Glutamine synthetase (GS) is the enzyme responsible for the biosynthesis of glutamine, providing the only source of endogenous glutamine necessary for several critical metabolic and developmental pathways. GS deficiency, caused by pathogenic variants in the glutamate‐ammonia ligase (GLUL) gene, is a rare autosomal recessive inborn error of metabolism characterized by systemic glutamine deficiency, persistent moderate hyperammonemia, and clinically devastating seizures and multi‐organ failure shortly after birth. The four cases reported thus far were caused by homozygous GLUL missense variants. We report a case of GS deficiency caused by homozygous GLUL gene deletion, diagnosed prenatally and likely representing the most severe end of the spectrum. We expand the known phenotype of this rare condition with novel dysmorphic, radiographic and neuropathologic features identified on post‐mortem examination. The biallelic deletion identified in this case also included the RNASEL gene and was associated with immune dysfunction in the fetus. This case demonstrates that total absence of the GLUL gene in humans is viable beyond the embryonic period, despite the early embryonic lethality found in GLUL animal models.

中文翻译：

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纯合 GLUL 缺失在胚胎上是可行的，并导致谷氨酰胺合成酶缺乏。

谷氨酰胺合成酶 (GS) 是负责谷氨酰胺生物合成的酶，是几种关键代谢和发育途径所需的内源性谷氨酰胺的唯一来源。由谷氨酸-氨连接酶 ( GLUL)基因中的致病变异引起的 GS 缺乏是一种罕见的常染色体隐性先天性代谢缺陷，其特征是全身性谷氨酰胺缺乏、持续的中度高氨血症以及出生后不久的临床破坏性癫痫发作和多器官衰竭。迄今为止报告的四个病例是由纯合GLUL错义变异引起的。我们报告了一例由纯合GLUL引起的 GS 缺乏症基因缺失，产前诊断，可能代表最严重的范围。我们扩展了这种罕见疾病的已知表型，并在尸检中发现了新的畸形、放射学和神经病理学特征。在这种情况下发现的双等位基因缺失还包括RNASEL基因，并且与胎儿的免疫功能障碍有关。该案例表明，尽管在GLUL动物模型中发现了早期胚胎致死率，但在胚胎期之后，人类完全不存在GLUL基因是可行的。