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Aim To describe a spectrum of intracerebral large artery disease in Aicardi-Goutières syndrome (AGS) associated with mutations in the AGS5 gene SAMHD1. Method We 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. [ABSTRACT FROM AUTHOR]

We report on two siblings doubly heterozygous for null mutations in the recently identified AGS5 gene SAMHD1. The older female child showed mild intellectual disability with microcephaly. Her brother demonstrated a significant spastic paraparesis with normal intellect and head size. Both children had an unclassified chronic inflammatory skin condition with chilblains, and recurrent mouth ulcers. One child had a chronic progressive deforming arthropathy of the small and large joints, with secondary contractures. This family illustrate the remarkable phenotypic diversity accruing from mutations in genes associated with Aicardi-Goutières syndrome (AGS). The association of arthropathy with SAMHD1 mutations highlights a phenotypic overlap of AGS with familial autoinflammatory disorders such as chronic infantile neurological cutaneous and articular syndrome (CINCA). This family therefore illustrate the need to consider mutation analysis of SAMHD1 in non-specific inflammatory phenotypes of childhood. We propose that arthropathy with progressive contractures should now be considered part of the spectrum of Aicardi-Goutières syndrome because of SAMHD1 mutations., ((c) 2010 Wiley-Liss, Inc.)