Intracerebral large artery disease in Aicardi–Goutières syndrome implicates SAMHD1 in vascular homeostasis

Abstract

AGS Aicardi-Goutires syndromeAIM To describe a spectrum of intracerebral large artery disease in Aicardi-Goutiè res syndrome (AGS) associated with mutations in the AGS5 gene SAMHD1. METHODWe used clinical and radiological description and molecular analysis. RESULTS Five individuals (three males, two females) were identified as having biallelic mutations in SAMHD1 and a cerebral arteriopathy in association with peripheral vessel involvement resulting in chilblains and ischaemic ulceration. The cerebral vasculopathy was primarily occlusive in three patients (with terminal carotid occlusion and basal collaterals reminiscent of moyamoya syndrome) and aneurysmal in two. Three of the five patients experienced intracerebral haemorrhage, which was fatal in two individuals. Post-mortem examination of one patient suggested that the arteriopathy was inflammatory in origin.INTERPRETATION Mutations in SAMHD1 are associated with a cerebral vasculopathy which is likely to have an inflammatory aetiology. A similar disease has not been observed in patients with mutations in AGS1 to AGS4, suggesting a particular role for SAMHD1 in vascular homeostasis. Our report raises important questions about the management of patients with mutations in SAMHD1.

Phenotypic Variation in Aicardi–Goutières Syndrome Explained by Cell-Specific IFN-Stimulated Gene Response and Cytokine Release

“…Recent clinical reports have described the presence of cerebrovascular disease, including ischemic and hemorrhagic strokes, in AGS patients carrying mutations for different genes (24)(25)(26)(27)(28). These clinical observations tie in with findings from our group describing that human astrocytes chronically exposed to IFN-a decrease the expression and release of proangiogenic and vascular trophic factors (21).…”

Neuroradiologic patterns and novel imaging findings in Aicardi-Goutières syndrome

“…Specifically, each AGS gene has different functions; therefore, we can expect differences in the pathogenesis and ultimately in the neuroradiologic picture in relation to the mutated gene. 9,19,21,23,24 We observed a significantly higher prevalence of frontotemporal white matter rarefaction and severe calcification in patients with TREX1 mutations and early age at onset. Mutated TREX1 was also associated with cysts outside the frontotemporal region.…”

Characterization of samhd1 Morphant Zebrafish Recapitulates Features of the Human Type I Interferonopathy Aicardi-Goutières Syndrome

“…In addition to the severe brain damage, likely occurring secondary to a microangiopathic process, which is common to all forms of AGS, SAMHD1 mutations also result in an apparently gene-specific cerebral vasculopathic phenotype frequently leading to intracerebral hemorrhage during early life (10)(11)(12)(13). As with all subtypes of the disorder, AGS5 is associated with a significant upregulation of ISGs (2).…”

“…It has been proposed that in SAMHD1-related AGS (AGS5), loss of SAMHD1 function leads to cytoplasmic accumulation of DNA derived from the reverse transcription of endogenous retroelements, which in turn induces an IFN response. Clinically, AGS5 differs from other AGS subtypes in that many patients demonstrate a distinct cerebral vasculopathy (10)(11)(12)(13). Remarkably, this vascular phenotype can manifest as both stenotic (vessel narrowing, leading to a moyamoya appearance) and aneurysmal (vessel bulging) disease, which carry a high risk of intracerebral hemorrhage and stroke.…”