Etiology of Moyamoya Disease
Primary Etiologic Framework
The etiology of moyamoya disease remains unknown, but it is most likely multifactorial, involving both genetic predisposition and environmental factors that contribute to the progressive arteriopathy. 1
Genetic Factors
Genetic predisposition is the predominant driver in moyamoya disease pathogenesis, with minimal contribution of environmental factors. 2
Key Genetic Evidence
RNF213 gene mutations represent the major susceptibility gene for moyamoya disease, particularly in East Asian populations, with the Arg4810Lys variant most strongly associated with the disease. 3
Familial clustering is substantial: up to 12% of patients with moyamoya disease have a positive family history, indicating strong genetic components. 1
Familial risk is dramatically elevated: individuals with affected first-degree relatives have a 132-fold higher risk compared to those without affected relatives, with risk increasing by degree of genetic relatedness (twins > siblings > parents). 2
Penetrance is incomplete: the Arg4810Lys variant has penetrance lower than 1%, suggesting synergistic relationships with additional genetic and environmental risk factors are necessary for disease manifestation. 3
Racial variation exists: White populations carry less common non-Arg4810Lys variants of RNF213, partly explaining the lower prevalence in European countries and the USA compared to East Asian countries. 3
Other genetic mutations increasingly represent etiologies of cerebral arteriopathy, including mutations in ACTA2 and CERC1 genes. 1
Environmental and Associated Factors
While genetic factors predominate, several environmental and clinical associations have been identified:
Associated Conditions (Moyamoya Syndrome)
When moyamoya vasculopathy occurs with specific comorbidities, it is designated moyamoya syndrome rather than moyamoya disease. 1, 4 Associated conditions include:
- Autoimmune diseases: systemic lupus erythematosus, antiphospholipid syndrome, polyarteritis nodosa, Sjögren syndrome. 1
- Infectious: meningitis. 1
- Neoplastic: brain tumors (meningioma, hemangioblastoma, craniopharyngioma, glioma). 1
- Genetic syndromes: Down syndrome, neurofibromatosis type 1. 1
- Iatrogenic: head irradiation. 1
- Hematologic: sickle cell disease (up to 40% of children with sickle cell disease may show moyamoya-like changes). 1
Environmental Exposures
- Cranial radiation has been identified as an environmental stressor associated with moyamoya development. 1
- Congenital malformations have been found in association with moyamoya. 1
- No spousal concordance was observed in population studies, further supporting genetic over shared environmental factors. 2
Pathophysiologic Mechanisms
The underlying pathophysiology involves:
- Progressive stenosis of the terminal portion of the internal carotid artery and proximal branches of the circle of Willis. 1
- Aberrant angiogenesis with development of characteristic collateral vessels (the "puff of smoke" appearance). 5
- Vascular remodeling involving changes in circulating endothelial/smooth muscle progenitor cells, cytokines related to angiogenesis, and endothelial proteins like caveolin. 5
Clinical Implications
Age and Sex Distribution
- Bimodal age distribution with peaks around age 10 and 40 years. 1
- Female predominance: women-to-men ratio ranges from 1.9:1 to 2.6:1 in various populations. 1
- Age-dependent familial risk: particularly high in younger age groups. 2
Important Caveats
The distinction between moyamoya disease (idiopathic) and moyamoya syndrome (secondary) is critical for treatment planning, as moyamoya syndrome may require disease-specific therapies in addition to cerebrovascular management. 4
Bilateral versus unilateral involvement: moyamoya disease is by definition bilateral (though may be asymmetric), while unilateral involvement is considered moyamoya syndrome. 1
The most recent 2021 Japanese Research Committee on Moyamoya Disease Guidelines removed the requirement for bilateral involvement, now accepting unilateral disease given evidence of progression to bilateral involvement. 1