Abstract：
Acute necrotizing encephalopathy (ANE) is a rapidly progressive encephalopathy of unknown etiology. The underlying mechanisms are highly heterogeneous, often including genetic backgrounds. Variants of LARS1, encoding the leucyl-tRNA synthetase 1, are responsible for infantile liver failure syndrome 1. We describe two siblings with ANE caused by compound heterozygous variants of LARS1. Patient 1 was a 17-month-old girl. She presented with generalized seizure and liver dysfunction due to influenza type A infection. Brain magnetic resonance imaging on day 4 of onset showed diffuse high-intensity signals consistent with ANE. She died on day 10. Patient 2, a younger male sibling of patient 1, had mild to moderate developmental delay and growth failure at the age of 18 months. He showed a markedly elevated level of transaminases triggered by infection with human herpesvirus 6. On day 4 of onset, he had generalized seizures. Brain computed tomography showed a diffuse symmetrical hypodensity consistent with ANE. He died on day 7. Whole exome sequencing identified the compound heterozygous variants in LARS1 (NM_020117.11) as c.83_88delinsAATGGGATA, p.(Arg28_Phe30delinsLysTryAspIle) and c.1283C>T, p.(Pro428Leu) in both siblings. The severe neurologic phenotype, found in our patients, reflects the complicated pathogenesis of LARS1-related disorder.
摘要：
急性坏死性脑病（ANE）是一种病因不明的快速进行性脑病。潜在的机制是高度异构的，通常包括遗传背景。编码亮氨酰-tRNA合成酶1的LARS1变体负责婴儿肝衰竭综合征1。我们描述了由LARS1的复合杂合变体引起的具有ANE的两个兄弟姐妹。患者1是一个17个月大的女孩。由于A型流感感染，她出现了全身性癫痫发作和肝功能障碍。发病第4天的脑磁共振成像显示与ANE一致的弥漫性高强度信号。她在第10天去世。患者2,患者1的年轻男性同胞,在18月龄时具有轻度至中度发育延迟和生长障碍。他显示出由人疱疹病毒6感染引发的转氨酶水平显着升高。在发病的第4天，他有全身性癫痫发作。脑计算机断层扫描显示弥漫性对称低密度与ANE一致。他在第七天去世。全外显子组测序将LARS1（NM_020117.11）中的复合杂合变体鉴定为c.83_88delinsAATGGGATA，p.（Arg28_Phe30delinsLysTryAspIle）和c.128C>T，p.（Pro428Leu）在两个兄弟姐妹中。严重的神经系统表型，在我们的病人身上发现的，反映了LARS1相关疾病的复杂发病机制。
