Moyamoya disease: insights into the clinical implications of the RNF213 gene

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Moyamoya disease (MMD) is a rare cerebrovascular disorder characterized by progressive stenosis of the terminal internal carotid arteries and the formation of compensatory collateral vessels, which appear as a “puff of smoke” on cerebral angiography. It is a significant cause of stroke in East Asia, with an incidence of 0.5 to 1.5 cases per 100,000 people annually. The etiology of MMD remains unclear; however, the identification of the RNF213 gene, particularly the R4810K variant, as a major susceptibility factor among the East Asian population, has provided crucial insights into the disease's pathophysiology and clinical manifestations. MMD typically presents with transient ischemic attacks, ischemic and hemorrhagic strokes, seizures, headaches, and cognitive deficits. Diagnostic criteria have evolved to emphasize advanced imaging techniques. Pathological features include fibrocellular intimal thickening, irregular undulation of the elastic lamina, and the formation of moyamoya vessels. The mutation in the RNF213 gene impairs the degradation of proteins involved in vessel development, leading to abnormal angiogenesis. Genotype-phenotype studies indicate that the RNF213 variant is associated with an earlier onset, transient ischemic attacks, infarctions, and involvement of the posterior cerebral artery, although its effects vary between regions. Additionally, the homozygous RNF213 variant consistently correlates with an earlier age of onset and a higher risk of cerebral infarction. However, further research is necessary to fully understand its long-term impacts and its relationship with revascularization outcomes. Ongoing research is crucial to fully comprehend the pathophysiology and genetics of MMD, improve prognostic predictions, and develop novel therapies.