HACE1基因变异所致伴或不伴癫痫发作的痉挛性截瘫和精神运动发育迟缓1例并文献复习  

Spastic paraplegia and psychomotor retardation with or without seizures caused by HACE1 gene mutation:a case report and literature review

作　　者：刘磊[1] 王彦红 张耀东 郑彬 刘菁 陈重芬 郑璇 张小慢 李东晓 Liu Lei;Wang Yanhong;Zhang Yaodong;Zheng Bin;Liu Jing;Chen Chongfen;Zheng Xuan;Zhang Xiaoman;Li Dongxiao(Institute of Pediatric Medicine,Children′s Hospital Affiliated to Zhengzhou University,Henan Children′s Hospital,Zhengzhou Children′s Hospital,Henan Key Laboratory of Children′s Genetics and Metabolic Diseases,Zhengzhou450018,China;Department of Medical Imaging,Children′s Hospital Affiliated to Zhengzhou University,Henan Children′s Hospital,Zhengzhou Children′s Hospital,Zhengzhou450018,Chi)

机构地区：[1]郑州大学附属儿童医院(河南省儿童医院,郑州儿童医院)儿科医学研究所,河南省儿童遗传代谢性疾病重点实验室,郑州450018 [2]郑州大学附属儿童医院(河南省儿童医院,郑州儿童医院)放射科,郑州450018

出　　处：《中华神经科杂志》2024年第12期1335-1341,共7页Chinese Journal of Neurology

基　　金：国家自然科学基金(82000850)。

摘　　要：目的探讨HACE1基因导致的伴或不伴癫痫发作的痉挛性截瘫和精神运动发育迟缓(SPPRS)患儿的临床及遗传学特征。方法收集2019年4月就诊于河南省儿童医院的1例SPPRS患儿的临床资料、辅助检查和基因检测结果,并分别以HACE1、SPPRS、癫痫、痉挛性截瘫为关键词,在中国知网数据库、万方数据库、PubMed数据库检索建库至2024年6月收录的文献,对SPPRS患儿的临床和基因型特征进行总结。结果患儿男性,11个月20 d,临床表现为全面发育迟缓、双腿频繁痉挛抖动、癫痫发作、肥胖、合并尿道口畸形。头颅磁共振成像示双侧脑室增宽、胼胝体发育不良、髓鞘化落后。基因检测结果显示患儿HACE1基因存在c.994C>T(p.R332*)和c.1679-2A>G复合杂合变异(参考转录本NM_020771),分别遗传自母亲和父亲,其中c.1679-2A>G为未报道过的新变异。共检索到相关中文文献0篇,英文文献6篇,共报道11个家系21例患儿。主要临床表现为全面发育迟缓(21例)、运动障碍(21例)、智力障碍(18例)、癫痫(13例)、肥胖(13例)、骨骼异常(11例)、小头畸形(9例)、眼部异常(9例)、特殊面容(5例)、感音神经性耳聋(5例)、身材矮小(3例)。头颅磁共振成像显示胼胝体发育不全、脑室扩张、白质减少和脑萎缩。没有发现明确的基因型-表型相关性。共报道13个HACE1基因变异位点,包括9个无义变异、2个移码变异、1个整码缺失变异和1个错义变异。11个家系中仅有2个家系5例患者为复合杂合变异所致,分别是c.1852_1853del(p.L832del)与c.454C>T(p.Q152*)、c.2242C>T(p.R748*)与c.2019_2020insTTTAGGTATTTTTAGGTATT(p.P674fs)复合杂合变异,另外9个家系16例患者由其余9个变异的纯合变异致病。结论SPPRS罕见,通常在婴儿期发病,主要临床表现为全面发育迟缓、运动障碍、癫痫等,目前尚未发现明确的基因型-表型相关性。HACE1基因c.1679-2A>G变异为首次报道,丰富了该基因变异Objective To investigate the clinical and genetic features of patients with spastic paraplegia and psychomotor retardation with or without seizures(SPPRS)caused by HACE1 gene mutation.Methods Clinical data,auxiliary examination and genetic test results of a child with SPPRS caused by HACE1 gene mutation who was admitted to Henan Children′s Hospital in April 2019 were collected.The clinical and genotypic characteristics of children with SPPRS were summarized by searching the relevant literature up to June 2024,retrieved from CNKI,Wanfang and PubMed databases with the terms of"HACE1""SPPRS""seizures""spastic paraplegia".Results The patient was a 11 months and 20 days old male,with a clinical phenotype including global developmental delay,leg spastic tremor,frequent epileptic seizures,obesity,and concurrent urethral malformation.Brain magnetic resonance imaging(MRI)showed enlarged bilateral ventricles,hypoplastic corpus callosum,delayed myelination.Genetic test results revealed compound heterozygous variants c.994C>T(p.R332*)and c.1679-2A>G in the HACE1 gene(according to the transcript NM_020771),respectively inherited from his mother and father,with c.1679-2A>G being a newly reported variant.A total of 6 English literatures reported 21 SPPRS patients in 11 families,and HACE1 gene mutations were mainly characterized by nonsense mutations.The main clinical manifestations included global developmental delay(21 cases),movement disorders(21 cases),intellectual disabilities(18 cases),seizures(13 cases),obesity(13 cases),skeletal abnormalities(11 cases),microcephaly(9 cases),ocular abnormalities(9 cases),distinctive facial features(5 cases),sensorineural hearing loss(5 cases),and short stature(3 cases).MRI predominantly showed hypoplasia of the corpus callosum,ventricular dilation,paucity of white matter and cerebral atrophy.There were no clear genotype-phenotype correlations.A total of 13 HACE1 gene mutations were reported,including 9 nonsense mutations,2 frameshift mutations,1 in-frame mutation,and 1 missense mutation

关 键 词：癫痫 痉挛性截瘫 遗传性 精神运动发育迟缓 神经发育障碍 HACE1基因 

分 类 号：R742.1[医药卫生—神经病学与精神病学]