Clinical spectrum and currently available treatment of type I interferonopathy Aicardi-Goutières syndrome

Abstract

Background: Aicardi-Goutières syndrome (AGS) is a genetically determined disorder with a variable phenotype. Since the original description of AGS, advances in gene sequencing techniques have resulted in a significant broadening of the phenotypic spectrum associated with AGS genes, and new clinical pictures have emerged beyond the classic presentation. The aim of this review is to provide a comprehensive analysis of the clinical spectrum of AGS and report currently available treatments and new immunosuppressive strategies.

Data sources: Literature reviews and original research articles were collected from databases, including PubMed and ClinicalTrials.gov. Relevant articles about AGS were included.

Results: The involvement of the nervous system certainly represents the major cause of mortality and morbidity in AGS patients. However, other clinical manifestations, such as chilblains, hepatosplenomegaly, and hematological disturbances, may lead to the diagnosis and considerably impact the prognosis and overall quality of life of these patients. Therapeutic approaches of AGS are limited to interventions aimed at specific symptoms and the management of multiple comorbidities. However, advances in understanding the pathogenesis of AGS could open new and more effective therapies.

Conclusions: The over-activation of innate immunity due to upregulated interferon production plays a critical role in AGS, leading to multi-organ damage with the main involvement of the central nervous system. To date, there is no specific and effective treatment for AGS. New drugs specifically targeting the interferon pathway may bring new hope to AGS patients.

Keywords: Aicardi–Goutières syndrome; Immunosuppressive drugs; Interferon-α; Neuroinflammation; Systemic lupus erythematosus.

Fig. 1

dsDNA interacts with cyclic GMP–AMP synthase (cGAS), which converts ATP and GTP to the second messenger 2′3′ cyclic GMP–AMP (cGAMP). In the endoplasmic reticulum, cGAMP binds and activates STING, leading to activation and phosphorylation of IRF3 by TANK-binding kinase 1. IRF3 forms homodimers and trans-locates into the nucleus to induce type I IFN expression. The RNA sensing pathway is also involved in AGS as a result of activation of the MDA5/MAVS pathway. STING stimulator of interferon genes, IRF3 interferon regulatory transcription factor 3, IFN interferon, AGS Aicardi–Goutières syndrome, MDA5 melanoma differentiation-associated gene 5, MAVS mitochondrial antiviral signaling