Role of RNF213 in Guiding Treatment of Moyamoya Disease with Unusual Phenotypic Presentation.

BACKGROUND

Moyamoya disease (MMD) is characterized by progressive carotid fork steno-occlusion and the development of "puff-of-smoke" collaterals on angiography. However, a subset of patients present with similar vascular changes but lack these hallmark collaterals, complicating both diagnosis and management. This "smokeless" phenotype, associated with ring finger protein 213 (RNF213) gene variants, challenges the traditional description of MMD. We describe a series of such patients who responded favorably to revascularization.

METHODS

In this ambispective observational study, we evaluated 12 patients with carotid fork steno-occlusive disease but without "puff-of-smoke" collaterals. Clinical, radiological and genetic assessments were assessed. Structural modeling of RNF213 protein variants was conducted through 3D homology modeling, validated via Ramachandran plots and further refined with COOT and PyMOL. Functional insights were derived through ConSurf analysis.

RESULTS

Of the 12 patients, 9 carried the RNF213 p.R4810K variant, 1 harboured a novel variant, 1 had both p.R4810K and a novel variant and 1 had p.R4859K. Initial misclassification as intracranial atherosclerosis or vasculitis led to inappropriate treatment. Following genetic confirmation, 9 patients underwent revascularization, with no stroke recurrence and a favorable clinical outcome. Structural modeling revealed minimal functional impact for the Val1529Met variant, whereas other variants significantly disrupted RNF213 stability and functionality.

CONCLUSIONS

"Smokeless moyamoya," characterized by carotid fork steno-occlusion without typical angiographic collaterals, represents a distinct clinical phenotype responsive to revascularization. RNF213 genetic screening enhances diagnostic precision, reshaping traditional paradigms and supporting tailored therapeutic approaches.