DNM1基因变异致早发性婴儿癫痫性脑病31型三例并文献复习

DNM1 gene pathogenic variation in 3 cases with early infantile epileptic encephalopathy-31 and Literature review

目的探讨DNM1基因变异导致早发性婴儿癫痫性脑病的临床、基因和预后特征。方法三例经基因检测证实为DNM1基因新发变异的患儿,回顾性分析其临床和基因表型以及预后,并在国内外数据库以“Dynamin-1”或“DNM1”检索相应文献,利用单因素方差方法分析临床和癫痫发作表型、抗癫痫药物疗效与基因变异位点结构域相关性。结果女1例,男2例;癫痫发病年龄2~17月龄,癫痫发作表型:2例为癫痫性痉挛发作,1例为局灶性一侧肢体阵挛或继发强直阵挛发作。基因检测结果显示3例患儿DNM1基因存在新发错义变异,2例为NM_004408.4:c.415 G>A(P.Gly 139Arg),1例为NM_004408.4:c.545 C>A(P.Ala 182Asp),随访至2~3岁时,均为肌张力低下、严重智力障碍、无行走能力和主动语言、耐药性癫痫、不能自主进食和不会咀嚼固体食物。经文献检索,至今国内外报道DNM1基因相关脑病36例,包括本组病例共计39例,肌张力低下与基因变异位点区域无关,GTPase酶结构域和中间区域变异存在严重或显著智力发育障碍。对31例诊断癫痫并且临床资料完整患儿进一步分析发现,癫痫性痉挛发作是常见的癫痫发作形式,变异位点位于GTPase酶结构域和中间区域的两组病例,失神发作在GTPase酶结构域更常见(P=0.02),而在性别、起病年龄、其他癫痫发作形式和药物治疗反应上均无统计学差异。结论肌张力低下、严重智力和运动障碍及早发型癫痫是DNM1相关脑病的主要表现,癫痫性痉挛发作是最常见的发作形式,除失神发作外,GTPase酶结构域和中间区域变异的临床和癫痫表型无明显区别,本组病例尚合并进食障碍。

Objective To explore the clinical,genetic and prognostic features of early infantile epileptic encephalopathy caused by DNM1 gene pathogenic variations.Methods Clinical phenotype,genotype and prognosis of 3 individuals with de novo variants in DNM1 gene were analyzed retrospectively.Through using“Dynamin-1”or“DNM1”as key words to search literature at database of China National Knowledge Infrastructure,Wanfang,PubMed and OMIM.Genotype-phenotype correlations were analyzed by analysis of variance(ANOVA).Result Among the 3 patients,1 female and 2 males.2 cases with epileptic spasm and 1 case with focal clonic seizure or secondary generalized tonic-clonic seizure were manifested with onset age from 2 to 17 months.De novo variants at NM_004408.4:c.415 G>A(P.Gly 139Arg)in 2 inviduals and NM_004408.4:c.545 C>A(P.Ala 182Asp)in 1 invidual of DNM1 gene were identified by gene testing.After follow-up at age of 2~3 years,all patients were presented with hypotonia,severe intellectual disability,non-verbal,non-ambulatory,drug-resistant epilepsy and feeding difficulties.36 cases with pathogenic DNM1 variants were reported by far,totally 39 cases were included.Of the 39 patients,hypotonia were found to be independent of the locus of genetic variants,while those inviduals with variants in the GTPase and middle domains almost presented severe or profound intellectual disability and epilepsy.31 patients diagnosed with epilepsy and complete clinical data were further analyzed,epileptic spasm was the most common types of seizure.Absent seizure was significantly more common in those patients with variants in the GTPase domains(P=0.02),compared to those patients with variants in the middle domains.No statistical differences were found in gender,onset age,other types of seizure and drug treatment response between variants in the GTPase and middle domains.Conclusion Hypotonia,early onset epilepsy,severe intellectual and movement disability were the common features in patients with DMN1 related encephalopathy.Epileptic spasm was the most common types of seizure,no significant differences were found in the phenotype between the GTPase and middle domains expect for absent seizure.Our patients also presented with feeding difficulties.