Moyamoya disease: epidemiology, clinical features, pathogenesis, diagnosis and therapeutic interventions.

Abstract

Moyamoya disease (MMD) is a rare cerebrovascular disorder characterized by progressive stenosis of the intracranial internal carotid arteries and the development of compensatory, fragile collateral vascular networks at the skull. Emerging evidence suggests that the pathogenesis of MMD involves genetic/epigenetic predisposition, dysregulated immune responses, and environmental triggers. Notably, the RNF213 p.R4810K variant has been identified as a key genetic susceptibility factor, particularly in East Asian populations. However, the molecular mechanisms underlying disease progression remain incompletely elucidated, primarily due to the limited availability of patient-derived cerebrovascular tissues and the lack of animal models that faithfully recapitulate the full spectrum of human MMD pathology. These constraints have impeded the development of targeted therapeutic interventions. Diagnostically, digital subtraction angiography (DSA) continues to serve as the gold standard for diagnosing MMD, enabling detailed visualization of steno-occlusive lesions and characteristic moyamoya vessels. Current clinical management relies predominantly on surgical revascularization to enhance cerebral perfusion, yet this strategy does not alter the fundamental disease process. Recent advances in patient-derived vascular organoids and serum-stimulated cellular models have facilitated drug screening and biomarker identification. In this review, we provide a systematic overview of the epidemiology, clinical manifestations, and genetic landscape of MMD, with a focus on recent progress in deciphering its molecular basis. We further discuss the transformative potential of induced pluripotent stem cell (iPSC) technology, particularly when combined with CRISPR-based gene editing, for modeling MMD vasculopathy, investigating the functional impact of RNF213 mutations, and exploring precision repair approaches. These innovative approaches offer novel insights into disease mechanisms and open new avenues for therapeutic intervention in MMD.