d至59岁)的ATP1A3基因变异类型为51种,96.9%(94/97)为错义变异。结论ATP1A3基因突变相关疾病患者多在婴幼儿期发病,主要临床表现为偏瘫、肌张力障碍和癫痫发作,其ATP1A3基因突变以错义变异为主,并可能存在生殖腺嵌合情况。

Objective To investigate clinical manifestations and pathogenic gene variations of ATP1A3-related disorders.Methods A Child with an ATP1A3-related disorders who visited the Department of Pediatric Rehabilitation,Jining No.1 People′s Hospital on January 28,2023 was selected into this study.Whole exome sequencing(WES)was carried out for the child and his family members,followed by validation using sanger sequencing.Retrieved literature of study on clinical characteristics and pathogenic gene variations of ATP1A3-related disorders were summarized based on domestic and foreign databases.This study was approved by the Medical Ethics Committee of Jining No.1 People′s Hospital(Approve No.2022-094).Results①This child is a 4-year-old boy with clinical features including left-sided hemiplegia of the upper and lower limbs,weakness in the distal muscles of the left lower limb,dystonia in the left limb,and weakness in the left knee tendon reflex.Brain MRI showed abnormal signals in the right parietal lobe,suspected to be an enlarged perivascular space,with no obvious abnormalities found on magnetic resonance angiography(MRA).This boy′s sister showed initial symptoms at the age of 4,which the left limb were not flexible,and the condition was getting worse.She had systemic involvement and quadriplegia by the age of 10.Sanger sequencing confirmed that both the affected child and his sister had harbored a heterozygous c.2401G>T(p.Asp801Tyr)variant of the ATP1A3 gene,while neither of their parents and younger sister had carried the same variant.Based on the guide lines from the American College of Medical Genetics and Genomics(ACMG),the variant was classified as pathogenic(PS2_verystrong+PM1+PM2_supporting+PP2+PP3).②Literature search results were as follow.According to the search strategy of this study,a total of 39 articles met the inclusion criteria of this study,involving 97 patients with ATP1A3-related disorders,onset age of 1 day to 59 years,of which 79.4%(77/97)were infancy.Hemiplegia in 45.4%(44/97)patients,dystonia in 37.1%(36/97)patients,and seizures in 22.7%(22/97)patients.There were 51 types of mutations in the ATP1A3 gene,and the vast majority(94/97)were missense variants.Conclusions ATP1A3-related disorders mostly occur in infants and young children.The clinical manifestations of ATP1A3-related disorders are mainly hemiplegia,dystonia and seizures.ATP1A3 gene variants are mainly missense variants,and possibly gonadal chimerism.