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
- PMID: 40812004
- DOI: 10.1016/j.pediatrneurol.2025.07.011
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
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.
Keywords: Aicardi-Goutières syndrome; Disease severity; IFN signature; RNASEH2B; Type I interferonopathy.
Copyright © 2025 The Author(s). Published by Elsevier Inc. All rights reserved.
Conflict of interest statement
Declaration of competing interest Vanderver, Gavazzi, and Adang have licensed the AGS scale and received funding for AGS research from Biogen, Eli Lilly, and Boehringer Ingelheim without any personal compensation. Del Boca, Politano, Galli, Fazzi, Tonduti, and Orcesi participate in a clinical trial by Transposon Therapeutics, Inc for patients with AGS without any personal compensation. Borgatti, Orcesi, and Battini report financial support was provided by Ministry of Health. Adang, Gavazzi, Vanderver, Del Boca, Politano, Garau, Dragoni, Galli, Fazzi, and Orcesi report financial support was provided by National Institutes of Health. Vanderver, Adang, and Gavazzi report relationships with Biogen, Eli Lilly, and Boehringer Ingelheim that include funding grants. Del Boca, Politano, Galli, Fazzi, Tonduti, and Orcesi report a relationship with Transposon Therapeutics, Inc that includes funding grants. The remaining authors declare that there are no conflicts of interests regarding the publication of this article.
