<b><i>ACTA2</i></b> Cerebral Arteriopathy: Not Just a Puff of Smoke

Abstract

Background: Missense mutations in the gene that codes for smooth muscle actin, ACTA2, cause diffuse smooth muscle dysfunction and a distinct cerebral arteriopathy collectively known as multisystemic smooth muscle dysfunction syndrome (MSMDS). Until recently, ACTA2 cerebral arteriopathy was considered to be a variant of moyamoya disease. However, recent basic science and clinical data have demonstrated that the cerebral arteriopathy caused by mutant ACTA2 exhibits genetic loci, histopathology, neurological sequelae, and radiographic findings unique from moyamoya disease. We conducted a literature review to provide insight into the history, clinical significance, and neurosurgical management of this recently described novel cerebral arteriopathy. Summary: We performed a literature search using PubMed with the key words “ACTA2 mutation,” “ACTA2 cerebral arteriopathy,” and “multisystemic smooth muscle dysfunction syndrome.” Case reports with confirmed ACTA2 mutations and cerebral arteriopathy were included in our review. Our literature search revealed 15 articles (58 cases) of confirmed ACTA2 cerebral arteriopathy. Distinctive features of this arteriopathy included an aberrant internal carotid circulation with dilatation of the proximal segments, occlusive disease at the distal segments, and dolichoectasia. As such, mutant ACTA2 predisposed patients to ischemic strokes as children. Direct and indirect cerebral revascularization procedures are the mainstay treatment options with varying degrees of success. Key Messages: ACTA2 cerebral arteriopathy is a recently described novel cerebrovascular disease seen in patients with MSMDS. Patients currently diagnosed with moyamoya disease who also have dysfunction of smooth muscle organs may benefit from reevaluation by a medical geneticist and ACTA2 genotyping.

The genetic landscape and clinical implication of pediatric Moyamoya angiopathy in an international cohort

“…Among other MMA-associated genes, pathogenic variants were found in ACTA2 (2 patients, both carrying the p.(Arg179His) variant), GUCY1A3 (Moyamoya 6 with achalasia, OMIM 615750, AR), JAG1 (Alagille syndrome, OMIM 118450, AD), ANK1 and SPTB (spherocytosis) and PCNT (microcephalic osteodysplastic primordial dwarfism, type II / MOPD type II, AR, OMIM 210720). Both ACTA2 patients in our cohort presented the typical angiographic pattern for this syndrome, which has been classified by some authors as representing a distinct form of cerebral arteriopathy from MMA [35]. 3A).…”

Neonatal diagnosis of ACTA2‐related disease: A case report and review of literature

“…Six isoforms of actin exist: two alpha isoforms specifically expressed in skeletal and cardiac tissue, beta and gamma cytosolic isoforms ubiquitously expressed in cells of muscle and non-muscle origin and two isoforms of smooth muscle actin (SMA). The two isoform of SMA include alpha2 and gamma-SMA, which are preferentially expessed in smooth muscle cells within blood vessels, hollow viscera, airways, uterus, eye irises, hair follicles, and lacrimal ducts (Cuoco et al, 2018;Lu et al, 2016;Milewicz et al, 2010). The crossing of two contractile proteins represents the base of the muscle contraction: the filamentous state of actin with myosin, forming a matrixlike network.…”

Moyamoya disease emerging as an immune-related angiopathy

“…Finally, mutations in other genes causing Mendelian forms of MMD, MMS, or related cerebral arteriopathies have also been described. These include biallelic loss-of-function mutations in the GUCY1A3 gene (encoding the major receptor for NO) causing autosomal recessive MMD with achalasia [76,77], heterozygous missense mutations in ACTA2 (encoding smooth muscle actin) causing a moyamoya-like cerebral arteriopathy phenotype [95][96][97], biallelic mutations in SAMHD1 causing an inflammatory syndrome with moyamoya-like vasculopathy [98], Xq28 deletions removing BRCC3 causing X-linked MMS with short stature and facial dysmorphism [99], and de novo mutations in CBL (encoding an E3 ubiquitin ligase) causing severe early-onset pediatric MMA [100]. In addition, other genetic conditions can be associated with MMS, including trisomy 21 [101] and neurofibromatosis type 1 [102].…”