Aberrant induction of type I IFN is a hallmark of the inherited encephalopathy Aicardi-Goutières syndrome (AGS), but the mechanisms triggering disease in the human central nervous system (CNS) remain elusive. Here, we generated human models of AGS using genetically modified and patient-derived pluripotent stem cells harboring TREX1 or RNASEH2B loss-of-function alleles. Genome-wide transcriptomic analysis reveals that spontaneous proinflammatory activation in AGS astrocytes initiates signaling cascades impacting multiple CNS cell subsets analyzed at the single-cell level. We identify accumulating DNA damage, with elevated R-loop and micronuclei formation, as a driver of STING- and NLRP3-related inflammatory responses leading to the secretion of neurotoxic mediators. Importantly, pharmacological inhibition of proapoptotic or inflammatory cascades in AGS astrocytes prevents neurotoxicity without apparent impact on their increased type I IFN responses. Together, our work identifies DNA damage as a major driver of neurotoxic inflammation in AGS astrocytes, suggests a role for AGS gene products in R-loop homeostasis, and identifies common denominators of disease that can be targeted to prevent astrocyte-mediated neurotoxicity in AGS.

Duchenne muscular dystrophy (DMD) is a severe genetic disorder characterized by progressive muscle degeneration, with respiratory and cardiac complications, caused by mutations in the DMD gene, encoding the protein dystrophin. Various DMD mutations result in different phenotypes and disease severity. Understanding genotype/phenotype correlations is essential to optimize clinical care, as mutation-specific therapies and innovative therapeutic approaches are becoming available. Disease modifier genes, trans-active variants influencing disease severity and phenotypic expressivity, may modulate the response to therapy, and become new therapeutic targets. Uncovering more disease modifier genes via extensive genomic mapping studies offers the potential to fine-tune prognostic assessments for individuals with DMD. This review provides insights into genotype/phenotype correlations and the influence of modifier genes in DMD.

Background/Objectives: The clinical management of hemophilia has evolved with the introduction of innovative therapies that are reshaping treatment paradigms. Real-world implementation of these approaches may vary across centers. This modified Delphi consensus study aimed to explore current clinical perspectives on hemophilia management in Italy among healthcare professionals. Methods: Eight hemophilia experts developed 38 statements covering seven domains, including therapeutic personalization, adherence and patient engagement, follow-up strategies, inhibitor management, comorbidity management in patients, musculoskeletal monitoring, and organizational aspects of care. Statements were evaluated through an anonymous web-based survey in a modified single-round Delphi process using a 5-point Likert scale. Consensus was defined a priori as ≥70% agreement or disagreement after exclusion of neutral responses. Results: Thirty-four clinicians from specialized hemophilia centers participated in the survey. Strong agreement emerged regarding the importance of personalized treatment strategies, active patient involvement in therapeutic decisions, and multidisciplinary management, particularly in ageing patients with comorbidities. Panelists also supported the role of joint ultrasound in monitoring musculoskeletal health and highlighted adherence as a key determinant of treatment outcomes. Areas of heterogeneity included criteria for transitioning between intravenous and subcutaneous therapies, the implementation of structured transition programs from pediatric to adult care, and the frequency of musculoskeletal imaging. Limited availability of psychological support and variable integration of patient-reported outcomes were also identified. Conclusions: Italian hemophilia specialists showed substantial agreement across key domains; however, future work should address remaining organizational and clinical gaps and incorporate patient perspectives to support more integrated and patient-centered management strategies for people with hemophilia.