The precise Epacadostat mechanisms relating RNASEH2, SAMHD1 and ADAR1 dysfunction to the AGS phenotype remain to be clarified. Of particular note, unlike the other AGS-related proteins, the RNASEH2 complex is not induced by interferon, and the RNaseH2B knock-out

mouse does not demonstrate an obvious up-regulation of innate immune signaling [28]. However, clinical and biochemical (see below) overlap observed in human studies across the six disease-associated genotypes leads us to predict that the pathogenesis of all forms of AGS relates to inappropriate stimulation of the innate immune system by nucleic acids. Because of already-accrued neurological damage, and also because of recognized intrafamilial variability, it will be difficult to monitor treatment efficacy using only clinical/radiological

criteria in the context of early, proof-of-principle clinical trials. Rather, it would be ideal to assess the effects of therapy by assaying a reactive biomarker. As discussed above, AGS is associated with increased levels of interferon alpha in the CSF and serum. Interferon alpha levels and white cell counts in the CSF of AGS patients have been reported to fall during the first few years of life, perhaps corresponding with the apparent ‘burning-out’ of the encephalopathic period already described [29]. However, due Z-VAD-FMK cost to the obvious difficulties of repeat CSF sampling, very few serial data are available

(i.e. systematic interferon alpha profiling beyond infancy has not been undertaken). Of significance, in currently unpublished data we have observed that >90% of AGS patients, of any genotype, sampled at any age, demonstrate a so-called ‘interferon signature’, i.e. increased expression of multiple type I interferon-stimulated genes (ISGs), in whole blood. Beyond the interesting biological questions that our findings raise, most particularly why we observe a persistent interferon signature when the disease is, apparently, ‘clinically quiescent’ (see earlier), we propose that the level of ISGs measured in blood samples from patients with AGS might Thiamine-diphosphate kinase be used as a biomarker of disease activity, and potentially of treatment efficacy. Other cytokines and chemokines are also increased in the CSF and serum of AGS subjects and may, similarly, be considered as possible biomarkers for the future assessment of therapeutic effect. Of note, for some patients/families, chilblains are a major disease-associated problem (e.g. precluding the use of splinting for the prevention of contractures). Because of their visibility, chilblain status could possibly also serve as an indicator of treatment efficacy. It is clear that AGS is a disorder of inappropriate immune activation, demonstrating some characteristics of both autoinflammatory and autoimmune disease.