新生儿发育性和癫痫性脑病109型1例并文献复习

A Case of Developmental and Epileptic Encephalopathy in Newborns with Type 109 and Literature Review

摘要: 目的：探讨1例FZR1相关发育性和癫痫性脑病109型新生儿的临床特点和分子遗传学特征。方法：回顾性分析2023年10月我院收治的1例FZR1基因突变导致发育性和癫痫性脑病109型(Developmental and Epileptic Encephalopathy 109, DEE109)患儿的临床表现、影像学及遗传学数据，并以“FZR1基因”“癫痫性脑病”“发育性癫痫性脑病”为关键词，分别在万方数据库、中国知网检索国内文献。以“FZR1”、“Epileptic Encephalopathy”、“Developmental and Epileptic Encephalopathy”、“DEE”为关键词在Pub Med数据库检索外文文献。总结FZR1基因突变导致的发育性和癫痫性脑病的临床和遗传学特征。结果：患儿，女，2天，因“间断青紫发作8小时”2023年10月就诊于青岛大学附属医院新生儿科。临床表现为：呼吸暂停伴有全身青紫，无明显的四肢肢体抖动，血氧饱和度降至60%，心率波动于70~80次/分。完善基因检测提示其FZR1基因存在c.1292C > T (p.Pro431Leu)位点杂合变异，该突变非新发突变，确诊发育性癫痫性脑病109型。现规律口服苯巴比妥控制。该变异被在线人类孟德尔遗传(OMIM)收录；未被人类基因突变数据库(HGMD)、基因组聚合数据库(gnomAD)中收录。文献检索到中文文献0篇，英文文献2篇，结合本例共5例患者。患者起病年龄不一，2例为新生儿期起病，所有患者均患有癫痫，国外报道4例患者患有神经发育迟缓，3例表现出轻度小脑共济失调，3例存在全面强直痉挛发作。4例国外报道患儿应用4种以上抗癫痫药物且表现出药物难治性。结论：FZR1基因变异导致的发育性癫痫性脑病临床表型类似，起病年龄不一，主要表现为宫内生长发育迟缓，发育不良，头围小，癫痫性脑病，智力发展受损，步态共济失调，脑电图异常，痉挛，脑成像中发现的髓鞘缺陷，轴向张力减退，行为异常，多动症，注意力问题，自闭症等。本例患儿的新生错义突变c.1292C > T既往未见报道，扩充了FZR1基因突变谱。

Abstract: Objective: To explore the clinical and molecular genetic characteristics of a newborn with developmental and epileptic encephalopathy 109. Methods: A retrospective analysis was conducted on the clinical manifestations, imaging, and genetic data of a child with developmental and epileptic encephalopathy 109 (DEE109) caused by FZR1 gene mutations admitted to our hospital in October 2023. Domestic literature was searched in Wanfang Database and CNKI using the keywords “FZR1 gene”, “epileptic encephalopathy”, and “developmental epileptic encephalopathy”. Search for foreign literature in the Pub Med database using keywords such as “FZR1”, “epileptic encephalopathy”, “developmental and epileptic encephalopathy”, and “DEE”. Summarize the clinical and genetic characteristics of developmental and epileptic encephalopathy caused by FZR1 gene mutations. Results: The patient, a female, 2 days old, was admitted to the Department of Neonatology at Qingdao University Affiliated Hospital in October 2023 due to an 8-hour intermittent cyanosis episode. The clinical manifestations are: apnea accompanied by cyanosis throughout the body, no obvious limb tremors, blood oxygen saturation dropping to 60%, and heart rate fluctuating between 70~80 beats per minute. Complete genetic testing suggests that there is a heterozygous mutation at the c.1292C > T (p.Pro431Leu) locus in the FZR1 gene, which is not a novel mutation and confirmed as developmental and epileptic encephalopathy 109. Regular oral administration of phenobarbital for control. This mutation is included in the online Human Mendelian Genetics (OMIM) database but not included in the Human Gene Mutation Database (HGMD) and Genome Aggregation Database (gnomAD). There were 0 Chinese literature and 2 English literature retrieved, and a total of 5 patients were included in this case. The onset age of the patients varies, with 2 cases occurring in the neonatal period and all patients suffering from epilepsy. According to foreign reports, 4 patients had delayed neurological development, 3 showed mild cerebellar ataxia, and 3 had generalized tetanic spasms. Four cases of foreign reported pediatric patients who were treated with four or more antiepileptic drugs and showed drug resistance. Conclusion: The clinical phenotype of developmental epileptic encephalopathy caused by FZR1 gene mutation is similar, with different onset ages. The main manifestations are intrauterine growth and development delay, dysplasia, small head circumference, epileptic encephalopathy, impaired intellectual development, gait ataxia, abnormal electroencephalogram, spasms, myelin defects found in brain imaging, decreased axial tension, behavioral abnormalities, ADHD, attention problems, autism, etc. The newly generated missense mutation c.1292C > T in this patient has not been reported in the past, expanding the FZR1 gene mutation spectrum.