Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Center for Molecular Medicine Cologne, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
Department of Pediatrics, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
Brain Dev. 2021 Feb;43(2):320-324. doi: 10.1016/j.braindev.2020.10.005. Epub 2020 Nov 4.
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.
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.
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.
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 TREX1、RNASEH2A、RNASEH2B、RNASEH2C、SAMHD1、ADAR1 和 IFIH1 基因相关。AGS 的临床诊断通常是在伴有基底节钙化或头颅 MRI 上白质异常的早发性脑病的背景下做出的，并且实验室证明 I 型干扰素激活。
我们报告了一例早发性脑病患者，表现为严重的神经发育倒退、进行性继发性小头畸形、癫痫、运动障碍和 T2 加权 MRI 图像上的白质高信号。通过全外显子组测序，我们在 PNPT1（NM_033109）中发现了一种新的纯合错义变异（c.1399C>T，p.Pro467Ser）。干扰素特征的纵向评估显示干扰素评分显著升高和慢性 I 型干扰素介导的自身炎症。
PNPT1 的双等位基因突变已在早发性脑病中报道。据推测，核 RNA 向线粒体的输入不足导致呼吸链中断是主要的潜在发病机制。最近的研究表明，PNPT1 缺乏会导致双链 mtRNA 在细胞质中积累，导致异常的 I 型干扰素激活，但缺乏纵向评估。在这里，我们报告了一例 AGS 病例，其 I 型干扰素特征持续升高，伴有新的可能致病性纯合 PNTP1 变异。我们强调了在原因不明的脑病患儿中评估干扰素特征的临床价值，并建议所有表现为 AGS 表型的患者均应筛查 PNPT1 突变。
