The Susceptibility Pathogenesis of Moyamoya Disease

Moyamoya disease (MMD) is a cerebrovascular disease characterized by progressive stenosis of the intracranial internal carotid arteries and their proximal branches. Epidemiologically, MMD is more prevalent in East Asia than any other region worldwide, and has been estimated at 0.94 per 100,000 in the Japanese and 0.43 per 100,000 in the Chinese population. The etiology of this rare disease, however, remains unknown. Regarding biomarkers, MMD is characterized by an increased expression of angiogenic factors and proinflammatory molecules such as vascular endothelial growth factors and matrix metalloproteinase-9, which may partly explain its clinical manifestations of the pathologic angiogenesis, spontaneous hemorrhage, and greater incidence of cerebral hyperperfusion after revascularization surgery. More recently, blockade of these proinflammatory molecules during the perioperative period is attempted to reduce the potential risk of surgical complications, including cerebral hyperperfusion syndrome. Recent genome-wide and locus-specific association studies identified RNF213 as an important susceptibility gene of MMD among the East Asian population. The exact mechanism by which the RNF213 abnormality relates to MMD remains unknown, whereas recently identified RNF213 encodes a 591-kDa protein containing enzymatically active P-loop ATPase and ubiquitin ligase domains and is involved in proper vascular development in zebrafish provide new insight for the pathogenesis of this rare entity. In this review article, we focused on the genetics and biomarkers of MMD and sought to discuss their clinical implication.