Prospective Screening of Extracranial Systemic Arteriopathy in Young Adults with Moyamoya Disease

Abstract

Background RNF213 is a major susceptibility gene for moyamoya disease (MMD), characterized by chronic progressive steno‐occlusion of the intracranial arteries. However, coincidental extracranial arteriopathy is sporadically described in a few cases and in children with MMD. Methods and Results This study prospectively enrolled 63 young adults (aged 20–49 years) without a known history of systemic vascular diseases who were confirmed to have definite (bilateral, n=54) or probable (unilateral, n=9) MMD, as per typical angiographic findings. Coronary and aorta computed tomography angiography was performed to characterize extracranial arteriopathy and investigate its correlation with clinical characteristics and MMD status, including the RNF213 p.Arg4810Lys variation (c.14429G>A, rs112735431). Altogether, 11 of 63 patients (17%) had significant (>50%) stenosis in the coronary (n=6), superior mesenteric (n=2), celiac (n=2), renal (n=1), and/or internal iliac artery (n=1). One patient showed both mesenteric and iliac artery stenosis. Patients with extracranial arteriopathy were more likely to have diabetes mellitus and posterior cerebral artery involvement. Moreover, a higher prevalence of extracranial arteriopathy was observed in the presence of the RNF213 p.Arg4810Lys variant (67% in homozygotes). After controlling for diabetes mellitus and posterior cerebral artery involvement, the p.Arg4810Lys variant was independently associated with extracranial arteriopathy (additive model; P =0.035; adjusted odds ratio, 4.57; 95% CI, 1.11–27.20). Conclusions Young adults with MMD may have concomitant extracranial arteriopathy in various locations. Patients with RNF213 variants, especially the p.Arg4810Lys homozygous variant, should be screened for systemic arteriopathy.

Pathophysiology of Vascular Stenosis and Remodeling in Moyamoya Disease

“…Stenosis of extracranial vessels in association with intracranial moyamoya is uncommon, but several studies have demonstrated associated stenosis of the renal artery in a minority of patients (39,40). In addition, a few studies have demonstrated associated stenosis of external carotid artery branches, coronary arteries, and abdominal arteries (41,42). However, other studies have specifically looked for involvement of branches of the external carotid artery or intraabdominal arteries and have failed to demonstrate stenosis in these segments (40,43).…”

Research progress of moyamoya disease combined with renovascular hypertension

“…In another large study in Asia, 40 of 706 pediatric patients with MMD (5.7%) had hypertension (HTN) and 22 of these 40 patients had renal artery stenosis (6). In a Korean study of adults, only 1 of 63 patients (2%) with MMD was diagnosed with renal artery stenosis (11). The large difference may be due to the difference in age stratification among study samples or it may be related to the late onset moyamoya disease in adults.…”

“…Bleeding is the leading cause of death in patients with moyamoya disease, and hypertension is associated with increased mortality (7). In recent years, many reports have pointed out that the changes of vascular stenosis in patients with moyamoya disease occurred not only in intracranial vessels, but also in extra cranial vessels, especially the changes of renal artery (8)(9)(10)(11). Renovascular hypertension is considered to be one of the important causes of hypertension in patients with moyamoya disease (6).…”

Moyamoya disease emerging as an immune-related angiopathy

“…It was also recently reported that RNF213 p.(R4810K) is associated with pulmonary arterial hypertension (PAH) and peripheral pulmonary artery stenosis regardless of the presence of MMD [25], and carriers of the variant appear to have a higher risk for poor clinical outcome [26]. Moreover, other systemic arteriopathies like coronary, renal, celiac, mesenteric, and iliac artery stenosis have been reported in RNF213 p.(R4810K) homozygous and heterozygous carriers, and systematic screening for extracranial vasculopathy has been recommended in adult and pediatric MMD [27,28]. Thus, there is increasing evidence for RNF213 p.(R4810K) being related to vasculopathy with a spectrum of clinical presentations that include MDD but also other intracranial and systemic vasculopathies [29].…”