Clinical Characterization of a Multicenter International Cohort of Patients With Aicardi-Goutières Syndrome Homozygous for the RNASEH2B:p.Ala177Thr Variant: Early Clinical Markers of Disease Severity

IF 2.1 3区医学 Q2 CLINICAL NEUROLOGY

Pediatric neurology Pub Date : 2025-07-25 DOI:10.1016/j.pediatrneurol.2025.07.011

Costanza Varesio MD, PhD , Davide Politano MD , Laura Adang MD, PhD , Elena Ballante MD, PhD , Roberta Battini MD, PhD , Enrico Bertini MD , Renato Borgatti MD , Valentina De Giorgis MD, PhD , Annamaria Del Boca MD , Francesca Dragoni PhD , Elisa Fazzi MD, PhD , Jessica Galli MD, PhD , Jessica Garau PhD , Francesco Gavazzi MD, PhD , Alice Gardani MSc , Roberta La Piana MD, PhD , Isabella Moroni MD , Francesco Nicita MD, PhD , Anna Pichiecchio MD , Antonella Pini MD, PhD , Simona Orcesi MD

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引用次数: 0

Abstract

Background

Aicardi-Goutières syndrome (AGS) is a rare monogenic leukodystrophy belonging to type I interferonopathies caused by alterations in one of nine genes. Among them, homozygous RNASEH2B:c.529G>A(p.Ala177Thr) is the most common variant worldwide and associated to AGS2. This variant typically leads to severe phenotypes, but individuals with later onset or milder clinical manifestations have been described, with recent finding of asymptomatic homozygous individuals. However, the cause for this intragenotypic clinical variability is unclear, as well as developmental trajectories and early prognostic factors. Our study objective is the description of phenotypic variability in patients with AGS2 and the identification of early clinical markers of prognosis.

Methods

A multicenter international retrospective natural history study was carried out by recruiting patients with AGS homozygous for p.Ala177Thr variant. Patients were categorized into three groups based on the clinical severity through the composite functional severity score, although comparison was made with the more recently introduced AGS severity score. Disease onset was divided into neonatal, infantile, and later onset. Demographic, clinical, and laboratory data were collected and compared between these groups.

Results

Irritability at onset correlates significantly to the three functional categories. Early age at onset and presence of extrapyramidal signs correlate to functional outcomes when comparing mild with severe patients. Furthermore, retrospective application of AGS severity score correlated well with the commonly used composite functional severity score.

Conclusion

The authors observed irritability, early onset, and extrapyramidal signs not to be exclusive to the severe group, hence the need for creation of a composite predictive biomarker for prognosis accuracy.

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aicardii - gouti综合征纯合子RNASEH2B多中心国际队列患者的临床特征。Ala177Thr变异：疾病严重程度的早期临床标志

背景：daicardii - gouti综合征（AGS）是一种罕见的单基因白质营养不良，属于I型干扰素病变，由9个基因之一的改变引起。其中，纯合子RNASEH2B:c.529G>；A（p.Ala177Thr）是世界范围内最常见的变异，与AGS2相关。这种变异通常导致严重的表型，但也有发病较晚或临床表现较轻的个体，最近发现了无症状的纯合子个体。然而，这种异型内临床变异性的原因以及发育轨迹和早期预后因素尚不清楚。我们的研究目的是描述AGS2患者的表型变异性，并确定预后的早期临床标志物。方法招募p.a ala177thr变异AGS纯合子患者，开展多中心国际回顾性自然病史研究。通过综合功能严重程度评分将患者根据临床严重程度分为三组，尽管与最近引入的AGS严重程度评分进行了比较。发病分为新生儿期、婴儿期和晚发病。收集这些组之间的人口学、临床和实验室数据并进行比较。结果起病时的可燃性与三种功能类别有显著相关性。发病年龄早和锥体外系体征的存在与轻、重度患者的功能结局相关。此外，回顾性应用AGS严重程度评分与常用的复合功能严重程度评分具有良好的相关性。结论作者观察到易怒、早发和锥体外系症状并非重症组独有，因此需要建立一种复合预测生物标志物来预测预后的准确性。

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

Pediatric neurology 医学-临床神经学

CiteScore

4.80

自引率

2.60%

发文量

176

审稿时长

78 days

期刊介绍： Pediatric Neurology publishes timely peer-reviewed clinical and research articles covering all aspects of the developing nervous system. Pediatric Neurology features up-to-the-minute publication of the latest advances in the diagnosis, management, and treatment of pediatric neurologic disorders. The journal''s editor, E. Steve Roach, in conjunction with the team of Associate Editors, heads an internationally recognized editorial board, ensuring the most authoritative and extensive coverage of the field. Among the topics covered are: epilepsy, mitochondrial diseases, congenital malformations, chromosomopathies, peripheral neuropathies, perinatal and childhood stroke, cerebral palsy, as well as other diseases affecting the developing nervous system.