BACKGROUND Aicardi-Goutières syndrome (AGS) is a clinically and genetically heterogenous autoinflammatory disorder caused by constitutive activation of the type I interferon axis. It has been associated with the genes TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, IFIH1. The clinical diagnosis of AGS is usually made in the context of early-onset encephalopathy in combination with basal ganglia calcification or white matter abnormalities on cranial MRI and laboratory prove of interferon I activation. CASE PRESENTATION We report a patient with early-onset encephalopathy, severe neurodevelopmental regression, progressive secondary microcephaly, epilepsy, movement disorder, and white matter hyperintensities on T2 weighted MRI images. Via whole-exome sequencing, we identified a novel homozygous missense variant (c.1399C > T, p.Pro467Ser) in PNPT1 (NM_033109). Longitudinal assessment of the interferon signature showed a massively elevated interferon score and chronic type I interferon-mediated autoinflammation. CONCLUSION Bi-allelic mutations in PNPT1 have been reported in early-onset encephalopathy. Insufficient nuclear RNA import into mitochondria with consecutive disruption of the respiratory chain was proposed as the main underlying pathomechanism. Recent studies have shown that PNPT1 deficiency causes an accumulation of double-stranded mtRNAs in the cytoplasm, leading to aberrant type I interferon activation, however, longitudinal assessment has been lacking. Here, we present a case of AGS with continuously elevated type I interferon signature with a novel likely-pathogenic homozygous PNTP1 variant. We highlight the clinical value of assessing the interferon signature in children with encephalopathy of unknown origin and suggest all patients presenting with a phenotype of AGS should be screened for mutations in PNPT1.

中文翻译：

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PNPT1 突变可能导致 Aicardi-Goutières-Syndrome

背景 Aicardi-Goutières 综合征 (AGS) 是一种由 I 型干扰素轴组成性激活引起的临床和遗传异质性自身炎症性疾病。它与基因 TREX1、RNASEH2A、RNASEH2B、RNASEH2C、SAMHD1、ADAR1、IFIH1 相关。AGS 的临床诊断通常是在早发性脑病合并基底节钙化或颅 MRI 白质异常和实验室证明干扰素 I 激活的情况下做出的。案例展示 我们报告了一名患有早发性脑病、严重神经发育退化、进行性继发性小头畸形、癫痫、运动障碍和 T2 加权 MRI 图像上白质高信号的患者。通过全外显子组测序，我们确定了一个新的纯合错义变异（c.1399C > T，p. Pro467Ser) 在 PNPT1 (NM_033109) 中。干扰素特征的纵向评估显示干扰素评分大幅升高和慢性 I 型干扰素介导的自身炎症。结论 早发性脑病中已经报道了 PNPT1 中的双等位基因突变。核 RNA 进入线粒体的不足以及呼吸链的连续中断被认为是主要的潜在病理机制。最近的研究表明，PNPT1 缺陷导致双链 mtRNA 在细胞质中的积累，导致异常的 I 型干扰素激活，然而，缺乏纵向评估。在这里，我们介绍了一个具有持续升高的 I 型干扰素特征的 AGS 病例，并带有一种新的可能致病的纯合 PNTP1 变体。