Pan Z, Wu T H, Chen C, Peng P, He Y W, Yi W Z, Yin F, Peng J
Department of Pediatrics, Hunan Intellectual and Developmental Disabilities Research Center, Xiangya Hospital of Central South University, Changsha 410008, China.
Department of Pediatrics, the People's Hospital of Hunan, Changsha 410005, China.
Zhonghua Er Ke Za Zhi. 2021 May 2;59(5):400-406. doi: 10.3760/cma.j.cn112140-20200921-00893.
To investigate the clinical characteristics of R403C variant in DNM1L gene caused encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1 (EMPF1). The clinical data of three patients, who carried R403C variant in the DNM1L gene, diagnosed at Xiangya Hospital from February 2018 to February 2020 were retrospectively summarized. Literature reviewing was performed by taking "DNM1L" or "encephalopathy, lethal, due to defective mitochondrial peroxisomal fission 1" as keywords for searching in online Mendelian inheritance in man (OMIM), PubMed, China national knowledge infrastructure (CNKI), and Wanfang data knowledge service platform up to July 2020. And the clinical manifestation, laboratory examination, imaging, treatment, and prognosis were reviewed. Case 1, a 7-year-old boy, developed seizures after a 9-day course of cough without fever. The seizures manifested as generalized tonic-clonic seizures (GTCS) and soon converted to focal status epilepticus (EPC) or focal myoclonus, which were resistant to multi-anti-epileptic drugs combined with sedative drugs. The boy died at the 2 week after seizure onset. Case 2, also a 7-year-old boy, developed seizures after a 10-day history of amygdalitis. The seizures manifested as focal to generalized tonic-clonic seizure and then converted to EPC or focal myoclonus. And all seizures showed poor responses to multi-anti-epileptic drugs combined with sedative drugs, ketogenic diet, and methylprednisolone treatment. The boy died after 1 month's treatment. Case 3, a 3-year and 5-month old girl, had seizures onset after a 2-week course of viral pneumonia. The seizures onset manifested as focal clonic seizure and converted to EPC, shortly. She was resistant to multi-anti-epiletic drugs combined with sedative drugs and ketogenic treatment. The girl died 3 months afte seizure onset. All of their images showed multifocal T1 low, T2, fluid attenuated inversion recovery, and diffusion-weighted imaging high signal lesions among the brain, and diffuse brain atrophy in case 3. The blood metabolic and cerebrospinal-fluid immunological assays were normal. Genetic analysis suggested a de novo, heterozygous, NM_012062.4: c.1207C>T, p.R403C variant in the DNM1L gene. According to their clinical manifestations, all of them were diagnosed with EMPF1. Literature review included 11 patients carrying this variant in the world. Summarizing the 14 cases, 8 cases had an infectious history before seizure onset, 8 cases had mild or moderate development delay. All of 14 cases had seizures, and the forms mainly included EPC (=9), focal myoclonus (=6), GTCS (=5) and focal clonic seizures (=4). All of them were refractory, and no effective anti-epileptic drugs were recommended. Early-stage cranial magnetic resonance imaging results showed multiple intracranial focal lesions (=10), including thalamus (=7), hippocampus (=5), basal ganglia (=4), frontal lobe (=3), and temporal lobe (=2). As the disease progressed, the brain manifested as diffused progressive atrophy (=10). Five of the 14 cases died at reported age. R403C variant in the DNM1L gene can cause mitochondrial fission dysfunction. Patients carrying this variant may manifest as refractory status epilepticus with or without mild-infection indction, development regression and brain atrophy.
为研究因线粒体过氧化物酶体分裂缺陷1（EMPF1）导致的致死性脑病中DNM1L基因R403C变异的临床特征。回顾性总结了2018年2月至2020年2月在湘雅医院确诊的3例携带DNM1L基因R403C变异患者的临床资料。以“DNM1L”或“因线粒体过氧化物酶体分裂缺陷1导致的致死性脑病”为关键词，在人类孟德尔遗传在线（OMIM）、PubMed、中国知网（CNKI）和万方数据知识服务平台进行文献检索，检索截至2020年7月，并对临床表现、实验室检查、影像学、治疗及预后进行了综述。病例1，一名7岁男孩，在无发热的9天咳嗽病程后出现癫痫发作。癫痫发作表现为全身强直阵挛发作（GTCS），很快转变为局灶性癫痫持续状态（EPC）或局灶性肌阵挛，对多种抗癫痫药物联合镇静药物治疗无效。该男孩在癫痫发作后2周死亡。病例2，也是一名7岁男孩，在有10天扁桃体炎病史后出现癫痫发作。癫痫发作表现为从局灶性发作发展为全身强直阵挛发作，然后转变为EPC或局灶性肌阵挛。所有癫痫发作对多种抗癫痫药物联合镇静药物、生酮饮食及甲泼尼龙治疗反应均不佳。该男孩在治疗1个月后死亡。病例3，一名3岁5个月大的女孩，在2周病毒性肺炎病程后出现癫痫发作。癫痫发作表现为局灶性阵挛发作，很快转变为EPC。她对多种抗癫痫药物联合镇静药物及生酮治疗均耐药。该女孩在癫痫发作后3个月死亡。他们所有人的影像学检查均显示脑内多发T1低信号、T2、液体衰减反转恢复序列及扩散加权成像高信号病灶，病例3有弥漫性脑萎缩。血液代谢及脑脊液免疫学检测均正常。基因分析提示DNM1L基因存在新发杂合变异NM_012062.4:c.1207C>T，p.R403C。根据临床表现，他们均被诊断为EMPF1。文献复习纳入了全球11例携带该变异的患者。总结这14例病例，8例在癫痫发作前有感染史，8例有轻度或中度发育迟缓。14例均有癫痫发作，发作形式主要包括EPC（9例）、局灶性肌阵挛（6例）、GTCS（5例）和局灶性阵挛发作（4例）。所有病例均为难治性癫痫，未推荐有效的抗癫痫药物。早期头颅磁共振成像结果显示颅内多发局灶性病变（10例），包括丘脑（7例）、海马（5例）、基底节（4例）、额叶（3例）和颞叶（2例）。随着疾病进展，脑表现为弥漫性进行性萎缩（10例）。14例中有5例在报道年龄时死亡。DNM1L基因R403C变异可导致线粒体分裂功能障碍。携带该变异的患者可能表现为难治性癫痫持续状态，可伴有或不伴有轻度感染诱因、发育倒退及脑萎缩。
