Moyamoya disease is an idiopathic, progressive cerebrovascular arteriopathy characterized by stenosis or occlusion of the circle of Willis and terminal internal carotid arteries with development of prominent basal collateral vessels that create the radiographic "puff-of-smoke" appearance.
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name: Moyamoya Disease
creation_date: "2026-05-04T22:23:50Z"
updated_date: "2026-05-05T00:56:18Z"
description: >-
Moyamoya disease is an idiopathic, progressive cerebrovascular arteriopathy
characterized by stenosis or occlusion of the circle of Willis and terminal
internal carotid arteries with development of prominent basal collateral
vessels that create the radiographic "puff-of-smoke" appearance.
category: Complex
disease_term:
preferred_term: Moyamoya disease
term:
id: MONDO:0016820
label: Moyamoya disease
parents:
- Vascular disorder
synonyms:
- MMD
- Moyamoya angiopathy
pathophysiology:
- name: Progressive steno-occlusive intracranial arteriopathy
description: >-
Progressive stenosis of the terminal internal carotid arteries and circle
of Willis lowers cerebral perfusion and drives formation of fragile
collateral vessels, which underlies ischemic and hemorrhagic presentations.
cell_types:
- preferred_term: endothelial cell
term:
id: CL:0000115
label: endothelial cell
biological_processes:
- preferred_term: vasculature development
modifier: ABNORMAL
term:
id: GO:0001944
label: vasculature development
evidence:
- reference: DOI:10.3171/2024.1.JNS221977
reference_title: "Management of moyamoya disease: a review of current and future therapeutic strategies"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Moyamoya disease (MMD) is characterized by idiopathic, progressive stenosis of the circle of Willis and the terminal portion of the internal carotid arteries with the development of prominent small collateral vessels and a characteristic moyamoya or puff-of-smoke radiographic appearance.
explanation: This review directly states the defining vascular pathology and collateralization.
- name: RNF213-associated angiogenic and remodeling dysregulation
description: >-
RNF213 variants, especially p.R4810K in East Asian populations, contribute
to susceptibility and may perturb endothelial angiogenesis, vascular
remodeling, and cerebral blood flow regulation.
cell_types:
- preferred_term: endothelial cell
term:
id: CL:0000115
label: endothelial cell
biological_processes:
- preferred_term: angiogenesis
modifier: ABNORMAL
term:
id: GO:0001525
label: angiogenesis
- preferred_term: vascular endothelial growth factor receptor signaling pathway
modifier: ABNORMAL
term:
id: GO:0048010
label: vascular endothelial growth factor receptor signaling pathway
evidence:
- reference: DOI:10.3390/biomedicines13010017
reference_title: "Exploring RNF213 in Ischemic Stroke and Moyamoya Disease: From Cellular Models to Clinical Insights"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
This gene encodes an E3 ubiquitin ligase with diverse roles in angiogenesis, vascular remodeling, lipid metabolism, and cerebral blood flow regulation, yet its exact mechanisms in cerebrovascular pathology remain incompletely understood.
explanation: This supports RNF213's proposed involvement in vascular remodeling and angiogenesis while preserving mechanistic uncertainty.
downstream:
- target: Progressive steno-occlusive intracranial arteriopathy
description: Dysregulated endothelial angiogenesis and vascular remodeling driven by RNF213 variants contributes to progressive intracranial arterial stenosis and collateral formation.
- name: RNF213 loss-of-function Hippo-YAP/TAZ-VEGFR2 activation
description: >-
Experimental RNF213 loss activates YAP/TAZ and VEGFR2-linked endothelial
angiogenic programs, providing a more specific signaling mechanism for
pathological angiogenesis in moyamoya disease.
cell_types:
- preferred_term: endothelial cell
term:
id: CL:0000115
label: endothelial cell
biological_processes:
- preferred_term: vascular endothelial growth factor receptor signaling pathway
modifier: INCREASED
term:
id: GO:0048010
label: vascular endothelial growth factor receptor signaling pathway
evidence:
- reference: DOI:10.1093/brain/awad225
reference_title: "<i>RNF213</i> loss-of-function promotes pathological angiogenesis in moyamoya disease via the Hippo pathway"
supports: SUPPORT
evidence_source: IN_VITRO
snippet: >-
Endothelial knockdown of RNF213 activated the Hippo pathway effector Yes-associated protein (YAP)/tafazzin (TAZ) and promoted the overexpression of the downstream effector VEGFR2.
explanation: This cell-based component of the study supports Hippo-YAP/TAZ-VEGFR2 activation after RNF213 knockdown.
downstream:
- target: RNF213-associated angiogenic and remodeling dysregulation
description: YAP/TAZ-driven VEGFR2 overexpression feeds into broader dysregulation of endothelial angiogenesis and vascular remodeling.
phenotypes:
- category: Neurological
name: Intracranial arterial stenosis
diagnostic: true
description: Progressive stenosis of intracranial arteries is the central diagnostic vascular abnormality.
phenotype_term:
preferred_term: Arterial stenosis
term:
id: HP:0100545
label: Arterial stenosis
evidence:
- reference: DOI:10.3171/2024.1.JNS221977
reference_title: "Management of moyamoya disease: a review of current and future therapeutic strategies"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Moyamoya disease (MMD) is characterized by idiopathic, progressive stenosis of the circle of Willis and the terminal portion of the internal carotid arteries with the development of prominent small collateral vessels and a characteristic moyamoya or puff-of-smoke radiographic appearance.
explanation: This defines the core steno-occlusive phenotype.
- category: Neurological
name: Ischemic symptoms and stroke
description: Ischemic symptoms are common across pediatric and adult populations.
phenotype_term:
preferred_term: Ischemic stroke
term:
id: HP:0002140
label: Ischemic stroke
evidence:
- reference: DOI:10.3171/2024.1.JNS221977
reference_title: "Management of moyamoya disease: a review of current and future therapeutic strategies"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Ischemic symptoms are the most common presentation in pediatric and adult populations, but adult patients are nearly twice as likely to present with intracranial hemorrhage compared to their pediatric counterparts.
explanation: This supports ischemic presentations and age-related hemorrhagic differences.
- category: Neurological
name: Transient ischemic attack
description: Transient ischemic attacks are part of the ischemic presentation spectrum in MMD.
phenotype_term:
preferred_term: Transient ischemic attack
term:
id: HP:0002326
label: Transient ischemic attack
evidence:
- reference: DOI:10.1159/000540254
reference_title: "Adult Moyamoya disease and moyamoya syndrome: what’s new?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In the Japan Adult Moyamoya trial, a randomized controlled trial for bilateral extracranial-intracranial direct bypass versus conservative therapy in patients with MMD, who had intracranial hemorrhage, recurrent bleeding, completed stroke or crescendo transient ischemic attack was significantly fewer with direct bypass than with conservative care.
explanation: This review of the adult randomized trial includes crescendo TIA among clinical outcomes in MMD.
- category: Neurological
name: Post-revascularization seizure
description: Seizures have been reported after surgical revascularization in patients with MMD.
phenotype_term:
preferred_term: Seizure
term:
id: HP:0001250
label: Seizure
review_notes: >-
Scoped to post-revascularization seizures because the supporting cohort
reports postoperative events. Reviewer-suggested HP:0025373 resolves locally
to interictal EEG abnormality, so the broader seizure term is retained.
evidence:
- reference: PMID:37995995
reference_title: Predictive Factors for Seizures after Revascularization in Patients with Moyamoya Disease.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Ten patients developed seizures after revascularization for MMD.
explanation: This cohort supports seizures specifically after revascularization in patients with MMD.
- category: Neurological
name: Cognitive impairment
description: Adult MMD cohorts show frequent domain-specific cognitive impairment.
phenotype_term:
preferred_term: Cognitive impairment
term:
id: HP:0100543
label: Cognitive impairment
evidence:
- reference: PMID:36996746
reference_title: Long-term study of the cognitive profile of Moyamoya Disease in adults.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Cognitive impairment was common.
explanation: This adult longitudinal cohort directly supports cognitive impairment in MMD.
- category: Neurological
name: Hemiparesis
description: Transient hemiparesis can occur in MMD as part of an ischemic or seizure-like presentation.
phenotype_term:
preferred_term: Hemiparesis
term:
id: HP:0001269
label: Hemiparesis
evidence:
- reference: PMID:31439486
reference_title: "Moyamoya disease with epileptic nystagmus: A case report."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
A 23-year-old woman presented with a headache and transient hemiparesis on her left side.
explanation: This case report directly supports transient hemiparesis in an MMD presentation.
- category: Neurological
name: Intracranial hemorrhage
description: Adult patients may present with intracranial hemorrhage from fragile collateral vessels.
phenotype_term:
preferred_term: Intracranial hemorrhage
term:
id: HP:0002170
label: Intracranial hemorrhage
evidence:
- reference: DOI:10.3171/2024.1.JNS221977
reference_title: "Management of moyamoya disease: a review of current and future therapeutic strategies"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Ischemic symptoms are the most common presentation in pediatric and adult populations, but adult patients are nearly twice as likely to present with intracranial hemorrhage compared to their pediatric counterparts.
explanation: This supports intracranial hemorrhage as an adult-enriched presentation.
genetic:
- name: RNF213 susceptibility
association: Predisposing
presence: Positive
gene_term:
preferred_term: RNF213
term:
id: hgnc:14539
label: RNF213
notes: >-
RNF213, particularly p.R4810K, is a major susceptibility locus in East Asian
moyamoya disease but is not deterministically causative in all patients.
evidence:
- reference: DOI:10.3390/biomedicines13010017
reference_title: "Exploring RNF213 in Ischemic Stroke and Moyamoya Disease: From Cellular Models to Clinical Insights"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Initially identified as the primary susceptibility gene for MMD, RNF213—notably the p.R4810K variant—has been strongly linked to intracranial artery stenosis (ICAS) and various ischemic stroke subtypes, particularly in East Asian populations.
explanation: This supports RNF213 p.R4810K as a susceptibility variant rather than a fully penetrant cause.
- name: RNF213 variant and infectious burden interaction
association: Predisposing
presence: Positive
gene_term:
preferred_term: RNF213
term:
id: hgnc:14539
label: RNF213
notes: >-
Prospective evidence supports combined genetic and infectious-burden
associations with severe intracranial arterial stenosis in MMD.
evidence:
- reference: DOI:10.1161/JAHA.124.036830
reference_title: "RNF213 Variant and Infectious Burden Associated With Intracranial Artery Stenosis in Moyamoya Disease"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The RNF213 variant and increased IB were associated with intracranial artery stenosis in MMD.
explanation: This supports a gene-environment association with stenosis severity.
- name: GUCY1A3-associated vascular signaling susceptibility
association: Predisposing
presence: Positive
gene_term:
preferred_term: GUCY1A3
term:
id: hgnc:4685
label: GUCY1A1
notes: >-
GUCY1A3 is an older synonym for the HGNC-approved symbol GUCY1A1, encoding
the soluble guanylate cyclase alpha subunit in the NO-sGC-cGMP pathway.
evidence:
- reference: PMID:34381413
reference_title: "RNF213 and GUCY1A3 in Moyamoya Disease: Key Regulators of Metabolism, Inflammation, and Vascular Stability."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Genetic studies identified RNF213/Mysterin and GUCY1A3 as disease-causing genes.
explanation: This review supports GUCY1A3/GUCY1A1 as a moyamoya-associated vascular signaling gene.
diagnosis:
- name: Neurovascular imaging
description: >-
Diagnosis is based on vascular imaging showing terminal internal carotid or
circle-of-Willis stenosis with moyamoya collateral vessels; advanced MRI may
help distinguish adult MMD from atherosclerosis.
diagnosis_term:
preferred_term: diagnostic imaging
results: Imaging demonstrates intracranial stenosis or occlusion and moyamoya collateral networks.
evidence:
- reference: DOI:10.1159/000540254
reference_title: "Adult Moyamoya disease and moyamoya syndrome: what’s new?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
3-dimensional constructive interference in steady-state MRI is useful for the differential diagnosis of MMD from atherosclerosis.
explanation: This supports MRI-based diagnostic differentiation in adult moyamoya.
- name: Updated unilateral moyamoya diagnostic criteria
description: >-
Updated Japanese diagnostic criteria no longer require bilateral
intracranial carotid involvement, reflecting evidence that unilateral MMD
can progress.
diagnosis_term:
preferred_term: diagnostic imaging
results: Unilateral terminal internal carotid involvement with moyamoya vessels can meet updated diagnostic criteria.
evidence:
- reference: DOI:10.1159/000540254
reference_title: "Adult Moyamoya disease and moyamoya syndrome: what’s new?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
The latest guidelines by the Research Committee on MMD of the Japanese Ministry of Health, Labor, and Welfare, removed limitations of the previous definition that required bilateral involvement of the intracranial carotid artery to make the diagnosis, given the increasing evidence of progression to bilateral involvement in unilateral MMD.
explanation: This supports unilateral MMD recognition in updated diagnostic criteria.
treatments:
- name: Surgical revascularization
description: >-
Surgical revascularization is the main treatment for symptomatic disease;
direct, indirect, or combined bypass approaches are selected based on age,
symptoms, anatomy, and center expertise.
treatment_term:
preferred_term: surgical procedure
term:
id: MAXO:0000004
label: surgical procedure
evidence:
- reference: DOI:10.3171/2024.1.JNS221977
reference_title: "Management of moyamoya disease: a review of current and future therapeutic strategies"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
Surgical revascularization is indicated in symptomatic cases, and antiplatelet therapy may be a useful adjunct to prevent recurrent symptoms.
explanation: This review directly supports revascularization for symptomatic MMD.
- reference: DOI:10.1159/000540254
reference_title: "Adult Moyamoya disease and moyamoya syndrome: what’s new?"
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: >-
In the Japan Adult Moyamoya trial, a randomized controlled trial for bilateral extracranial-intracranial direct bypass versus conservative therapy in patients with MMD, who had intracranial hemorrhage, recurrent bleeding, completed stroke or crescendo transient ischemic attack was significantly fewer with direct bypass than with conservative care.
explanation: This supports direct bypass benefit over conservative care for hemorrhagic or high-risk adult MMD presentations.
- name: Antiplatelet therapy
description: >-
Antiplatelet therapy can be considered as an adjunct in selected patients,
particularly to reduce recurrent ischemic symptoms.
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
evidence:
- reference: DOI:10.1159/000540254
reference_title: "Adult Moyamoya disease and moyamoya syndrome: what’s new?"
supports: PARTIAL
evidence_source: HUMAN_CLINICAL
snippet: >-
The latest Japanese Guidelines and American Scientific Statement described that antiplatelet therapy can be considered reasonable.
explanation: This supports guideline-consistent adjunctive use but not definitive disease modification.
Moyamoya disease (MMD) is a chronic, progressive cerebrovascular arteriopathy characterized by stenosis/occlusion centered on the terminal intracranial internal carotid arteries (and proximal branches) with development of abnormal collateral networks that produce a classic “moyamoya” (“puff-of-smoke”) appearance on angiography and related imaging (kappel2024managementofmoyamoya pages 1-2, kappel2024managementofmoyamoya pages 2-3, uchiyama2024adultmoyamoyadisease pages 2-3, uchiyama2024adultmoyamoyadisease pages 3-4).
Direct abstract quote (management review, 2024): “Moyamoya disease (MMD) is characterized by idiopathic, progressive stenosis of the circle of Willis and the terminal portion of the internal carotid arteries with the development of prominent small collateral vessels and a characteristic moyamoya or puff-of-smoke radiographic appearance.” (Oct 2024, Journal of Neurosurgery; URL: https://doi.org/10.3171/2024.1.jns221977) (kappel2024managementofmoyamoya pages 1-2).
In the retrieved evidence, only OMIM:252350 was explicitly observed; MONDO, Orphanet (ORPHA), ICD-10/ICD-11 codes, and MeSH unique IDs were not present in the accessible excerpts (artifact-00). (kappel2024managementofmoyamoya pages 1-2, santos2025managementofmoyamoyab pages 3-4).
Common alternate labels used in the retrieved literature include moyamoya vasculopathy, moyamoya arteriopathy, moyamoya syndrome (MMS) (syndromic/secondary forms), and quasi-moyamoya disease (calandrelli2026moyamoyavasculopathyand pages 1-2, kappel2024managementofmoyamoya pages 1-2, uchiyama2024adultmoyamoyadisease pages 1-2).
The information in this report is derived primarily from aggregated disease-level resources (peer-reviewed reviews, meta-analyses, and primary research studies), rather than individual EHR-derived patient summaries (artifact-00). (kappel2024managementofmoyamoya pages 1-2, uchiyama2024adultmoyamoyadisease pages 1-2).
| Field | Value | Notes/Evidence |
|---|---|---|
| Disease name | Moyamoya disease | Canonical name used throughout recent reviews; abbreviated MMD (kappel2024managementofmoyamoya pages 1-2, uchiyama2024adultmoyamoyadisease pages 1-2) |
| Abbreviation | MMD | Explicitly defined as “Moyamoya disease (MMD)” (kappel2024managementofmoyamoya pages 1-2, uchiyama2024adultmoyamoyadisease pages 1-2) |
| Related condition name | Moyamoya syndrome | Distinct term for moyamoya-like vasculopathy associated with other diseases/conditions; abbreviated MMS (kappel2024managementofmoyamoya pages 1-2, uchiyama2024adultmoyamoyadisease pages 1-2) |
| Abbreviation | MMS | Explicitly defined as “moyamoya syndrome (MMS)” (kappel2024managementofmoyamoya pages 1-2, uchiyama2024adultmoyamoyadisease pages 1-2) |
| Umbrella term / broader label | Moyamoya vasculopathy | Used as an umbrella term (MMV) in review literature (calandrelli2026moyamoyavasculopathyand pages 1-2, uchiyama2024adultmoyamoyadisease pages 1-2) |
| Abbreviation | MMV | Explicitly defined as “Moyamoya vasculopathy (MMV)” (calandrelli2026moyamoyavasculopathyand pages 1-2) |
| Synonym / related descriptor | Moyamoya arteriopathy | Used in recent management review as a related descriptor (kappel2024managementofmoyamoya pages 1-2) |
| Synonym / related descriptor | Quasi-moyamoya disease | Reported as a synonym/related label for syndromic or associated forms in review literature (kappel2024managementofmoyamoya pages 1-2) |
| Synonym / related descriptor | Moyamoya-like vasculopathy | Used to describe associated/systemic-disease forms (uchiyama2024adultmoyamoyadisease pages 1-2) |
| Synonym / related descriptor | Moyamoya-like patterns | Used for atypical radiologic patterns within the moyamoya spectrum (calandrelli2026moyamoyavasculopathyand pages 1-2) |
| Descriptive imaging phrase | Puff-of-smoke appearance | Characteristic collateral appearance repeatedly cited as descriptive terminology rather than a formal synonym (calandrelli2026moyamoyavasculopathyand pages 1-2, kappel2024managementofmoyamoya pages 1-2) |
| OMIM | 252350 | Retrieved evidence includes OMIM:252350 linked to moyamoya disease in older literature snippets (uchiyama2024adultmoyamoyadisease media e5baf62b) |
| MONDO ID | Not found in retrieved sources | No explicit MONDO identifier present in the provided evidence excerpts (calandrelli2026moyamoyavasculopathyand pages 1-2, kappel2024managementofmoyamoya pages 1-2, uchiyama2024adultmoyamoyadisease pages 1-2) |
| Orphanet / ORPHA ID | Not found in retrieved sources | No explicit Orphanet identifier present in the provided evidence excerpts (calandrelli2026moyamoyavasculopathyand pages 1-2, kappel2024managementofmoyamoya pages 1-2, uchiyama2024adultmoyamoyadisease pages 1-2) |
| ICD-10 code | Not found in retrieved sources | No explicit ICD-10 code present in the provided evidence excerpts (calandrelli2026moyamoyavasculopathyand pages 1-2, kappel2024managementofmoyamoya pages 1-2, uchiyama2024adultmoyamoyadisease pages 1-2) |
| ICD-11 code | Not found in retrieved sources | No explicit ICD-11 code present in the provided evidence excerpts (calandrelli2026moyamoyavasculopathyand pages 1-2, kappel2024managementofmoyamoya pages 1-2, uchiyama2024adultmoyamoyadisease pages 1-2) |
| MeSH descriptor | Moyamoya disease | MeSH-tagged disease term explicitly present in systematic-review indexing text, though no MeSH ID was provided in the evidence (santos2025managementofmoyamoyab pages 3-4, santos2025managementofmoyamoyaa pages 3-4) |
| MeSH ID | Not found in retrieved sources | Evidence shows MeSH term usage/subheadings but not the numeric/unique MeSH identifier (santos2025managementofmoyamoyab pages 3-4, santos2025managementofmoyamoyaa pages 3-4) |
| Evidence source level | Aggregated disease-level resources and reviews | Information summarized in retrieved evidence comes from reviews/guidelines and disease-level literature, not individual-patient EHR datasets (kappel2024managementofmoyamoya pages 1-2, uchiyama2024adultmoyamoyadisease pages 1-2) |
Table: This table compiles the key names, abbreviations, and formal identifiers for Moyamoya disease that were explicitly available in the retrieved evidence. It is useful for normalizing terminology for a disease knowledge base while clearly flagging identifiers not found in the provided sources.
MMD is widely treated as a multifactorial disease with strong genetic susceptibility (most prominently RNF213 in East Asian populations) and additional environmental/inflammatory “second hits” contributing to penetrance and progression (kappel2024managementofmoyamoya pages 2-3, tan2024exploringrnf213in pages 4-6).
Key genetic susceptibility is emphasized in 2024–2025 reviews, including RNF213 and additional genes (e.g., ACTA2, DIAPH1, HLA, and rare Mendelian causes such as GUCY1A3 and BRCC3 in syndromic/familial contexts) (kappel2024managementofmoyamoya pages 1-2, he2025advancesinmoyamoya pages 8-10, he2025advancesinmoyamoya pages 13-14).
RNF213 p.R4810K (c.14576G>A; founder in East Asia) is strongly enriched among East Asian MMD patients compared with the general population, with reported patient frequencies Japanese 90.1%, Korean 78.9%, Chinese 23.1% versus population carrier frequencies Japanese 2.5%, Korean 2.7%, Chinese 0.9% (Jul 2024 review; URL: https://doi.org/10.1159/000540254) (uchiyama2024adultmoyamoyadisease pages 2-3). A 2024 review further summarizes very large effect sizes in meta-analysis (ORs ~184 Japan, ~110 Korea, ~32 China) and also reports association with overall stroke risk in broader cohorts (OR 1.91, 95% CI 1.55–2.36) (Dec 2024 review; URL: https://doi.org/10.3390/biomedicines13010017) (tan2024exploringrnf213in pages 2-4).
Incomplete penetrance and zygosity effects: a 2024 RNF213-focused review reports low penetrance among heterozygotes (“1/150–1/300 of heterozygous carriers actually develop MMD”) with much higher incidence among homozygotes (“exceeding 78%”), emphasizing the need for additional modifiers and caution about population screening (tan2024exploringrnf213in pages 4-6).
Radiation exposure is emphasized as a risk factor for moyamoya syndrome (secondary moyamoya arteriopathy) (kappel2024managementofmoyamoya pages 2-3).
Infectious/immune exposure as a progression modifier (gene–environment interaction): In a prospective cohort of 275 MMD patients, both RNF213 p.R4810K carrier status and a composite infectious-burden (IB) score were independently associated with more severe intracranial stenosis (Willis narrowing score). The RNF213 variant had OR 2.832 (95% CI 1.347–5.955; P=0.006) and IB had OR 1.771 (95% CI 1.286–2.439; P<0.001) for severe stenosis; high IB (≥5) corresponded to 50.0% severe stenosis vs 21.6% in low IB, adjusted aOR 3.212 (95% CI 1.861–5.542) (Mar 2025; URL: https://doi.org/10.1161/jaha.124.036830) (zeng2025rnf213variantand pages 5-8).
No explicit protective genetic variants or modifiable protective exposures were identified in the retrieved evidence excerpts; therefore, this section remains incompletely populated from available sources.
The 2025 prospective cohort provides direct evidence of gene–environment contributions to stenosis severity (RNF213 variant and infectious burden), and further shows interaction with modifiable metabolic factors: stronger IB effects in subgroups with higher BMI, triglycerides, and homocysteine (interaction P values reported <0.05 in the cohort report) (zeng2025rnf213variantand pages 1-2, zeng2025rnf213variantand pages 5-8).
Common clinical manifestations across the lifespan include transient ischemic attacks (TIAs), ischemic stroke, intracranial hemorrhage (more prominent in adults), seizures, headache, and cognitive impairment/cognitive decline (kappel2024managementofmoyamoya pages 1-2, kappel2024managementofmoyamoya pages 2-3, chakrabarti2025moyamoyadiseasephysiological pages 3-4).
Epidemiologic phenotype patterns reported in the 2024 management review include: - Pediatric series: 67.8% presenting with stroke and 2.8% hemorrhage (kappel2024managementofmoyamoya pages 1-2). - Adult Japanese cohort: 21% intracerebral hemorrhage (kappel2024managementofmoyamoya pages 1-2).
MMD shows a bimodal age distribution, with pediatric diagnoses typically in ages ~5–9 years and adult presentation commonly in the 5th–6th decades (kappel2024managementofmoyamoya pages 2-3).
Recent reviews emphasize neurocognitive sequelae and cognitive deficits as important contributors to morbidity and quality-of-life impact, motivating ongoing registry studies centered on cognition and imaging biomarkers (NCT05619068 chunk 1, kappel2024managementofmoyamoya pages 1-2).
A structured phenotype-to-HPO mapping based on the retrieved evidence is provided below.
| Clinical phenotype | Suggested HPO term(s) | Typical age group (pediatric/adult) | Notes on frequency/severity if available from evidence |
|---|---|---|---|
| Ischemic stroke / cerebral infarction | HP:0001297 Cerebral infarction; Ischemic stroke | Both; especially pediatric | Most common presentation overall; pediatric series cited in review reported 67.8% presenting with stroke, while children more often present with ischemia than hemorrhage (kappel2024managementofmoyamoya pages 1-2, uchiyama2024adultmoyamoyadisease pages 2-3) |
| Transient ischemic attack | HP:0002326 Transient ischemic attack | Both; common in pediatric and early disease | Frequently reported presenting manifestation; pediatric patients often present with stroke/TIA; RNF213-associated disease linked to earlier onset and TIAs in some summaries (kappel2024managementofmoyamoya pages 2-3, bagyinszky2025multisystemicimpactof pages 4-6) |
| Intracranial hemorrhage / hemorrhagic stroke | HP:0002170 Intracranial hemorrhage; Hemorrhagic stroke | More common in adults | Adult patients are nearly twice as likely as pediatric patients to present with intracranial hemorrhage; one adult Japanese cohort cited 21% intracerebral hemorrhage, versus only 2.8% hemorrhage in a pediatric series (kappel2024managementofmoyamoya pages 1-2, kappel2024managementofmoyamoya pages 2-3) |
| Seizures | HP:0001250 Seizure | Both; often pediatric but can occur in either | Recognized clinical manifestation; listed among common presentations in recent reviews, though no robust frequency estimate was provided in retrieved evidence (chakrabarti2025moyamoyadiseasephysiological pages 3-4, calandrelli2026moyamoyavasculopathyand pages 5-6) |
| Headache | HP:0002315 Headache | Both | Reported as a common presenting symptom in recent reviews; frequency not quantified in retrieved evidence (chakrabarti2025moyamoyadiseasephysiological pages 3-4) |
| Cognitive impairment / cognitive decline | HP:0100543 Cognitive impairment; Neurocognitive dysfunction | Both; may be more evident in chronic disease and adults | Reviews note cognitive deficits and neurocognitive sequelae affecting quality of life; homozygous RNF213 carriers may have greater cognitive impairment (chakrabarti2025moyamoyadiseasephysiological pages 3-4, bagyinszky2025multisystemicimpactof pages 4-6) |
| Developmental delay / neurodevelopmental impact | HP:0001263 Global developmental delay; Developmental delay | Pediatric | Pediatric chronic cerebral hypoperfusion can manifest with developmental delay; highlighted in review-level evidence rather than quantified cohort data (chakrabarti2025moyamoyadiseasephysiological pages 3-4) |
| Hemiparesis / focal neurologic deficit | HP:0001269 Hemiparesis; Focal neurologic deficit | Both | Common downstream manifestation of ischemic or hemorrhagic events; not separately quantified in retrieved evidence but clinically central to stroke presentation (kappel2024managementofmoyamoya pages 1-2, chakrabarti2025moyamoyadiseasephysiological pages 3-4) |
| Posterior cerebral artery involvement | HP term label: Posterior cerebral artery stenosis/occlusion | Both; associated with more severe disease | Important vascular phenotype and risk marker; associated with perioperative cerebral infarction risk (OR 2.62) and with RNF213-related severity in several reports (uchiyama2024adultmoyamoyadisease pages 3-4, bagyinszky2025multisystemicimpactof pages 4-6) |
| Progressive intracranial arterial stenosis / occlusion | HP term label: Intracranial arterial stenosis; Cerebral artery occlusion | Both | Core vascular phenotype of disease; terminal ICA-centered stenosis/occlusion with moyamoya collaterals is required for diagnosis. Severe stenosis is associated with RNF213 variant carriage and higher infectious burden (RNF213 OR 2.832; IB OR 1.771 for severe WNS) (uchiyama2024adultmoyamoyadisease pages 3-4, zeng2025rnf213variantand pages 5-8, zeng2025rnf213variantand pages 1-2) |
| Abnormal collateral vessel formation ("puff-of-smoke") | HP term label: Abnormal cerebral collateral circulation | Both | Hallmark angiographic phenotype; characteristic collateral network defines the disease radiographically, but this is an imaging phenotype rather than a patient-reported symptom (kappel2024managementofmoyamoya pages 1-2, uchiyama2024adultmoyamoyadisease pages 2-3, uchiyama2024adultmoyamoyadisease pages 3-4) |
| Asymptomatic moyamoya arteriopathy | HP term label: Asymptomatic cerebrovascular disease | Both; increasingly detected in adults | Increasingly recognized through imaging; historical reports in review cite asymptomatic cases rising from 1.5% to 17.8%, with AMORE showing 1.0% annual stroke risk per hemisphere over 5 years (kappel2024managementofmoyamoya pages 1-2, kappel2024managementofmoyamoya pages 5-6) |
Table: This table maps major clinical and vascular phenotypes of moyamoya disease to suggested HPO terms and summarizes age-pattern and severity/frequency notes drawn from the retrieved evidence. It is useful for structured phenotype annotation in a disease knowledge base.
RNF213 is the major susceptibility gene in East Asian MMD and is also discussed as a broader vasculopathy gene with diverse phenotypes (uchiyama2024adultmoyamoyadisease pages 2-3, tan2024exploringrnf213in pages 2-4).
Additional MMD-related genes are highlighted in 2024–2025 review literature (often as syndromic or secondary moyamoya causes/associations): GUCY1A3, BRCC3, and genes implicated in vascular smooth muscle and arterial disease spectra such as ACTA2, DIAPH1, and immune loci such as HLA (kappel2024managementofmoyamoya pages 1-2, he2025advancesinmoyamoya pages 8-10, he2025advancesinmoyamoya pages 13-14).
| Gene (HGNC symbol) | Variant/example | Evidence type (human genetic association/functional model) | Key finding | Key quantitative statistic | Source (PMID/DOI/URL if in evidence) |
|---|---|---|---|---|---|
| RNF213 | p.R4810K / c.14576G>A (also described as p.R4859K in one review) | Human genetic association | Major East Asian founder susceptibility variant for moyamoya disease; strongly enriched in familial and sporadic cases; associated with earlier onset and more severe disease | Japanese/Korean/Chinese MMD patient frequencies 90.1% / 78.9% / 23.1% vs general population 2.5% / 2.7% / 0.9%; OR ~144 for definite MMD and ~54 for unilateral MMD in cited cohorts (uchiyama2024adultmoyamoyadisease pages 2-3). Another review: Japan OR 184.04, Korea 109.77, China 31.53; stroke OR 1.91 (95% CI 1.55–2.36) (tan2024exploringrnf213in pages 2-4) | Uchiyama & Fujimura 2024, DOI: 10.1159/000540254, https://doi.org/10.1159/000540254 (uchiyama2024adultmoyamoyadisease pages 2-3); Tan et al. 2024, DOI: 10.3390/biomedicines13010017, https://doi.org/10.3390/biomedicines13010017 (tan2024exploringrnf213in pages 2-4) |
| RNF213 | p.R4810K / c.14576G>A | Human genetic association; penetrance analysis | Strong effect but incomplete penetrance; zygosity influences severity and age at onset | General East Asian population frequency around 1–2%; only ~1/150–1/300 heterozygous carriers develop MMD, while homozygous disease incidence exceeds 78%; homozygotes median onset 3 years vs 7 years in heterozygotes (tan2024exploringrnf213in pages 4-6, tan2024exploringrnf213in pages 2-4) | Tan et al. 2024, DOI: 10.3390/biomedicines13010017, https://doi.org/10.3390/biomedicines13010017 (tan2024exploringrnf213in pages 2-4, tan2024exploringrnf213in pages 4-6) |
| RNF213 | Loss-of-function; pathogenic mutations including CNV deletion and disease-associated missense variants | Functional model + human pathology | RNF213 loss promotes pathological angiogenesis and vascular remodeling; implicated in Hippo/YAP/TAZ→VEGFR2 dysregulation and intimal hyperplasia | In HBMECs, RNF213 knockdown increased endothelial proliferation/migration/tube formation; YAP/TAZ activation with p-TAZ/TAZ ~0.61 and p-YAP/YAP ~0.43; surface VEGFR2 ~1.28-fold and intracellular VEGFR2 ~0.59-fold vs control; severe WNS OR 2.832 for RNF213 variant in a prospective cohort (ye2023rnf213lossoffunctionpromotes pages 11-13, ye2023rnf213lossoffunctionpromotes pages 10-11, zeng2025rnf213variantand pages 5-8) | Ye et al. 2023, DOI: 10.1093/brain/awad225, https://doi.org/10.1093/brain/awad225 (ye2023rnf213lossoffunctionpromotes pages 11-13, ye2023rnf213lossoffunctionpromotes pages 10-11, ye2023rnf213lossoffunctionpromotes pages 1-2, ye2023rnf213lossoffunctionpromotes pages 2-3); Zeng et al. 2025, DOI: 10.1161/JAHA.124.036830, https://doi.org/10.1161/jaha.124.036830 (zeng2025rnf213variantand pages 5-8) |
| RNF213 | Rare C-terminal / non-p.R4810K variants | Human genetic association | Allelic heterogeneity outside East Asia; rare C-terminal RNF213 variants reported in Caucasian moyamoya cases | Variant rare/absent in White/Caucasian cohorts in one review (maximum allele frequency reported 0.0006; absent in one WES series of 125 Caucasian patients) (he2025advancesinmoyamoya pages 8-10) | He et al. 2025, DOI: 10.1002/mco2.70054, https://doi.org/10.1002/mco2.70054 (he2025advancesinmoyamoya pages 8-10, bagyinszky2025multisystemicimpactof pages 17-18) |
| GUCY1A3 | Loss-of-function mutations; compound heterozygous familial variants | Human genetic association | Supports nitric oxide/soluble guanylate cyclase pathway involvement; implicated in familial/syndromic moyamoya | Two compound heterozygotes among 96 sequenced cases in one report; larger case-control study (255 patients vs 300 controls) showed no association in another dataset (he2025advancesinmoyamoya pages 13-14) | He et al. 2025, DOI: 10.1002/mco2.70054, https://doi.org/10.1002/mco2.70054 (he2025advancesinmoyamoya pages 13-14) |
| BRCC3 | Deletions / loss-of-function | Human genetic association | Causes X-linked syndromic moyamoya in case reports/families; supports abnormal angiogenesis pathway | Population studies referenced in a review showed no difference outside syndromic cases; quantitative association not established in broader cohorts in retrieved evidence (he2025advancesinmoyamoya pages 13-14) | He et al. 2025, DOI: 10.1002/mco2.70054, https://doi.org/10.1002/mco2.70054 (he2025advancesinmoyamoya pages 13-14) |
| ACTA2 | Pathogenic mutations (specific variant not provided in retrieved evidence) | Review-level human genetic association | Implicated as a moyamoya-related gene beyond RNF213; especially relevant to syndromic/monogenic vasculopathy spectrum | No variant-specific quantitative statistic provided in retrieved evidence | He et al. 2025, DOI: 10.1002/mco2.70054, https://doi.org/10.1002/mco2.70054 (he2025advancesinmoyamoya pages 8-10); Kappel et al. 2024, DOI: 10.3171/2024.1.JNS221977, https://doi.org/10.3171/2024.1.jns221977 (kappel2024managementofmoyamoya pages 1-2) |
| DIAPH1 | Pathogenic mutations (specific variant not provided in retrieved evidence) | Review-level human genetic association | Listed among MMD-related genes beyond RNF213 in recent review literature | No variant-specific quantitative statistic provided in retrieved evidence | He et al. 2025, DOI: 10.1002/mco2.70054, https://doi.org/10.1002/mco2.70054 (he2025advancesinmoyamoya pages 8-10) |
| HLA | HLA susceptibility loci/alleles (not specified in retrieved evidence) | Review-level human genetic association | HLA-region genetic susceptibility has been reported in MMD, supporting immune/inflammatory contribution | No variant-specific quantitative statistic provided in retrieved evidence | He et al. 2025, DOI: 10.1002/mco2.70054, https://doi.org/10.1002/mco2.70054 (he2025advancesinmoyamoya pages 8-10) |
Table: This table summarizes the principal genes and representative variants implicated in moyamoya disease from the retrieved evidence, emphasizing RNF213 p.R4810K and other genes named in recent reviews. It is useful for quickly distinguishing strong human genetic associations from lower-detail review-level gene mentions and mechanistic model evidence.
A key 2023 Brain paper provides multi-system mechanistic evidence that RNF213 loss-of-function promotes pathological angiogenesis via Hippo pathway dysregulation:
Direct abstract quote (Jul 2023, Brain): “RNF213 deletion exacerbated pathological angiogenesis… Reduced RNF213 expression led to increased endothelial cell proliferation, migration and tube formation… Endothelial knockdown of RNF213 activated the Hippo pathway effector Yes-associated protein (YAP)/tafazzin (TAZ) and promoted the overexpression of the downstream effector VEGFR2… inhibition of YAP/TAZ… reversed RNF213 knockdown-induced angiogenesis.” (URL: https://doi.org/10.1093/brain/awad225) (ye2023rnf213lossoffunctionpromotes pages 1-2).
Quantitative molecular readouts reported include altered Hippo phosphorylation ratios and VEGFR2 trafficking: p-TAZ/TAZ ~0.61 and p-YAP/YAP ~0.43 (lower than control), with increased surface VEGFR2 (~1.28-fold) and reduced intracellular VEGFR2 (~0.59-fold) in RNF213 knockdown endothelial cells (ye2023rnf213lossoffunctionpromotes pages 11-13).
RNF213 p.R4810K shows incomplete penetrance in heterozygotes with very high incidence in homozygotes, consistent with a “susceptibility + second hit” model rather than a fully penetrant Mendelian cause in most populations (tan2024exploringrnf213in pages 4-6).
The retrieved excerpts do not provide a validated list of modifier genes with quantified effect on severity; however, multiple reviews frame MMD as polygenic/multifactorial with additional genes (ACTA2/DIAPH1/HLA and others) that may influence phenotype heterogeneity (he2025advancesinmoyamoya pages 8-10).
A 2024 Molecular Therapy – Nucleic Acids review summarizes multiple epigenetic layers implicated in MMD: - DNA methylation: promoter hypomethylation of SORT1 in endothelial colony-forming cells (ECFCs) from MMD patients, with increased SORT1 expression and downstream pro-angiogenic factor changes (VEGF/VEGFR-1/bFGF/MMP9 up; Ang-1 and thrombospondin 2 down) (xu2024insightsintothe pages 3-4). - Histone modifications: reduced acetyl-histone H3K27 binding at RALDH2 promoter with reduced RALDH2 expression (retinoic acid synthesis) in ECFCs; HDAC inhibitor panobinostat reportedly restored impaired angiogenic potential in that context (xu2024insightsintothe pages 3-4). - Noncoding RNAs: multiple circulating or CSF miRNA/circRNA signatures are discussed as candidate biomarkers and mechanistic drivers; examples include serum let-7c, CSF exosome miRNA panels, and multiple differentially expressed circRNAs (xu2024insightsintothe pages 16-17, xu2024insightsintothe pages 13-14).
The retrieved 2024 management review identifies CNS infections and radiation exposure (particularly for moyamoya syndrome) as notable non-genetic contributors, alongside circulating cytokines/growth factors and autoantibodies as signals of inflammatory contribution (kappel2024managementofmoyamoya pages 1-2).
The prospective gene–environment cohort indicates that infectious-burden associations with stenosis severity were amplified among patients with higher BMI, triglycerides, and homocysteine—suggesting potentially modifiable metabolic contexts may influence progression (zeng2025rnf213variantand pages 1-2).
The infectious-burden score in the prospective cohort was built from antibody titers to HSV-1/2, CMV, Toxoplasma, rubella, and EBV, and was associated with more severe stenosis in MMD (zeng2025rnf213variantand pages 2-4, zeng2025rnf213variantand pages 5-8).
A synthesis supported by the retrieved evidence is: 1) Genetic susceptibility (especially RNF213 p.R4810K in East Asia) establishes a predisposition with incomplete penetrance (uchiyama2024adultmoyamoyadisease pages 2-3, tan2024exploringrnf213in pages 4-6). 2) Second-hit exposures (e.g., inflammatory/infectious burden; radiation in syndromic cases) and metabolic context can contribute to progression/severity (zeng2025rnf213variantand pages 5-8, kappel2024managementofmoyamoya pages 2-3). 3) At the vessel wall level, disease is characterized by steno-occlusive remodeling and collateral network formation; RNF213 perturbation can drive endothelial dysfunction and aberrant angiogenesis (kappel2024managementofmoyamoya pages 1-2, ye2023rnf213lossoffunctionpromotes pages 1-2). 4) A demonstrated molecular axis in endothelial models is Hippo pathway “off” signaling → YAP/TAZ activation → VEGFR2 dysregulation/trafficking changes → hyperangiogenic phenotype, observed in human brain microvascular endothelial cells and corroborated in mouse and zebrafish models (ye2023rnf213lossoffunctionpromotes pages 10-11, ye2023rnf213lossoffunctionpromotes pages 11-13, ye2023rnf213lossoffunctionpromotes pages 1-2).
Immune/inflammatory contributions are supported by (i) review-level discussions of cytokines/autoantibodies/infections and (ii) the prospective infectious-burden severity association (kappel2024managementofmoyamoya pages 1-2, zeng2025rnf213variantand pages 5-8).
GO biological process (suggestions): angiogenesis; regulation of endothelial cell proliferation; regulation of endothelial cell migration; VEGF receptor signaling pathway; Hippo signaling; regulation of vascular remodeling; inflammatory response; blood–brain barrier maintenance (ye2023rnf213lossoffunctionpromotes pages 1-2, kappel2024managementofmoyamoya pages 2-3).
CL cell types (suggestions): brain microvascular endothelial cell; vascular smooth muscle cell; endothelial colony-forming cell (ECFC) (ye2023rnf213lossoffunctionpromotes pages 1-2, xu2024insightsintothe pages 3-4).
Primary involvement is intracranial arterial circulation centered on the terminal intracranial internal carotid artery and proximal MCA/ACA involvement; collateral networks form near the lesions (uchiyama2024adultmoyamoyadisease pages 3-4).
Updated diagnostic criteria allow unilateral disease; unilateral cases can progress to bilateral disease (uchiyama2024adultmoyamoyadisease pages 1-2, uchiyama2024adultmoyamoyadisease pages 3-4).
Intracranial internal carotid artery; middle cerebral artery; anterior cerebral artery; circle of Willis; basal ganglia; periventricular white matter.
Bimodal onset/diagnosis: pediatric (~5–9 years) and adult (5th–6th decades) (kappel2024managementofmoyamoya pages 2-3).
MMD is described as progressive steno-occlusive arteriopathy. In asymptomatic cases, a disease registry analysis cited in the management review reports an annual stroke risk of 1.0% per moyamoya hemisphere over the first 5 years, with a predominance of hemorrhagic strokes among events (85.7%) (kappel2024managementofmoyamoya pages 2-3, kappel2024managementofmoyamoya pages 5-6).
The 2024 management review provides region-specific incidence and prevalence trends: - Japan incidence reported 0.35/100,000 (1994) to 0.54/100,000 (2003) (kappel2024managementofmoyamoya pages 2-3). - Korea incidence increased 1.7→2.3/100,000 (2007–2011) and prevalence increased 8.2→16.1/100,000 by 2011 (kappel2024managementofmoyamoya pages 2-3). - Taiwan incidence increased 0.14→0.20/100,000 person-years (2000–2011) (kappel2024managementofmoyamoya pages 2-3). - Denmark incidence ~0.07/100,000 person-years (2008–2017) and U.S. ~0.086/100,000 person-years (kappel2024managementofmoyamoya pages 2-3).
Sex ratio: approximately 1.8–2.2 female-to-male ratio is reported (kappel2024managementofmoyamoya pages 1-2, kappel2024managementofmoyamoya pages 2-3).
Familial aggregation: family history reported in ~10–15% (kappel2024managementofmoyamoya pages 2-3).
RNF213 p.R4810K is best described (in these sources) as a strong susceptibility allele with autosomal-dominant pattern and incomplete penetrance; penetrance is very low for heterozygotes but much higher for homozygotes (tan2024exploringrnf213in pages 4-6, tan2024exploringrnf213in pages 2-4).
The 2021 Revised Diagnostic Criteria for MMD (Japanese RCMD guidance, summarized in 2024 review literature) include: - Diagnosis can be made in unilateral or bilateral cases. - Required radiologic features include stenosis/occlusion centered on the terminal intracranial ICA and the presence of moyamoya vessels (abnormal vascular networks) near the occlusive lesions. - Heavy T2-weighted MRI demonstration of decreased outer diameter of terminal ICA/horizontal MCA is emphasized to distinguish MMD from atherosclerosis; 3D-CISS MRI is highlighted as useful for this differentiation (uchiyama2024adultmoyamoyadisease pages 3-4, uchiyama2024adultmoyamoyadisease pages 1-2).
A visual table from the 2024 review shows the Suzuki angiographic staging system (I–VI) and indicates where the diagnostic criteria table is located in the paper (uchiyama2024adultmoyamoyadisease media e5baf62b, uchiyama2024adultmoyamoyadisease media aace831c).
Quantitative MRA scoring (Houkin MRA score) correlating with Suzuki staging is used to grade arterial involvement (uchiyama2024adultmoyamoyadisease pages 2-3, uchiyama2024adultmoyamoyadisease pages 3-4).
MMD must be distinguished from mimics such as intracranial atherosclerosis; imaging emphasis on outer arterial diameter reduction on heavy T2/3D-CISS supports this differentiation (uchiyama2024adultmoyamoyadisease pages 3-4).
Asymptomatic MMD is increasingly detected on imaging; a registry analysis cited in the 2024 management review reported 1.0% annual stroke risk per hemisphere over 5 years, with 85.7% hemorrhagic among observed strokes (kappel2024managementofmoyamoya pages 1-2, kappel2024managementofmoyamoya pages 5-6).
In pediatric revascularization meta-analysis (37 studies; 2,460 patients; 4,432 hemispheres), functional outcomes at last follow-up (mRS 0–1) were pooled at ~80.38% for indirect bypass and ~87.44% for direct/combined bypass; mortality was very low (pooled indirect bypass mortality 0.30%) (Feb 2023; URL: https://doi.org/10.1007/s00381-023-05868-6) (lee2023surgicalrevascularizationsfor pages 12-13).
Surgical revascularization is the mainstay for symptomatic MMD, including direct, indirect, and combined extracranial-intracranial bypass techniques; indirect approaches rely on angiogenic potential and are described as more effective in children, while direct/combined bypasses are described as more effective in adults (kappel2024managementofmoyamoya pages 5-6).
Adjunctive antiplatelet therapy (e.g., aspirin in pediatric practice in the U.S.) is used for ischemic symptom prevention, though the retrieved evidence excerpts did not provide pooled randomized effect estimates (kappel2024managementofmoyamoya pages 5-6).
Pediatric meta-analysis found no significant differences between direct/combined versus indirect bypass for stroke recurrence, morbidity, or mortality, but direct/combined had better angiographic revascularization (Matsushima Grade A/B RR 1.12, 95% CI 1.02–1.24) and higher wound complication risk (RR 2.54, 95% CI 1.82–3.55) (lee2023surgicalrevascularizationsfor pages 1-2).
A 2025 systematic review/meta-analysis supports noninvasive ultrasonography for postoperative bypass assessment with predictive changes in STA/ECA flow parameters (e.g., STA PSV MD 28.26 within 2 weeks for high bypass capacity) (santos2025managementofmoyamoyaa pages 1-3).
A structured treatment-to-MAXO mapping (labels suggested) is provided below.
| Treatment/strategy | MAXO term suggestion (label) | Indication (e.g., symptomatic ischemic, hemorrhagic, pediatric) | Evidence summary | Key quantitative outcome if available | Sources |
|---|---|---|---|---|---|
| Direct extracranial-intracranial bypass (e.g., STA-MCA bypass) | surgical revascularization procedure; extracranial-intracranial arterial bypass | Symptomatic adult MMD, especially ischemic; also used in hemorrhagic disease | Review evidence indicates surgical revascularization is the mainstay for symptomatic disease; direct and combined bypass appear more effective than indirect bypass in adults for prevention of recurrent stroke/hemorrhage. Endovascular stenting has generally not prevented progression, reinforcing surgery as standard definitive therapy. | Adult comparative metrics not quantified in retrieved full evidence excerpts; qualitative consensus favors direct/combined over indirect in adults. | (kappel2024managementofmoyamoya pages 5-6, uchiyama2024adultmoyamoyadisease pages 1-2) |
| Indirect bypass (e.g., EDAS/EMS/encephaloduroarteriosynangiosis-based approaches) | indirect cerebral revascularization procedure | Pediatric MMD/MMS; symptomatic ischemic disease; patients with small recipient vessels | Indirect procedures rely on angiogenic potential and are described as particularly effective in children. Pediatric meta-analysis found indirect bypass to be overall safe and effective, though angiographic collateralization was somewhat better with direct/combined strategies. | In pediatric meta-analysis, no significant difference vs direct/combined for stroke recurrence, morbidity, or mortality; wound complications were lower than direct/combined. | (kappel2024managementofmoyamoya pages 5-6, lee2023surgicalrevascularizationsfor pages 1-2, lee2023surgicalrevascularizationsfor pages 12-13) |
| Combined direct + indirect bypass | combined surgical revascularization procedure | Adult symptomatic MMD; selected pediatric cases; situations seeking immediate + delayed collateral supply | Reviews report combined/direct bypasses perform better in adults than indirect alone. Pediatric meta-analysis suggests improved long-term angiographic revascularization versus indirect bypass, but without clear long-term stroke or mortality advantage. | Matsushima Grade A/B angiographic revascularization favored direct/combined over indirect: RR 1.12 (95% CI 1.02-1.24); wound complications higher with direct/combined: RR 2.54 (95% CI 1.82-3.55). | (kappel2024managementofmoyamoya pages 5-6, lee2023surgicalrevascularizationsfor pages 1-2, lee2023surgicalrevascularizationsfor pages 12-13) |
| Antiplatelet therapy (aspirin; clopidogrel; short dual antiplatelet therapy in some adults) | antiplatelet therapy | Adjunctive therapy for ischemic presentations; peri-diagnostic/medical management; pediatric aspirin commonly used in U.S. practice | Antiplatelet therapy is used as adjunctive medical management, especially for ischemic symptoms. Review notes aspirin is commonly used in children and some adult studies suggest fewer ischemic events with aspirin, clopidogrel, or short dual therapy, but this is adjunctive rather than disease-modifying. | No pooled effect size provided in retrieved evidence excerpts. | (kappel2024managementofmoyamoya pages 5-6, uchiyama2024adultmoyamoyadisease pages 1-2) |
| Conservative management with serial imaging surveillance | clinical surveillance; watchful waiting | Asymptomatic MMD; some stable MMS/MMV cases; patients without clear hemodynamic compromise | Asymptomatic disease is generally managed conservatively with watchful waiting and serial imaging. For moyamoya syndrome/vasculopathy, conservative management plus treatment of the underlying disorder is emphasized unless progressive symptoms or chronic hemodynamic insufficiency develop. | AMORE study cited in review: annual stroke risk 1.0% per moyamoya hemisphere over 5 years; 85.7% of strokes were hemorrhagic. | (kappel2024managementofmoyamoya pages 5-6, kappel2024managementofmoyamoya pages 2-3, calandrelli2026moyamoyavasculopathyand pages 5-6, kappel2024managementofmoyamoya pages 1-2) |
| Secondary prevention directed at underlying syndrome/comorbidity | secondary prevention strategy; treatment of underlying disease | Moyamoya syndrome / quasi-moyamoya associated with radiation, autoimmune disease, sickle cell disease, NF1, etc. | MMS is defined by moyamoya-pattern arteriopathy with comorbid conditions. Management is pattern-specific and often conservative, emphasizing treatment of the associated condition and surveillance; revascularization is considered for progressive neurologic symptoms/hemodynamic insufficiency. | No quantitative comparative outcome in retrieved excerpts. | (uchiyama2024adultmoyamoyadisease pages 2-3, calandrelli2026moyamoyavasculopathyand pages 5-6, kappel2024managementofmoyamoya pages 1-2, uchiyama2024adultmoyamoyadisease pages 1-2) |
| Postoperative ultrasonographic bypass assessment | postoperative imaging assessment; ultrasonography monitoring | After revascularization surgery to assess bypass function/capacity | Ultrasound is a noninvasive postoperative monitoring tool for bypass capacity when compared with confirmatory imaging. It is useful for identifying high bypass capacity after surgery. | Meta-analysis of 8 cohort studies/301 hemispheres: early high-capacity bypass associated with increased STA PSV (MD 28.26, p<0.0001), MFV (MD 22.97, p=0.03), EDV (MD 33.45, p<0.0001), and lower RI (MD -0.09, p=0.006). | (santos2025managementofmoyamoyaa pages 1-3) |
| Risk-stratified perioperative management | perioperative management | Surgical candidates with prior infarction, PCA involvement, advanced MRA severity | Meta-analysis identified factors associated with perioperative cerebral infarction, supporting enhanced perioperative monitoring and risk stratification rather than a distinct therapy. | Posterior cerebral artery involvement OR 2.62 (95% CI 1.36-5.06); higher preoperative MRA grade OR 2.81 (95% CI 1.27-6.22); previous infarction OR 2.52 (95% CI 1.69-3.75). | (santos2025managementofmoyamoyaa pages 1-3) |
| Growth-factor/angiogenesis adjuncts (VEGF, HGF, PDGF; investigational) | pro-angiogenic therapy | Experimental adjunct to improve collateral formation after bypass | Current reviews describe no approved disease-modifying therapy; proposed future approaches include growth-factor augmentation to improve neovascularization and bypass vessel ingrowth. | No clinical efficacy data in retrieved evidence excerpts. | (kappel2024managementofmoyamoya pages 5-6) |
| Gene-targeted therapy / CRISPR-style approaches (investigational) | gene therapy | Future personalized therapy for familial/genetically susceptible MMD | Reviews highlight RNF213 and other susceptibility genes as rationale for future genome-informed therapies, but these remain conceptual/experimental and not established clinical care. | No human outcome data in retrieved evidence excerpts. | (kappel2024managementofmoyamoya pages 5-6, ye2023rnf213lossoffunctionpromotes pages 11-13, ye2023rnf213lossoffunctionpromotes pages 1-2) |
Table: This table summarizes current and emerging management strategies for moyamoya disease, aligned to suggested MAXO-style action labels. It is useful for mapping evidence-based interventions, indications, and quantitative outcomes into a structured disease knowledge base.
Recent/ongoing ClinicalTrials.gov records in the retrieved evidence include: - NCT04205578 (Phase 3 RCT): dl-3-n-butylphthalide (NBP) perioperative adjunct after EC–IC bypass; planned enrollment 450; primary endpoints include perioperative ischemic stroke and death within 30 days (registered 2020) (NCT04205578 chunk 1). - NCT04917003 (randomized controlled interventional; phase NA): remote ischemic conditioning (RIC) + EDAS vs EDAS in ischemic MMD; enrollment 60; primary outcome change in relative CBF in operative MCA territory at 3 months (registered 2021) (NCT04917003 chunk 1). - NCT02319980 (Phase 3 randomized): combined revascularization (STA–MCA + EDMS) vs conservative management in adult hemorrhagic MMD; enrollment 360; primary includes strokes/death within 30 days and ipsilateral recurrent bleeding up to 5 years (registered 2015) (NCT02319980 chunk 1). - NCT02982135 (non-randomized interventional): direct vs indirect bypass in adult hemorrhagic MMD; enrollment 300; primary outcome rebleeding events over 5–10 years (registered 2016) (NCT02982135 chunk 1). - NCT05619068 (prospective observational registry): evolution/prognosis with imaging biomarkers and cognitive decline; enrollment 300; compares conservative vs revascularization pathways (registered 2022) (NCT05619068 chunk 1).
No validated primary prevention strategy is established in the retrieved evidence excerpts; genetic susceptibility has incomplete penetrance and likely requires additional triggers (tan2024exploringrnf213in pages 4-6).
Secondary prevention focuses on stroke prevention and surveillance, including conservative management with serial imaging for asymptomatic cases and surgical revascularization for symptomatic or hemodynamically compromised disease, with adjunctive antiplatelet therapy commonly used for ischemic presentations (kappel2024managementofmoyamoya pages 5-6).
No naturally occurring disease in non-human species was identified in the retrieved evidence excerpts.
A high-impact 2023 study used RNF213-deficient mice and zebrafish to demonstrate increased/pathological angiogenesis, and used human brain microvascular endothelial cell (HBMEC) knockdown to demonstrate increased proliferation/migration/tube formation linked to Hippo/YAP/TAZ→VEGFR2 signaling (ye2023rnf213lossoffunctionpromotes pages 1-2, ye2023rnf213lossoffunctionpromotes pages 11-13).
These models support a mechanistic link from genetic perturbation (RNF213 loss-of-function) to endothelial behavior changes and abnormal vascular network development consistent with moyamoya-like collateral formation, while recognizing that reproducing the full steno-occlusive large-artery phenotype in models remains challenging (ye2023rnf213lossoffunctionpromotes pages 1-2).
Tables summarizing the Suzuki angiographic staging system and the 2021 RCMD diagnostic/imaging criteria are present as extracted images from the 2024 review (uchiyama2024adultmoyamoyadisease media e5baf62b, uchiyama2024adultmoyamoyadisease media aace831c).
References
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(kappel2024managementofmoyamoya pages 2-3): Ari D Kappel, Abdullah H. Feroze, Erickson F. Torio, Madhav Sukumaran, and Rose Du. Management of moyamoya disease: a review of current and future therapeutic strategies. Journal of Neurosurgery, 141:975-982, Oct 2024. URL: https://doi.org/10.3171/2024.1.jns221977, doi:10.3171/2024.1.jns221977. This article has 27 citations and is from a domain leading peer-reviewed journal.
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(bagyinszky2025multisystemicimpactof pages 4-6): Eva Bagyinszky, YoungSoon Yang, and Seong Soo A. An. Multisystemic impact of rnf213 arg4810lys: a comprehensive review of moyamoya disease and associated vasculopathies. International Journal of Molecular Sciences, 26:7864, Aug 2025. URL: https://doi.org/10.3390/ijms26167864, doi:10.3390/ijms26167864. This article has 5 citations.
(calandrelli2026moyamoyavasculopathyand pages 5-6): Rosalinda Calandrelli, Carlo Augusto Mallio, Caterina Bernetti, Luca Massimi, and Fabio Pilato. Moyamoya vasculopathy and atypical moyamoya-like patterns: insights into diagnosis and therapeutic implications. NeuroSci, 7:27, Feb 2026. URL: https://doi.org/10.3390/neurosci7010027, doi:10.3390/neurosci7010027. This article has 0 citations.
(kappel2024managementofmoyamoya pages 5-6): Ari D Kappel, Abdullah H. Feroze, Erickson F. Torio, Madhav Sukumaran, and Rose Du. Management of moyamoya disease: a review of current and future therapeutic strategies. Journal of Neurosurgery, 141:975-982, Oct 2024. URL: https://doi.org/10.3171/2024.1.jns221977, doi:10.3171/2024.1.jns221977. This article has 27 citations and is from a domain leading peer-reviewed journal.
(ye2023rnf213lossoffunctionpromotes pages 11-13): Fei Ye, Xingyang Niu, Feng Liang, Yuanyuan Dai, Jie Liang, Jiaoxing Li, Xiaoxin Wu, Hanyue Zheng, Tiewei Qi, and Wenli Sheng. Rnf213 loss-of-function promotes pathological angiogenesis in moyamoya disease via the hippo pathway. Brain, 146:4674-4689, Jul 2023. URL: https://doi.org/10.1093/brain/awad225, doi:10.1093/brain/awad225. This article has 60 citations and is from a highest quality peer-reviewed journal.
(ye2023rnf213lossoffunctionpromotes pages 10-11): Fei Ye, Xingyang Niu, Feng Liang, Yuanyuan Dai, Jie Liang, Jiaoxing Li, Xiaoxin Wu, Hanyue Zheng, Tiewei Qi, and Wenli Sheng. Rnf213 loss-of-function promotes pathological angiogenesis in moyamoya disease via the hippo pathway. Brain, 146:4674-4689, Jul 2023. URL: https://doi.org/10.1093/brain/awad225, doi:10.1093/brain/awad225. This article has 60 citations and is from a highest quality peer-reviewed journal.
(ye2023rnf213lossoffunctionpromotes pages 1-2): Fei Ye, Xingyang Niu, Feng Liang, Yuanyuan Dai, Jie Liang, Jiaoxing Li, Xiaoxin Wu, Hanyue Zheng, Tiewei Qi, and Wenli Sheng. Rnf213 loss-of-function promotes pathological angiogenesis in moyamoya disease via the hippo pathway. Brain, 146:4674-4689, Jul 2023. URL: https://doi.org/10.1093/brain/awad225, doi:10.1093/brain/awad225. This article has 60 citations and is from a highest quality peer-reviewed journal.
(ye2023rnf213lossoffunctionpromotes pages 2-3): Fei Ye, Xingyang Niu, Feng Liang, Yuanyuan Dai, Jie Liang, Jiaoxing Li, Xiaoxin Wu, Hanyue Zheng, Tiewei Qi, and Wenli Sheng. Rnf213 loss-of-function promotes pathological angiogenesis in moyamoya disease via the hippo pathway. Brain, 146:4674-4689, Jul 2023. URL: https://doi.org/10.1093/brain/awad225, doi:10.1093/brain/awad225. This article has 60 citations and is from a highest quality peer-reviewed journal.
(bagyinszky2025multisystemicimpactof pages 17-18): Eva Bagyinszky, YoungSoon Yang, and Seong Soo A. An. Multisystemic impact of rnf213 arg4810lys: a comprehensive review of moyamoya disease and associated vasculopathies. International Journal of Molecular Sciences, 26:7864, Aug 2025. URL: https://doi.org/10.3390/ijms26167864, doi:10.3390/ijms26167864. This article has 5 citations.
(xu2024insightsintothe pages 3-4): Shuangxiang Xu, Tong-Tong Chen, Jin Yu, Lei Wan, Jianjian Zhang, Jincao Chen, Wei Wei, and Xiang Li. Insights into the regulatory role of epigenetics in moyamoya disease: current advances and future prospectives. Molecular Therapy - Nucleic Acids, 35:102281, Sep 2024. URL: https://doi.org/10.1016/j.omtn.2024.102281, doi:10.1016/j.omtn.2024.102281. This article has 12 citations.
(xu2024insightsintothe pages 16-17): Shuangxiang Xu, Tong-Tong Chen, Jin Yu, Lei Wan, Jianjian Zhang, Jincao Chen, Wei Wei, and Xiang Li. Insights into the regulatory role of epigenetics in moyamoya disease: current advances and future prospectives. Molecular Therapy - Nucleic Acids, 35:102281, Sep 2024. URL: https://doi.org/10.1016/j.omtn.2024.102281, doi:10.1016/j.omtn.2024.102281. This article has 12 citations.
(xu2024insightsintothe pages 13-14): Shuangxiang Xu, Tong-Tong Chen, Jin Yu, Lei Wan, Jianjian Zhang, Jincao Chen, Wei Wei, and Xiang Li. Insights into the regulatory role of epigenetics in moyamoya disease: current advances and future prospectives. Molecular Therapy - Nucleic Acids, 35:102281, Sep 2024. URL: https://doi.org/10.1016/j.omtn.2024.102281, doi:10.1016/j.omtn.2024.102281. This article has 12 citations.
(zeng2025rnf213variantand pages 2-4): Chaofan Zeng, Peicong Ge, Zihan Yin, Junlin Lu, Xiaofan Yu, Junsheng Li, Yuanren Zhai, Chenglong Liu, Qiheng He, Wei Liu, Jia Wang, Xingju Liu, Xun Ye, Qian Zhang, Rong Wang, Yan Zhang, Dong Zhang, and Jizong Zhao. rnf213 variant and infectious burden associated with intracranial artery stenosis in moyamoya disease. Journal of the American Heart Association, Mar 2025. URL: https://doi.org/10.1161/jaha.124.036830, doi:10.1161/jaha.124.036830. This article has 2 citations.
(uchiyama2024adultmoyamoyadisease media aace831c): S. Uchiyama and Miki Fujimura. Adult moyamoya disease and moyamoya syndrome: what is new? Cerebrovascular Diseases Extra, 14:86-94, Jul 2024. URL: https://doi.org/10.1159/000540254, doi:10.1159/000540254. This article has 15 citations and is from a peer-reviewed journal.
(lee2023surgicalrevascularizationsfor pages 12-13): Keng Siang Lee, John J. Y. Zhang, Sanjay Bhate, Vijeya Ganesan, Dominic Thompson, Greg James, and Adikarige Haritha Dulanka Silva. Surgical revascularizations for pediatric moyamoya: a systematic review, meta-analysis, and meta-regression analysis. Child's Nervous System, 39:1225-1243, Feb 2023. URL: https://doi.org/10.1007/s00381-023-05868-6, doi:10.1007/s00381-023-05868-6. This article has 23 citations.
(lee2023surgicalrevascularizationsfor pages 1-2): Keng Siang Lee, John J. Y. Zhang, Sanjay Bhate, Vijeya Ganesan, Dominic Thompson, Greg James, and Adikarige Haritha Dulanka Silva. Surgical revascularizations for pediatric moyamoya: a systematic review, meta-analysis, and meta-regression analysis. Child's Nervous System, 39:1225-1243, Feb 2023. URL: https://doi.org/10.1007/s00381-023-05868-6, doi:10.1007/s00381-023-05868-6. This article has 23 citations.
(santos2025managementofmoyamoyaa pages 1-3): DE Santos, G Chmutin, and E Chmutin. Management of moyamoya disease: a systematic review and meta-analysis on surgical revascularization, outcomes and clinical manifestations. Unknown journal, 2025.
(NCT04205578 chunk 1): yuanli Zhao. NBP in Patients With Moyamoya Disease of High Risk for Ischemic Cerebrovascular Events. yuanli Zhao. 2020. ClinicalTrials.gov Identifier: NCT04205578
(NCT04917003 chunk 1): Ji Xunming,MD,PhD. Safety and Efficacy of Remote Ischemic Conditioning Combined EDAS on Ischemic Moyamoya Disease. Capital Medical University. 2021. ClinicalTrials.gov Identifier: NCT04917003
(NCT02319980 chunk 1): Hanqiang Jiang,MD. The Adult Hemorrhagic Moyamoya Surgery Study. Huashan Hospital. 2015. ClinicalTrials.gov Identifier: NCT02319980
(NCT02982135 chunk 1): liuxingju. Direct Bypass Versus Indirect Bypass in Treatment of Adults Hemorrhagic Moyamoya Disease. liuxingju. 2016. ClinicalTrials.gov Identifier: NCT02982135