Is Moyamoya disease genetic or hereditary?

Moyamoya Disease: Genetic and Hereditary Aspects

Yes, Moyamoya disease has a significant genetic component with autosomal dominant inheritance pattern and incomplete penetrance, with the RNF213 gene being the primary susceptibility gene, especially in East Asian populations. 1

Genetic Basis of Moyamoya Disease

Key Genetic Factors

• Up to 12% of patients with Moyamoya disease (MMD) have a positive family history 1
• The Ring Finger Protein 213 (RNF213) is the primary susceptibility gene for MMD 1
• RNF213 R4810K variant is particularly prevalent in East Asians (Japanese and Korean populations) 1
• Non-R4810K variants increase MMD risk in non-East Asian and certain Chinese populations 1

Inheritance Pattern

• Most likely autosomal dominant with incomplete penetrance 1, 2
• Penetrance rates vary significantly:
  • Heterozygotes of RNF213 R4810K: approximately 0.67% (1 per 150)
  • Homozygotes of RNF213 R4810K: >78% 1

Population Differences

• Familial occurrence is more common in East Asian populations 1
• Familial occurrence is rare in White/Caucasian individuals 1, 3
• The prevalence is higher in East Asia than in Western countries 4
• Ethnicity-specific incidence rate ratios compared to whites:
  • 4.6 for Asian Americans
  • 2.2 for Black Americans
  • 0.5 for Hispanic Americans 1

Unique Inheritance Characteristics

Maternal Transmission Pattern

• Transmission is predominantly maternal 1
• Affected mothers more often produce female offspring, explaining the female predominance 1, 2
• Affected mothers are more likely to produce late-onset (adult-onset or asymptomatic) female offspring 2
• Epigenetic modification such as genomic imprinting may be associated with MMD 1, 2

Familial Risk Patterns

• Familial incidence and risk of MMD in first-degree relatives is highest in:
  1. Individuals with an affected twin
  2. Individuals with an affected sibling
  3. Individuals with an affected mother
  4. Individuals with an affected father (lowest risk) 1

Genetic Testing Considerations

When Genetic Testing May Be Helpful

• In East Asian individuals, to differentiate MMD from other causes of intracranial steno-occlusive diseases 1
• In patients with moyamoya vasculopathy and evidence of manifestations concerning for associated systemic diseases:
  • Achalasia: screen for GUCY1A3
  • Down syndrome features: chromosomal analysis
  • Noonan syndrome-like symptoms: PTPN11 and CBL screening
  • Neurofibromatosis type 1 manifestations: NF-1 gene testing 1

Limitations of Genetic Testing

• Limited benefit in the general population due to incomplete penetrance 1
• Uncertain role in non-Asian populations where MMD incidence is low 1
• Limited benefit for unaffected members in familial cases 1

Associated Conditions and Syndromes

Moyamoya syndrome (MMS) occurs when MMD is associated with other conditions:

• Autoimmune diseases (systemic lupus erythematosus, antiphospholipid syndrome, etc.)
• Down syndrome
• Neurofibromatosis type 1
• Sickle cell disease
• Head irradiation
• Meningitis
• Brain tumors 1

Clinical Implications of Genetic Factors

• Patients carrying the RNF213 polymorphism exhibit significantly earlier disease onset and more severe forms of MMD 4
• The disease shows a bimodal age distribution with different clinical presentations:
  • Around age 10: predominantly ischemic symptoms
  • Ages 30-45: higher risk of hemorrhagic presentation 4
• Understanding the genetic basis may help identify potential therapeutic targets 1

In summary, while Moyamoya disease has a clear genetic component with autosomal dominant inheritance and incomplete penetrance, the exact mechanisms and full genetic profile remain under investigation. The RNF213 gene is the most significant genetic factor identified to date, particularly in East Asian populations.