Cerebrovascular Diseases

Review

Free Access

ACTA2 Cerebral Arteriopathy: Not Just a Puff of Smoke

Cuoco J.A.a,b,c,d · Busch C.M.a,b,c,d · Klein B.J.a,b,c,d · Benko M.J.a,b,c,d · Stein R.d · Nicholson A.D.a,b,c,d · Marvin E.A.a,b,c,d

Author affiliations

aCarilion Clinic, Section of Neurosurgery, Roanoke, VA, USA
bVirginia Tech Carilion School of Medicine, Roanoke, VA, USA
cVirginia Tech School of Neuroscience, Blacksburg, VA, USA
dEdward Via College of Osteopathic Medicine, Blacksburg, VA, USA

Corresponding Author

Joshua A. Cuoco, DO, MS

Carilion Clinic, Section of Neurosurgery

2331 Franklin Road

Roanoke, VA 24014 (USA)

E-Mail jacuoco@carilionclinic.org

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Cerebrovasc Dis 2018;46:159–169

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.

© 2018 S. Karger AG, Basel


Introduction

Smooth muscle cells (SMCs) are foundational components of blood vessels and hollow viscera. Physiologically, vascular SMCs contract in response to stretch due to pulsatile blood flow. The molecular architecture necessary for SMC contraction consists of actin and myosin filaments crossing each other forming a matrix-like network. Six isoforms of actin are expressed in humans, each of which is encoded by a different gene. These actin isoforms include 2 α isoforms specifically expressed in skeletal and cardiac tissue, β and γ cytosolic isoforms ubiquitously expressed in cells of muscle and non-muscle origin, and 2 isoforms of smooth muscle actin (SMA) [1]. The 2 isoforms of SMA include α2-SMA and γ-SMA, which are preferentially expressed in SMCs within vasculature and hollow viscera respectively. Importantly, the gene ACTA2 on chromosome 10q23.31 encodes α2-SMA [1]. Missense mutations in ACTA2, such as Arg179His, cause notable biochemical defects in vitro, such as impairment of actin-myosin interaction, which results in smooth muscle contractile dysfunction [1]. These molecular defects culminate in a vascular phenotype that demonstrates medial layer fibrosis and weakening of arterial vessels [2].

The clinical significance of physiologic SMA can be grossly appreciated in individuals who exhibit mutant ACTA2. De novo heterozygous mutations substituting arginine for histidine, leucine, cysteine, or serine at position 179 in the ACTA2 gene are associated with the etiopathogenesis of the clinical entity known as multisystemic smooth muscle dysfunction syndrome (MSMDS) [1-2]. The pleiotropic effects of ACTA2 missense mutations are vast. Most patients with MSMDS present with aortic aneurysms, patent ductus arteriosus, congenital mydriasis, and importantly, distinct cerebrovascular anomalies. These unique vascular features include an extensively diseased internal carotid circulation with dilatation of the proximal segments, occlusive disease at the distal segments, and dolichoectasia (Fig. 1, 2). As such, a mutated ACTA2 gene product predisposes patients to ischemic stroke.

Fig. 1.

Time-of-flight magnetic resonance angiography demonstrating fusiform dilatation of the proximal segments, stenosis of the distal segments, and dolichoectasia of the internal carotid artery. a Top down view. b Lateral view. c Coronal view of the post-processed image. d Lateral view of the post-processed image. (Case courtesy of Dr Chow, Radiopaedia.org, rID: 42870).

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Fig. 2.

Digital subtraction angiography demonstrating fusiform dilatation of the proximal segments, stenosis of the distal segments, and dolichoectasia of the internal carotid artery. a–b Frontal views. c–d Lateral views. (Case courtesy of Dr. Chow, Radiopaedia.org, rID: 42870).

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Until recently, cerebral arteriopathy associated with MSMDS was considered to be a variant of moyamoya disease [2-4]. However, ACTA2 cerebral arteriopathy is now classified as a novel cerebrovascular disease with unique genetic loci, histopathologic findings, and cerebrovascular features. To date, only 58 cases of MSMDS with ACTA2 cerebral arteriopathy have been reported and confirmed via genotyping [2-16]. Here, we provide a literature review of ACTA2 cerebral arteriopathy encompassing the history of the disease from first observation to new classification, clinical significance and neurosurgical management strategies.

First Observation to New Classification

In 1985, Hanson et al. [17] reported 3 cases of congenital anomalies of the optic disc (i.e., 2 morning glory disc anomalies plus one disc coloboma) with angiographic aberrancies of the carotid circulation such as dolichoectasia and large trunk occlusions. The authors proposed that an insult to early embryogenesis might be responsible for the phenotypic manifestations observed in these cases [17]. Subsequent to these findings, numerous case studies were reported describing cerebrovasculature anomalies in combination with either ocular aberrations or cardiovascular malformations. However, in 2004, Khan et al. [18] was first to report 2 patients with moyamoya disease and dolichoectatic internal carotid arteries plus bilateral fixed dilated pupils with iris hypoplasia and patent ductus arteriosus. The authors proposed that the combination of these separate congenital developmental diagnoses was not coincidence; rather, they postulated these cases were the clinical manifestations of an unknown syndromic entity likely driven by genetic mutation(s) [18]. Notably, neither of these cases were confirmed cases of MSMDS associated ACTA2 cerebral arteriopathy, as genotyping was not performed.

In 2007, Guo et al. [19] reported ACTA2 mutations in patients with thoracic aortic aneurysms and aortic dissections. Two years later, the same group led by Guo et al. [20] expanded their findings, reporting that mutations of ACTA2 caused a multitude of vascular pathologies in addition to thoracic aortic aneurysms and dissections including early onset coronary artery disease, premature ischemic stroke and moyamoya disease. The authors identified several ACTA2 mutations (i.e., Arg212Gln, Arg258Cys, and Arg258His) in the 6 patients with moyamoya disease [19]. These data established that heterozygous ACTA2 mutations increased the risk for developing several vasculopathies, including moyamoya disease, and demonstrated a potential genetic predisposition to moyamoya disease [19, 20]. However, 3 succeeding studies in 3 distinct ethic populations could not replicate the findings reported by Guo et al. [19, 20].

The first study to contradict the findings of Guo et al. [19, 20] was published by Shimojima and Yamamoto [21] who searched for ACTA2 mutations in Japanese patients diagnosed with moyamoya disease. Of note, most cases of moyamoya disease have been reported in the Japanese and Korean populations, as it is rare in non-Asian populations [22]. The authors sequenced the 9 coding exons of ACTA2 from 53 Japanese patients with moyamoya disease (46 familial cases and 7 non-familial cases), which did not reveal any ACTA2 mutations [21]. Second, Roder et al. [23] sequenced the exons of ACTA2 from 39 European patients with moyamoya disease, which did not reveal mutations previously identified. However, one novel missense mutation (Arg179His) on chromosome 6, not previously reported by Guo et al. [19, 20] was identified [23]. Third, Hu et al. [24] sequenced ACTA2 from 55 Chinese patients with moyamoya disease and did not find any ACTA2 mutations in these patients. Furthermore, several whole-genome linkage studies have shown the molecular etiology of moyamoya disease to be linked to the chromosomal regions 3p24.2-26, 6q25, 8q23, and 17q25.3, which do not include the locus of ACTA2 at 10q23.31 [25-28]. For example, Kamada et al. [29] recently identified the RNF213 gene (RNF213) on chromosome 17 (17q25-ter region) as a novel susceptibility gene for moyamoya disease in the East Asian population [28]. This group performed a genome-wide association study of 785,720 single nucleotide polymorphisms in 72 Japanese individuals with moyamoya disease and 45 Japanese healthy controls [29]. Genetic analysis of the RNF213 locus identified a founder mutation in RNF213 in 95% of familial cases of moyamoya disease and 79% of spontaneous cases of moyamoya disease compared to 1.4% in healthy controls [29]. These data suggested that ACTA2 mutations were not a major disease-causing gene for moyamoya disease.

In 2010, Milewicz et al. [2] identified 5 Northern European patients with a novel de novo heterozygous ACTA2 Arg179His missense mutation. These patients demonstrated a unique clinical syndrome characterized by widespread SMC dysfunction in organs throughout the body. All 5 patients exhibited ascending aortic aneurysms, patent ductus arteriosus, congenital mydriasis, hypotonic bladder, periventricular white matter hyperintensities and, importantly, significant cerebrovascular irregularities. Cerebral angiography in these patients demonstrated: (i) fusiform dilatation from the cavernous to the clinoid segments of the internal carotid artery, (ii) stenosis of the terminal segment of the internal carotid artery frequently extending into the sphenoidal segment of the middle cerebral artery and pre-communicating segment of the anterior cerebral artery, and (iii) absence of “moyamoya” basal collaterals [2]. Of note, one patient was reported to have colpocephaly. This case series established that de novo ACTA2 missense mutation causes a novel syndrome, coined MSMDS, which includes disease of the cerebrovasculature.

In 2012, Munot et al. [4] performed a detailed neuroimaging analysis of patients with heterozygous ACTA2 missense mutations. The analyses included 6 new patients (5 with Arg179His and one with Arg179Leu), 5 patients with Arg179His reported by Milewicz et al. [2] and 1 patient with Arg179His reported by Richer et al. [5]. All patients exhibited a similar unique syndrome encompassing cerebrovascular disease, congenital mydriasis, and patent ductus arteriosus [4]. The authors identified cerebrovascular features similar to those observed by Milewicz et al. [2] in all patients. Key differences from moyamoya disease were dilatation of the internal carotid artery, a more diffuse arteriopathy with arterial ectasia, as well as the absence of distinguishing “moyamoya” basal collaterals. Imaging findings suggested that the change in vessel caliber from dilated to stenosed, although not absolute, may arise around the cavernous segment of the internal carotid artery. Of note, the cavernous segment is the location whereby the external elastic lamina dissipates from the walls of internal carotid arteries. This study reproduced the imaging findings by Milewicz et al. [2] and confirmed that patients with MSMDS exhibit a distinct cerebrovascular phenotype from moyamoya disease, which the authors termed ACTA2 cerebral arteriopathy [4].

Histopathologic Correlates

A novel study by Georgescu et al. [9] presented the first comprehensive histopathologic examination of ACTA2 cerebral arteriopathy of a MSMDS patient. The patient was a 31-year-old female with undiagnosed Arg179His-positive MSMDS (“moyamoya disease,” multiple aortic aneurysm repairs, surgical closure of a patent ductus arteriosus, congenital mydriasis, intestinal malrotation, and pulmonary disease) who expired 2 days after presenting to the emergency department with acute ischemic infarction of bilateral anterior cerebral arteries (ACA) and left middle cerebral artery (MCA). Compared to gender- and age-matched controls, histological analysis of the patient’s vasculature revealed significant intimal thickening in all of the major arteries of the anterior circulation and varying thickening in the arteries of the posterior circulation. As observed angiographically, the authors correlated reduced diameter and area of arterial lumens to be consequential to thickening of the intima layer [9]. Splitting between the intimal and media layer of the internal elastic lamina was observed, which, in addition to postmortem artifact, is suggestive of further adhesive dysfunction between the intima and media. Moreover, a marked increase in collagen and increased quantity of SMCs was found in the medial layer. The authors suggested that these findings, including increased wall thickness and marked media fibrosis, might account for the straight appearance of cerebral arteries found on imaging studies [9]. It should be noted that fibromuscular proliferation of the intima is also characteristic of moyamoya disease as well as atherosclerosis [30]. For example, Oka et al. [30] reported variable intimal elastofibrosis of the circle of Willis and its major branches in autopsy cases of moyamoya disease. However, contrary to moyamoya disease, 3 important differences were observed in the study by Georgescu et al. [9] including: (i) reduced folding of the internal elastic lamina compared to a more intricate folding occasionally reported in moyamoya disease, (ii) distinct media changes (i.e., fibrosis and SMC invasion) compared to media weakening seen in moyamoya disease and (iii) absent compensatory basal collaterals seen in moyamoya disease. Furthermore, the pathognomonic findings of atherosclerosis, such as macrophage accretion and cholesterol plaque formation, were not demonstrated in ACTA2 pathology samples.

Clinical Significance

Patients with MSMDS demonstrate discrete cerebrovascular anomalies that are fully penetrant with age. As such, these patients exhibit an elevated risk of developing vaso-occlusive strokes and various other neurologic sequelae, all of which may occur as early as the neonatal period (Table 1). In the largest MSMDS study to date, Regalado et al. [16] reported the clinical neurologic history of 33 patients (including 7 patients from Milewicz et al. [2] plus addendum) diagnosed with MSMDS. The median age of these patients was 12 years and the median age at diagnosis was 11 years. Twenty-one (64%) were females and 12 (36%) were males. Twenty-six were of European ancestry, 5 were Asian, 1 was African-American, and 1 was Hispanic [16]. These individuals exhibited various ACTA2 missense mutations at position 179 including Arg179His (24 patients), Arg179Cys (7 patients), Arg179Ser (1 patient), and Arg179Leu (1 patient). The authors reported proximal internal carotid artery stenosis in 77% of patients [16]. Fifty-three percent of patients demonstrated multi-vessel disease with the second most common site being one of the cerebral arteries (60%). The most common neurologic complication reported in patient’s histories was cerebral ischemic stroke. Stroke occurred in 8 females and one male (27% of patients) occurring at a median age of 4 years [16]. The youngest age at stroke was reported in a 2-day-old child with infarction of the bilateral watershed areas and basal ganglia. Various other neurologic manifestations were reported in clinical histories including: developmental delay (19%), seizure (18%), hemiparesis (16%), learning difficulties (7%), lower-extremity spasticity (6%), and upper extremity spasticity (3%) [16]. It is postulated that such neurologic sequelae may be a consequence of chronic hypotension in the setting of a diseased intracranial circulation compromising cerebral blood flow and autoregulation. Interestingly, 95% of patients exhibited periventricular white matter signal changes on T2-weighted magnetic resonance imaging (MRI). White matter disease is a distinctive feature in patients with ACTA2 mutations, as such features are infrequently observed in moyamoya disease. Milewicz et al. [2] hypothesized that periventricular and subcortical white matter disease may result from the occlusion of small vessels or watershed lesions resulting from stenosis of the internal carotid circulation.

Table 1.

Summary of neurologic symptomatology and radiographic imaging observed in patients with ACTA2 cerebral arteriopathy confirmed by genotyping

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Brain development anomalies appear to be a prominent feature in patients specifically with the ACTA2 Arg179Cys mutation. Indeed, 3 of the 4 reported cases with this mutation demonstrated some degree of irregular brain development [7, 15]. For example, Meuwissen et al. [7] reported a 2-year-old female with ACTA2 Arg179Cys; her MRI revealed a dysplastic corpus callosum with a small genu and an absent rostrum and lamina terminalis. The cingulate gyrus was abnormally positioned and sulcation of the medial cerebral hemispheres was abnormal, resulting in anomalous anatomy of the frontal lobes. de Grazia et al. [15] described the first case of newborn siblings with MSMDS who, coincidentally, had the ACTA2 Arg179Cys mutation and significant brain anomalies. Of note, both parents’ DNA tested negative for ACTA2 mutations indicating mutation genesis was due to germ line mosaicism in both siblings. The first sibling, a 2-week-old female, exhibited thalamic and basal ganglia lesions, indicative of severe hypoxic-ischemic injury, and a dysplastic corpus callosum. The second sibling, a 3-day-old male, presented with lesions of the periventricular and callosal splenium also suggestive of hypoxic-ischemic damage. Moreover, the second sibling exhibited incomplete opercularization of the insula. These observations support that the gene product of ACTA2 may play an essential yet unknown role in brain development.

Neurosurgical Management

While direct and indirect cerebral revascularization techniques are recognized treatment modalities for patients with moyamoya disease, literature on revascularization outcomes in patients with ACTA2 cerebral arteriopathy is scarce (Table 2) [4, 31]. Unfortunately, most of the literature reporting revascularization procedures for patient with ACTA2 arteriopathy does not specify the details of neurosurgical technique (i.e., direct versus indirect procedure). Munot et al. [4] reported a limited series of cerebral revascularization complication rates in 3 pediatric patients with mutant ACTA2. Two of the 3 patients had an arterial ischemic stroke after revascularization. Comparatively, in a series reported from the same institution, 3 of 73 pediatric patients (4.1%) who underwent cerebral revascularization for moyamoya disease had an arterial ischemic stroke postoperatively [4]. Indeed, neurosurgical revascularization for moyamoya disease demonstrates a significant protective effect in preventing the recurrence of stroke; however, a similar reduction in the incidence of future stroke with revascularization is not observed in ACTA2 cerebral arteriopathy patients [4, 31]. Moller et al. [3] described a 6-year-old who underwent a 2-step bilateral bypass revascularization procedure, which was complicated by significant right hemispheric ischemic infarction. A second patient reported by Moller et al. [3] was a 4-year-old who underwent bilateral bypass for a previous right hemispheric infarction. The patient made a full recovery.

Table 2.

Summary of the neurosurgical management in patients with ACTA2 cerebral arteriopathy confirmed by genotyping

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Georgescu et al. [9] reported a female patient who underwent a left superficial temporal artery (STA) encephaloduroarteriosynangiosis at 28 years of age. Postoperative complications were minimal including paresthesias and transient hemiparesis. However, the patient expired at 31 years of age due to extensive ischemic infarction of the bilateral anterior cerebral arteries and left middle cerebral artery territories. Kantamneni et al. [14] reported ­encephaloduroarteriomyosynangiosis (EDAMS) revascularization outcomes, compared to encephaloduroarteriosynangiosis by Georgescu et al. [9] in 2 patients with known ACTA2 arteriopathy. The first patient was diagnosed with mutant ACTA2 at 6 years of age after imaging revealed numerous cerebral infarctions. The patient ­underwent a left EDAMS at 8 years of age without postoperative complications. Three-year follow-up MRI revealed a new right hemispheric ischemic infarct. The second patient presented at 7 years of age with encephalopathy. Mutant ACTA2 was confirmed and MRI revealed multiterritorial infarcts. The patient underwent bilateral EDAMS with no postoperative complications. Kantamneni et al. [14] concluded that EDAMS can be implemented safely for ACTA2 cerebral arteriopathy and is an effective revascularization strategy in preventing future ischemic infarcts. Rutledge et al. [13] described a 6-year-old patient with ACTA2 cerebral arteriopathy who ­underwent both indirect and direct cerebral revascularization. The patient presented at 3 years of age with symptomatology consistent with MSMDS and an acute left-sided hemiparesis. She was found to have a right MCA ischemic infarct and diffuse cerebral arteriopathy. A right-sided combined STA synangiosis and temporalis muscle onlay was performed. The patient remained asymptomatic until 6 years of age when she developed transient bilateral lower extremity hemiparesis. Repeat imaging revealed progressive diffuse cerebral arteriopathy. The patient subsequently underwent a left STA to ACA bypass using the left posterior auricular artery as graft plus left temporalis muscle onlay. On postoperative day 3, she developed right hemiparesis and expressive aphasia due to extensive acute ischemic infarction involving the left ACA and MCA. Although the patient was affected by extensive post-operative infarction, the authors concluded that the direct bypass might have prevented the magnitude of infarction involving the medial frontal lobe [13].

Screening and Surveillance Recommendations

Based on the clinical neurologic history of 33 patients (including 7 patients from Milewicz et al. [2] plus addendum) diagnosed with ACTA2 cerebral arteriopathy, Regalado et al. [16] proposed screening and surveillance recommendations for neurologic complications. The authors recommend a baseline brain MRI as well as head and neck magnetic resonance angiography at time of diagnosis to screen for ischemic insult and degree of cerebrovascular stenosis respectively [16]. Optimal surveillance intervals of ACTA2 cerebral arteriopathy is yet to be established as disease progression is not well understood; nevertheless, Regalado et al. [16] recommend transcranial Doppler ultrasonography as an imaging modality to monitor cerebrovascular disease progression. Moreover, the authors advise the reservation of conventional catheter angiogram for patients with focal neurologic deficits or evidence of critical or progressive stenosis of cerebrovasculature on transcranial Doppler ultrasonography or magnetic resonance angiography. Despite these surveillance recommendations for disease progression, there are currently no standard indications for neurosurgical revascularization. The absence of revascularization indications for ACTA2 arteriopathy may be due in part to the paucity of reported cases as well as the high risk of postoperative stroke in the limited number of cases that have been described.

Conclusions

ACTA2 missense mutations cause diffuse dysfunction of smooth muscle and a unique cerebral arteriopathy. Indeed, ACTA2 arteriopathy exhibits genetic loci, histopathology, neurologic sequelae, and radiographic findings that are distinct from moyamoya disease. With each reported case, we gain a better understanding of this unique neurovasculopathy and further elucidate the potential role for neurosurgical intervention.

Disclosure Statement

The authors declare that they have no conflicts of interest to disclose.

Funding Sources

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.



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Author Contacts

Joshua A. Cuoco, DO, MS

Carilion Clinic, Section of Neurosurgery

2331 Franklin Road

Roanoke, VA 24014 (USA)

E-Mail jacuoco@carilionclinic.org


Article / Publication Details

First-Page Preview
Abstract of Review

Received: June 29, 2018
Accepted: September 18, 2018
Published online: October 09, 2018
Issue release date: November 2018

Number of Print Pages: 11
Number of Figures: 2
Number of Tables: 2

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References

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