Two siblings with acute necrotizing encephalopathy associated with variants of LARS1

IF 1.7 4区 生物学 Q3 GENETICS & HEREDITY
Takeshi Uehara, Eijun Seki, Yutaka Nonoda, Tatsuro Kumaki, Yu Tsuyusaki, Noriko Aida, Yumi Enomoto, Kenji Ishikura, Kenji Kurosawa
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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.

两兄妹患有与 LARS1 变异有关的急性坏死性脑病。
急性坏死性脑病(ANE)是一种病因不明的快速进展性脑病。其发病机制非常复杂,通常包括遗传背景。编码亮氨酰-tRNA合成酶1的LARS1变体是导致婴儿肝衰竭综合征1的原因。我们描述了两对因 LARS1 复合杂合子变异而导致 ANE 的兄妹。患者1是一名17个月大的女孩。她因感染甲型流感而出现全身抽搐和肝功能异常。发病第 4 天,脑磁共振成像显示与 ANE 一致的弥漫性高强度信号。她于第 10 天死亡。患者 2 是患者 1 年幼的男性兄弟姐妹,18 个月大时出现轻度至中度发育迟缓和生长迟缓。他因感染人类疱疹病毒 6 而导致转氨酶水平明显升高。发病第 4 天,他出现全身抽搐。脑部计算机断层扫描显示,弥漫性对称性低密度与ANE一致。他于第 7 天死亡。全外显子测序确定了两个兄弟姐妹的 LARS1(NM_020117.11)复合杂合变异为 c.83_88delinsAATGGATA,p.(Arg28_Phe30delinsLysTryAspIle) 和 c.1283C>T,p.(Pro428Leu)。在我们的患者中发现的严重神经系统表型反映了 LARS1 相关疾病的复杂发病机制。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
CiteScore
3.50
自引率
5.00%
发文量
432
审稿时长
2-4 weeks
期刊介绍: The American Journal of Medical Genetics - Part A (AJMG) gives you continuous coverage of all biological and medical aspects of genetic disorders and birth defects, as well as in-depth documentation of phenotype analysis within the current context of genotype/phenotype correlations. In addition to Part A , AJMG also publishes two other parts: Part B: Neuropsychiatric Genetics , covering experimental and clinical investigations of the genetic mechanisms underlying neurologic and psychiatric disorders. Part C: Seminars in Medical Genetics , guest-edited collections of thematic reviews of topical interest to the readership of AJMG .
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