Although the majority of recognized patients conform to the relatively stereotyped ‘classical’ phenotype just described, there is now an extensive literature reporting a broader spectrum

of disease presentation, progression and outcome. These ‘non-classical’ cases highlight a remarkable paradox relating to the diagnosis of AGS; that is, patients with mutations in the AGS-associated genes are observed frequently to demonstrate the absence of one or more, and even all in rare cases, of the original diagnostic criteria as outlined by Aicardi and Goutières in their 1984 paper [5]. Thus, neurological dysfunction is not always severe Everolimus price nor, indeed, necessarily present at all; microcephaly is not invariable; buy LGK-974 onset is not always in the first year of life; intracranial calcification and white matter changes are not inevitable; and a CSF lymphocytosis is often absent. Importantly,

disparity in the clinical phenotype can be seen even within the same family, thus highlighting the role of modifying factors [6]. With the integration of new sequencing technologies into standard clinical practice, we predict that the spectrum of phenotypes associated with mutations in the AGS-related genes will broaden further. These observations beg the question as to whether such cases should actually be referred to as AGS. The important point is that these phenotypes will probably all relate to a common pathology, and therefore potentially benefit from similar therapeutic strategies. At least relating to the classical presentation of AGS, the period of neurological damage appears to be limited to an initial encephalopathic phase, generally lasting for

a period of a few months, after which further disease progression is apparently unusual. This important statement is based on the testament of many families with affected children, and the follow-up of a number of children into adulthood. Thus, although we are aware of some Rebamipide patients seeming to experience intermittent ‘decompensations’, we believe that in most cases AGS can be considered to follow a non-regressive course. Although, in our view, AGS is generally non-progressive, it is of note that chilblains, seen in approximately 40% of cases, frequently persist/recur, particularly so in the winter months [7, 8]; and an inflammatory intracranial large-vessel phenotype, which has so far been recorded only in patients with mutations in SAMHD1, seems to constitute an ongoing disease risk [9-12]. We have also observed frank autoimmune disease, albeit in a minority of cases. Thus, at least some aspects of the AGS phenotype appear to be ongoing (Fig. 1). How the AGS-associated disease process is triggered, and apparently ‘abates’ neurologically (while the skin disease is frequently recurrent), and whether or not certain patients (e.g.