A novel distinctive cerebrovascular phenotype is associated with heterozygous Arg179 ACTA2 mutations

Abstract

Mutations in the ACTA2 gene lead to diffuse and diverse vascular diseases; the Arg179His mutation is associated with an early onset severe phenotype due to global smooth muscle dysfunction. Cerebrovascular disease associated with ACTA2 mutations has been likened to moyamoya disease, but appears to have distinctive features. This study involved the analysis of neuroimaging of 13 patients with heterozygous missense mutations in ACTA2 disrupting Arg179. All patients had persistent ductus arteriosus and congenital mydriasis, and variable presentation of pulmonary hypertension, bladder and gastrointestinal problems associated with this mutation. Distinctive cerebrovascular features were dilatation of proximal internal carotid artery, occlusive disease of terminal internal carotid artery, an abnormally straight course of intracranial arteries, and absent basal 'moyamoya' collaterals. Patterns of brain injury supported both large and small vessel disease. Key differences from moyamoya disease were more widespread arteriopathy, the combination of arterial ectasia and stenosis and, importantly, absence of the typical basal 'moyamoya' collaterals. Evaluation of previously published cases suggests some of these features are also seen in the ACTA2 mutations disrupting Arg258. The observation that transition from dilated to normal/stenotic arterial calibre coincides with where the internal carotid artery changes from an elastic to muscular artery supports the hypothesis that abnormal smooth muscle cell proliferation caused by ACTA2 mutations is modulated by arterial wall components. Patients with persistent ductus arteriosus or congenital mydriasis with a label of 'moyamoya' should be re-evaluated to ensure the distinctive neuroimaging features of an ACTA2 mutation have not been overlooked. This diagnosis has prognostic and genetic implications, and mandates surveillance of other organ systems, in particular the aorta, to prevent life-threatening aortic dissection.

Figure 1

Axial T₂-weighted and FLAIR images of Patients 1–13 (excluding Patient 6) (a–f, m–r) and their corresponding intracranial magnetic resonance angiograms and internal carotid artery injection of a cerebral angiography (g–l, s–x). The imaging of the brain parenchyma reveals the periventricular and deep white matter lesions (a–e, m, n, p and q) and cortical infarctions (e, f, m and o). Patient 13 has normal brain parenchyma (r). The lateral projections (h, j, l) and the (s) anterior-posterior view of the intracranial angiograms show dilatation of the internal carotid artery to the terminal portion, occlusive disease of distal intracranial circulation, an abnormally straight course of intracranial arteries and absence of ‘moyamoya’, other basal and leptomeningeal collaterals. Tortuous small vessels can be seen on the cerebral angiograms on Patients 2 and 4 (h and j). Posterior circulation involvement was manifest as basilar artery and posterior cerebral artery stenosis (i) and vertebral artery dilatation (u and v).

Figure 2

2D reconstruction of CT angiography of the neck of Patient 1 showing (A) dilatation of the right common carotid artery within the neck to its origin (short arrows) and marked dilatation of the aortic arch. The petrous component of both internal carotid arteries can be seen to be dilated (long arrow). (B) A more posterior coronal slice showing the left common carotid artery, entire left internal carotid artery and aortic root dilatation.

Figure 3

The images show representative small arterial dural vessels stained with haematoxylin and eosin (H&E), elastin Van Gieson (EVG) and smooth muscle actin (SMA). There is focal abnormality of the intima, which is most prominent in Patient 1 but subtle in Patients 7 and 8. There is focal intimal thickening with deposition of elastin (black on the elastin Van Gieson). There is focal reduplication of the internal elastic lamina in Patient 7.

Figure 4

The lateral view of the internal carotid artery injections of a cerebral angiogram of (A) an unaffected 3-year-old child, (B) a child with ACTA2 Arg179H is and (C) a child with idiopathic moyamoya disease. (B) Distinctive cerebrovascular features of ACTA2 mutations with dilatation of the proximal internal carotid artery, occlusive disease of distal intracranial circulation, an abnormally straight course of intracranial arteries and absence of ‘moyamoya’, other basal and leptomeningeal collaterals, which are prolific in (C), the child with moyamoya disease. A persistent posterior communicating artery (arrow) is a frequent feature in children with moyamoya disease, (C), but not seen in children with ACTA2 mutations.