What are the risk factors for Moya Moya disease?

Risk Factors for Moyamoya Disease

Moyamoya disease has both genetic and acquired risk factors, with the most significant being East Asian ancestry, RNF213 gene variants (particularly R4810K in East Asians), family history, and specific medical conditions including Down syndrome, neurofibromatosis type 1, sickle cell disease, cranial radiation exposure, and autoimmune disorders. 1

Genetic Risk Factors

Ethnicity and Geographic Distribution

• East Asian ancestry is the strongest demographic risk factor, with incidence rates 4.6 times higher in Asian Americans compared to whites 1
• Black populations have 2.2 times higher incidence than whites, while Hispanic populations have lower rates (0.5 times) 1
• The disease is most prevalent in Japanese and Korean populations, with slightly lower prevalence in Chinese populations 2
• Familial occurrence in white individuals is rare 1

Family History and Inheritance Pattern

• Up to 12% of patients with moyamoya disease have a positive family history 1
• Familial incidence in first-degree relatives ranges from 7-12% in Japan and 6% in U.S. series 1
• Risk hierarchy among first-degree relatives: affected twin (highest risk) > sibling > mother > father (lowest risk) 1
• Transmission is predominantly maternal, with affected mothers more often producing female offspring, explaining the female predominance (2:1 female-to-male ratio) 1, 3
• Inheritance pattern is likely autosomal dominant with incomplete penetrance 1

RNF213 Gene Variants

• RNF213 is the major susceptibility gene for moyamoya disease in both East Asian and non-East Asian populations 1
• The R4810K variant is the major founder variant in East Asians (especially Japanese and Korean) 1
• Non-R4810K variants increase risk in non-East Asian and certain Chinese populations 1
• Penetrance is extremely low in heterozygotes (0.67% or 1 in 150) but exceeds 78% in homozygotes 1
• RNF213 functions as an antimicrobial protein with immune system roles, suggesting infection may trigger disease in genetically susceptible individuals 1

Other Genetic Associations

• HLA-B40 antigen in patients <10 years of age 1
• HLA-B52 antigen in patients >10 years of age 1
• Additional HLA associations: AW24, BW46, B51-DR4, and BW54 antigens 1

Medical Conditions Associated with Moyamoya Syndrome

High-Risk Conditions Requiring Screening Consideration

• Down syndrome - should undergo chromosomal analysis if moyamoya vasculopathy suspected 1
• Neurofibromatosis type 1 - should undergo NF-1 gene testing; risk dramatically increases with cranial radiation (up to 60% in those receiving radiation for optic nerve gliomas) 1
• Sickle cell disease 1

Radiation Exposure

• Cranial radiation for brain tumors carries 2-4.3% risk of developing moyamoya vasculopathy 1
• Risk increases to 60% in neurofibromatosis type 1 patients undergoing radiation for optic nerve gliomas 1

Autoimmune Conditions

• Systemic lupus erythematosus 1
• Antiphospholipid syndrome 1
• Rheumatoid arthritis 1
• Polyarteritis nodosa 1
• Sjögren syndrome 1

Infectious Triggers

• Leptospirosis 1
• HIV infection 1
• Meningitis 1

Other Associated Conditions

• Brain tumors (meningioma, hemangioblastoma, craniopharyngioma, glioma) 1
• Achalasia - should prompt GUCY1A3 screening 1
• Noonan syndrome-like features - should prompt PTPN11 and CBL screening 1

Age and Sex Distribution

• Bimodal age distribution: first peak around 10 years of age (pediatric), second peak at 30-40 years (adult) 1, 3, 2
• Peak occurs later in women than men 2
• Overall female-to-male ratio is approximately 2:1 3

Clinical Pitfalls

Important caveat: Despite identifying RNF213 variants, genetic testing has limited clinical utility due to extremely low penetrance (0.67% in heterozygotes), meaning most carriers will never develop disease 1. Therefore, routine genetic screening is not recommended for the general population or even for unaffected family members in most cases 1.

Screening considerations: While routine vascular screening for moyamoya is not supported by data, it may be considered in high-risk individuals with neurofibromatosis type 1, Down syndrome, and sickle cell disease 1. There is little evidence to justify screening first-degree relatives when only a single family member is affected 1.