A familial missense ACTA2 variant p.Arg198Cys leading to Moyamoya-like arteriopathy with straight course of the intracranial arteries, aortic aneurysm and lethal aortic dissection.

Background: Cerebral vasculopathies frequently lead to severe medical conditions such as stroke or intracranial hemorrhage and have a broad range of possible etiologies that require different therapeutic regimens. However, vasculopathies sometimes present with characteristic angiographic findings, that - if recognized - can guide a more specific diagnostic work-up. Certain ACTA2 variants are associated with a distinctive cerebrovascular phenotype characterized by an anomalously straight course of intracranial arteries, dilatation of proximal ICA and stenosis of distal ICA, in the absence of a compensatory basal collateral network found in Moyamoya disease. Until recently, this ACTA2 cerebral arteriopathy has been reported only in ACTA2 variants impairing Arg179.

Methods and materials: We report a familial case of a missense ACTA2 variant p.Arg198Cys with angiographic features of an ACTA2 cerebral arteriopathy. We analyzed the neuroimaging features of all four variant carrying family members and discussed the cerebrovascular abnormalities we found on the background of the current literature on ACTA2 arteriopathies.

Results: Neuroimaging of the variant carriers revealed angiographic abnormalities characteristic for ACTA2 cerebral arteriopathy such as stenoses of the terminal internal carotid artery, occlusion of the proximal middle cerebral artery and an anomalously straight course of the intracranial arteries. In our index patient catheter angiography showed a Moyamoya-like basal collateral network alongside with the above-mentioned features of an ACTA2 cerebral arteriopathy. The detected missense ACTA2 variant p.Arg198Cys was not known to be associated a cerebral arteriopathy, so far. One of the patients later died from aortic dissection - a common vascular complication of ACTA2 variants.

Conclusion: The familial case expands the phenotype of the detected ACTA2 variant p.Arg198Cys and hereby broadens the range of ACTA2 variants associated with a cerebral arteriopathy. Further, it emphasizes the importance of an interdisciplinary approach of vasculopathies.