Moyamoya disease

Moyamoya disease is a chronic, progressive vasculopathy of the internal carotid arteries producing both with consequent cerebral hypoperfusion, stroke, and neovascularization, commonly resulting in seizures, neurocognitive and motor delay and decline. Age of onset is bimodal, with a paediatric peak in the first decade of life and an adult peak between the third and fifth decades. Paediatric presentation is dominated by ischaemic events, including transient ischaemic attacks, recurrent strokes, motor deficits, seizures, headaches and involuntary movements. Adult presentation more frequently involves haemorrhagic stroke from rupture of the fragile collateral vessels. Cognitive decline, headaches, and visual disturbances may complicate the course. The vasculopathy is typically bilateral; unilateral involvement is classified as probable moyamoya disease and may progress contralaterally over time.

The estimated annual incidence is 0.5-1.5 per 100,000 individuals in Asian countries and approximately 0.1 per 100,000 in other regions.

Moyamoya disease results from germline pathogenic variants in vascular-susceptibility genes. RNF213 (17q25.3) encodes a large RING-finger protein implicated in angiogenesis, lipid metabolism, and NF-kappaB-mediated inflammation, and is the principal susceptibility gene; a founder variant p.(Arg4810Lys) is recognised in East-Asian populations. GUCY1A3 (4q32.1) contributes through nitric-oxide and soluble-guanylate-cyclase signalling. The vasculopathy is characterised by fibrocellular intimal thickening, vascular smooth-muscle-cell proliferation, fragmentation of the internal elastic lamina, and abnormal compensatory collateral vessel formation.

Moyamoya disease is inherited in an autosomal dominant manner for RNF213 related cases and autosomal recessive in GUCY1A3 related cases. Prenatal molecular testing is technically possible once the familial pathogenic variant has been identified.

The diagnosis follows the , and meeting these criteria establishes the clinical diagnosis. Cerebral angiography (digital subtraction or magnetic-resonance) demonstrates bilateral steno-occlusion of the terminal internal carotid arteries with abnormal collateral networks at the base of the brain. Angiographic progression is graded by the Suzuki staging system (stages I-VI).

• Establishing the diagnosis: Molecular genetic testing confirms the clinical diagnosis and resolves diagnostic uncertainty.
• Individualised surveillance: A confirmed molecular diagnosis is a prerequisite for targeted medical care and informs individualised surveillance, decided by the treating physicians in consultation with the affected individual.
• Testing of at-risk family members: Once the familial pathogenic variant has been identified, predictive testing can be offered to at-risk relatives.

• Ognibene M, Scala M, Iacomino M, Schiavetti I, Madia F, Traverso M, et al. Moyamoya vasculopathy in neurofibromatosis type 1 pediatric patients: the role of rare variants of RNF213. Cancers (Basel). 2023;15(6):1916. PMID: .
• Wang XP, Zou ZX, Bao XY, Wang QN, Ren B, Yu D, et al. Clinical and genetic factors associated with contralateral progression in unilateral moyamoya disease: longitudinal and cross-sectional study. Heliyon. 2024;10(4). PMID: .
• Mineharu Y, Miyamoto S. RNF213 and GUCY1A3 in moyamoya disease: key regulators of metabolism, inflammation, and vascular stability. Front Neurol. 2021;12:687088. PMID: .
• Strong A, O’Grady G, Shih E, Bishop JR, Loomes K, Diamond T, et al. A new syndrome of moyamoya disease, kidney dysplasia, aminotransferase elevation, and skin disease associated with de novo variants in RNF213. Am J Med Genet A. 2021;185(7):2168-2174. PMID: .
• Fujimura M, Tominaga T, Kuroda S, Takahashi JC, Endo H, Ogasawara K, et al. 2021 Japanese guidelines for the management of moyamoya disease: guidelines from the Research Committee on Moyamoya Disease and Japan Stroke Society. Neurol Med Chir (Tokyo). 2022;62(4):165-170. PMID: .