Aicardi-Goutières syndrome (AGS)
https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1453496/full
This study explored a four-generation family carrying a specific change in the ADAR gene (c.3019G>A) to understand how it affects the immune system and the brain. The ADAR gene normally helps regulate the body’s immune response by editing RNA, and when it doesn’t function properly, the immune system may become overactive and produce too much type-I interferon, which can harm the nervous system. In this family, two individuals with the mutation developed serious neurological symptoms, such as muscle weakness, difficulty walking, and developmental decline, and both showed high levels of interferon in their blood. However, five other relatives with the same mutation had no symptoms, even though many of them also had elevated interferon activity. This reveals “incomplete penetrance”, meaning not everyone with the mutation becomes ill, and “variable expressivity”, where symptoms differ widely among those who are affected. In summary, the study shows that this ADAR variant increases the risk of neurological disease but does not guarantee it will occur. Monitoring interferon levels may help identify individuals at risk before symptoms start, and in the future, treatments that target the interferon pathway could help prevent or reduce damage. These findings highlight the importance of combining genetic testing with immune system monitoring to improve early diagnosis and personalised treatment strategies.