Cerebral arteriopathy in ACTA2 mutations: a spectrum of disease highlighted by a case of variable penetrance in two siblings

Until recently, cerebral arteriopathy due to heterozygous mutations of the ACTA2 gene was considered a variant of moyamoya disease. However, radiographic analysis of patients with these mutations reveals a distinctive angiographic appearance from that seen in moyamoya disease. Several heterozygous missense ACTA2 mutations have been implicated in the development of this distinct cerebrovascular entity; however, the penetrance and systemic manifestations of these mutations vary based on the location of the amino acid replacement within the α-smooth muscle actin protein. The severity of the phenotype may also differ among patients within a single mutation type. There is limited literature on the safety and efficacy of revascularization procedures for ACTA2 arteriopathy, which have been limited to those patients with known Arg179His mutations. The authors provide a review of the breadth of mutations within the ACTA2 literature and report a case of two siblings with de novo ACTA2 Arg258Cys mutations with differing clinical courses, highlighting the utility of indirect revascularization with 8-year follow-up data. This case highlights the importance of early recognition of the angiographic appearance of ACTA2 cerebral arteriopathy and performance of genetic testing, as the location of the mutation impacts clinical presentation and outcomes.