Review
Matsanga Leyila Kaseka, Mubeen F. Rafay, Marta Bertamino, Dana B. Harrar, Janette Mailo, Daniel Davila-Williams, Ming Lim, Sabas Sabanathan, Manish Parakh, Laura Lehman
Introduction
Moyamoya is a chronic, steno-occlusive arteriopathy characterized by progressive stenosis at the terminal portion of the internal carotid artery and its branches and an abnormal vascular collateral network at the base of the brain. Resultant chronic brain ischemia leads to recurrent transient ischemic attacks and strokes, debilitating headaches, and various neurological and cognitive deficits (1, 2). The main pathological changes observed in moyamoya include concentric and eccentric fibrocellular thickening of the intima, attenuation of the media with fragmentation of the inner elastic lamina due to increased proliferation of intimal smooth muscle cells (SMCs) migrating from the media, and endothelial mesenchymal transition, with minimal inflammatory cell infiltration(3). Current treatment options include anti-thrombotic therapy and revascularization surgery which has been shown to reduce the risk of stroke. These modalities, however, have no effect on the progression of arterial stenosis and do not reverse or halt the relentless progression of the primary arteriopathy.
Moyamoya is a complex multifactorial and heterogeneous disorder, comprising diverse genetic diseases and syndromes, genetically predisposing conditions with variable patterns of inheritance, or acquired causes (e.g., cranial radiation, autoimmune diseases). The association with specific ethnic groups and the prevalence of familial cases in up to 12% of the patients, support the role of genetic factors in moyamoya(4). Genetic conditions associated with moyamoya include neurofibromatosis type 1 (NF1), Down syndrome or sickle cell disease, and many more syndromes or genetic disorders. Despite the strong ethnicity-related effect, data from monozygotic twins in East Asia showed discordant phenotypes, supporting the polygenic genetic effect, with both genetic predisposition and environmental triggers implicated. Multiple genetic approaches employed over the years to clarify the genetic background of the disease demonstrate various genetic risk factors for moyamoya. Since the 1990s, several genome-wide linkage analyses and genome-wide association studies (GWAS) have been performed, mostly in East Asian populations to map and identify moyamoya genes. These studies identified multiple associations with various polymorphisms including HLA types, growth factors, and cytokines(5). In 2011, the first susceptibility gene for moyamoya, RNF213, was identified(4, 6). Since then, the list of single-gene disorders associated with moyamoya has been steadily growing. Currently, at least 18 genes have been identified in Mendelian forms of Moyamoya; however, they account for only a small proportion of cases(7, 8). Advances in molecular biology and next-generation sequencing technologies made it possible to study disease mechanisms. This has resulted in the recognition of associations between various signaling pathways and moyamoya pathophysiology including the nitric oxide pathway and disorders of the RAS pathway. However, the effect of genetic factors on the occurrence, presentation, and outcomes of moyamoya is not entirely clear, and direct genotype-phenotype correlations to guide management and prognostication are lacking. In this review, we examine moyamoya’s most common genetic causes and explore how genetic etiology interacts with clinical care.
From Genotype to Phenotype: Clinical and Radiographic Features of Monogenic Moyamoya
Each monogenic etiology associated with moyamoya exhibits distinct clinical and radiological features (table 1). Comprehensive data on the natural history and progression of moyamoya within each genetic syndrome remain limited. The traditional dichotomy between moyamoya disease (MMD), which may potentially includes patients with RNF213 mutations presening with isolated moyamoya, and moyamoya syndrome (MMS), which encompasses a range of genetic and non-genetic causes (e.g radiation-related arteriopathy), complicates our understanding of clinical behavior across these subtype. Historically, MMD is characterized by earlier onset (50.7 ± 43.4 versus 75.7 ± 47.4 months, p = 0.0277), transient ischemic attacks as the initial presentation (as opposed to stroke), and severe, progressive, and bilateral arteriopathy. In contrast MMS has often been described as presenting more asymptomatically(9-11). However, this paradigm may not apply to all monogenic causes. For example, while patients with NF1 often exhibit asymptomatic, and non-progressive disease with low infarct burden, those with Down syndrome or sickle cell anemia more frequently present symptomatically(10, 11). These findings suggest that certain genetic forms classified as MMS may exhibit phenotypes more consistent with classic MMD, challenging the conventional distinction between these categories. In addition, many patients with (idiopathic) MMD are now being diagnosed with mutations in RNF213. However, those harboring homozygous, as well as rare or de novo heterozygous variants in RNF213 have been reported to exhibit multisystem vascular and non-vascular involvement in several cohorts and could therefore be regarded as MMS(12-15).
These contradictions challenge the traditional dichotomization of MMD versus MMS and suggest that a gene/group of genes-related moyamoya classification would be more suitable moving forward.
Notably, the true prevalence of multisystem involvement is likely underestimated, as comprehensive vascular screening is not routinely performed in all MMD patients. The presence of variable penetrance and expressivity further complicates classification, especially since individuals with the same variant may exhibit isolated cerebral arteriopathy or a syndromic phenotype with systemic vascular features. It may be more accurate to view moyamoya as a spectrum disorder, where most individuals—especially those with a monogenic etiology—carry some degree of risk for multisystem involvement, modulated by genetic background, environmental triggers, and potentially epigenetic regulation.
Furthermore, certain monogenic disorders associated with moyamoya exhibit distinct neuroimaging features that differ from the typical presentation seen in idiopathic cases. For instance, abnormalities in the posterior circulation — including stenosis or occlusion of the posterior cerebral arteries can be observed in specific genetic syndromes like NF1, YY1AP1 or ANO1-related moyamoya (5, 8, 16). Notably, posterior circulation involvement may sometimes reflect a developmental or static vascular pattern rather than active arteriopathy. Therefore, recognizing syndrome-specific imaging patterns is essential to avoid overestimating disease severity and to tailor management strategies accordingly.
SYNDROME-BASED GENETIC ETIOLOGIES
Neurofibromatosis Type 1 and Other RASopathies-related Moyamoya
The RAS/MAPK pathway is necessary for cellular proliferation, survival, differentiation, metabolism, and angiogenesis(17). RASopathies are disorders caused by germline mutations in genes encoding components of the RAS/MAPK pathway resulting in increased signaling through this pathway. Moyamoya has been reported in several RASopathies, mainly neurofibromatosis type 1 (NF1)(18) as well as reported sporadically in Costello(19), Noonan(20), and Legius syndromes(21). NF1 is the most prevalent RASopathy (approximately 1:3000 live births)(22) and its association with moyamoya has been the best characterized. Endothelial cell (EC) and SMC dysfunction play a role in NF1-moyamoya pathogenesis. Cell-based models suggest that NF1 knock-out induces abnormal EC organization and proliferation(23) and animal models demonstrate that NF1 knock-out mice develop intimal and SMC hyperproliferation after vascular injury(24). The need for a second hit, such as a vessel injury, to induce pathogenesis may explain why only 2.5-7.4% of NF1 subjects(18) develop moyamoya. Other studies suggest that the co-occurrence of mutations in other susceptibility genes, such as RNF213, also impacts moyamoya incidence and severity in patients with NF1. For example, a study comparing NF1 patients with and without moyamoya showed that 18% of subjects with moyamoya had an RNF213 variant compared to none in subjects without vasculopathy(25) while another reported a more severe phenotype in NF1 subjects with an RNF213 variant(26).
RNF213-related Moyamoya
RNF213 is the major susceptibility gene for moyamoya, and the most common non-syndromic monogenic disorder associated with moyamoya. The High familial rate in East Asia (10-15%) and the geographical distribution of the disease are attributed to a founder variant in RNF213 (p.R4810K and p.R4859K). The inheritance pattern is mainly Autosomal dominant with incomplete penetrance; however, autosomal recessive inheritance is also reported, associated with a more severe phenotype. In children with p.R4810K variant, a distinct clinical and angiographic phenotype was reported, characterized by an earlier age at symptom onset, higher frequency of cortical and watershed ischemic strokes involving multiple vascular territories and frequent bilateral posterior circulation involvement, and more anastomosing vessels from PCA to anterior circulation post vascularization, compared to non-RNF213 moyamoya cases (9, 26). A gene dosage effect has been noted for the RNF213 p.R4810K variant in Japanese and Korean moyamoya cases, in which homozygous states highly correlate with early onset and more severe disease and cognitive outcomes(9, 27, 28). Despite these shared phenotypic characteristics, there is significant heterogeneity in RNF213-related moyamoya presentations, with diverse clinical symptoms and involvement of other vascular beds. This heterogeneity, in conjunction with the observed low disease penetrance of RNF213 mutations, suggests that the presence of these mutations may not be sufficient to cause moyamoya, highlighting the potential influence of other genetic or environmental factors. Due to the low disease penetrance, and the lack of data on the natural history and risk for stroke or hemorrhage in asymptomatic patients, family screening is generally not recommended for RNF213-related disease but should be considered in selected cases.
MECHANISTIC AND PATHWAY-BASED ETIOLOGIES
Nitric Oxide Pathway Dysfunction-related Moyamoya
The role of nitric oxide (NO) in SMC function and its impact on moyamoya pathogenesis has been highlighted in recent literature. For instance, mutations in GUCY1A3, which encodes the α1 subunit of soluble guanylate cyclase (sGC), the major receptor for NO, have been reported in three families with moyamoya and achalasia(29). The NO-sGC-cGMP pathway controls vascular smooth-muscle relaxation, and vascular tone and remodeling. This pathway is also affected in Alagille syndrome, another cause of moyamoya, associated with mutations in NOTCH2 or JAG1. These genes were shown to affect the communication between ECs and SMCs thereby impacting angiogenesis and NO availability within SMCs(30, 31).
Inflammatory-Related Pathways and Moyamoya
The role of inflammation in the pathogenesis of moyamoya has been an important question and has been thoroughly reviewed recently(32, 33). However, whether anti-inflammatory medications can alter the progression of arteriopathy remains unknown. An autopsy study in 1993 demonstrated co-localization of inflammatory cells—macrophages and T cells—with proliferating SMCs in the occlusive segments of intracranial arteries(34). Epidemiological studies have suggested a higher than anticipated prevalence of autoimmune diseases (e.g., type 1 diabetes mellitus, Graves’ disease, rheumatoid arthritis) in patients with moyamoya (35-37). Although most known monogenic causes of moyamoya are not primary disorders of the immune system, Down syndrome, associated with high autoimmunity, and SAMHD1-related disorder, leading to a lupus-like auto-inflammatory syndrome, are associated with moyamoya(38-40). Additionally, inflammation and/or infection were suggested to be essential in inducing the first step of moyamoya pathophysiology in in-vitro and in-vivo models of RNF213, with pro-inflammatory cytokines activation mediated by RNF213 in endothelial cells and SMCs(41, 42). These associations suggest that moyamoya tends to develop in the context of a double-hit phenomenon through the occurrence of an environmental stressor, such as inflammation, in patients with a susceptibility gene mutation. Whether genetic variation within inflammatory pathways could plausibly modify moyamoya disease onset, progression, susceptibility to infarction, or the downstream inflammatory effects of infarction that impact stroke severity and long-term neurological outcomes is currently unknown. Given the potential therapeutic implications, further research is needed to elucidate the role of immune dysregulation in moyamoya.
Epigenetic Regulation and Chromatin Remodeling in Moyamoya
Epigenetic mechanisms—including DNA methylation, histone modification, and chromatin remodeling—play a critical role in regulating gene expression during vascular development and homeostasis. Chromatin remodeling defects have been directly implicated in rare monogenic syndromes associated with moyamoya. For example, deletions involving the BRCC3 gene, which encodes a chromatin-remodeling protein involved in DNA damage response and transcriptional regulation, have been linked to moyamoya-like vasculopathy. Individuals with BRCC3/MTCP1 deletions often present with arterial hypertension, dilated cardiomyopathy, and other systemic features in addition to cerebrovascular involvement (43). In addition, other moyamoya-associated genes are involved in chromatin remodeling (CHD4, CNOT3, and SETD5)(44). Although the direct contribution of chromatin dysregulation to moyamoya pathogenesis remains to be fully elucidated, these findings raise the possibility that epigenetic factors may modulate vascular phenotype, influencing interaction with environmental stressors such as inflammation.
Clinical Approach to the Genetic Workup of Moyamoya in Clinical Setup
Evaluation of children with moyamoya should include a detailed family history, a thorough physical examination, and an assessment of neuroimaging patterns. These may direct the clinical suspicion of a Mendelian disorder. Clinical clues for specific genetic syndromes include characteristic dysmorphic features in Down syndrome, Williams or Alagille syndrome, evidence of café au lait in NF1 or other Rasopathies, and microcephaly, developmental delay, or chilblains in SAMHD1-related disorder. Laboratory tests should include a complete blood count including hemoglobin electrophoresis in selected cases and should be performed according to the clinical and radiological phenotype. If a certain monogenic disorder or syndrome is suspected, such as RNF213-related moyamoya in Asians or moyamoya in the context of café-au-lait spots, targeted testing using a single gene panel may be the most efficient and cost-effective approach. In children without clinical or laboratory indications of an associated genetic cause, the decision regarding genetic testing becomes more complex in the current era of genetic discovery and is not uniformly performed. Options include a targeted gene panel covering only known genes associated with moyamoya such as RNF213, or a broader approach such as whole exome or whole genome sequence. However, the diagnostic yield of these broader methods is relatively low and additional data is needed to better assess their utility(7, 45).
Management of Monogenic Moyamoya
Management of these patients should be tailored to cerebrovascular and peripheral vascular system involvement, as well as to the associated comorbidities, which may influence therapeutic decisions, and inform multidisciplinary management. Assessment of other vascular beds should be considered depending on the specific clinical and genetic phenotype (e.g NF1 or RNF213-related disorders)(12).
If a genetic condition, such as RNF213 is detected in a patient with MMD, parental testing may be warranted with subsequent testing of siblings if an affected parent is identified. In children without an identifiable genetic cause, while the risk of other children in the family being affected by MMD is low, consideration of MRI and MRA screening in selected cases to alleviate familial anxiety and improve quality of life is reasonable(46, 47).
Please see the article on the medical management of moyamoya for an elaborated section on specific management according to a genetic cause of moyamoya).
Does the Genetic Etiology of Moyamoya Affect Surgical Management?
Recent advances in phenotypic and genetic characterization have broadened our understanding of moyamoya, shifting it from isolated intracranial carotid artery stenosis with perforating artery collaterals to a systemic vasculopathy with multi-organ involvement(5). For instance, GUCY1A3-related moyamoya, is associated with arterial hypertension as well as low platelet count, while deletion of BRCC3/MTCP1, may be associated with dilated cardiomyopathy and arterial hypertension (5), all of which should be taken into account prior to surgery. Still, the impact of genetic background on revascularization risk and outcomes remains incompletely understood. Surgical outcomes in moyamoya are influenced by both the characteristics of the intracranial vasculopathy and inherent patient-specific factors, such as age at onset and systemic comorbidities. Several disease-related features are known to increase perioperative risk, including young age, posterior circulation involvement, and intracranial aneurysms, which may predispose patients to complications such as brainstem infarction or hemorrhage during or after revascularization. In parallel, certain monogenic moyamoya syndromes increase perioperative risk by contributing to systemic manifestations that compromise surgical preparation and recovery. Patients with RNF213 rare variants, for example, may develop renal artery stenosis, cardiomyopathy, mesenteric ischemia, or aortic branch vasculopathy, leading to hypertension or poor general condition at the time of surgery(8, 13). These systemic complications complicate anesthetic management and increase the risk of ischemic or hemorrhagic stroke during revascularization. Notably, posterior circulation moyamoya, more frequently observed with ANO1 variants, is associated with particularly poor neurologic outcomes following surgery (8, 48).
In contrast, some variants inRNF213 (p.R4810K) have been associated with more favorable revascularization outcomes in East Asians populations(49), highlighting the heterogeneity of genetic impact and the importance of individualized risk stratification. Together, these findings emphasize that the genetic etiology of moyamoya can significantly influence surgical management, both through its effect on the nature of the intracranial vasculopathy and through associated systemic disease. Careful genetic evaluation, paired with comprehensive preoperative assessment, is essential for optimizing management and reducing procedural risk.
Knowledge Gaps and Future Research Avenues
Although our understanding of the genetics of moyamoya has advanced over time, there remain several knowledge gaps that would be suitable for future research endeavors. There is a great need to highlight other novel genetic causes of moyamoya as well as to investigate novel variants in known genes implicated in moyamoya angiopathy using modern sequencing technologies, such as short-read and long-read genome sequencing and RNA sequencing. Innovative approaches to collecting and sequencing affected tissue to identify local epigenetic modifications that contribute to disease development and heterogeneity are warranted. A better understanding of the genetic landscape of moyamoya will lead to improved insight into final common pathways that may be disrupted and subsequently, novel treatments targeting these disrupted pathways.
Conclusions
Moyamoya is one of the most important causes of stroke in childhood with significant disease burden affecting both children and adults. Familial clustering and ethnic predispositions further highlight the genetic basis of moyamoya. However, despite substantial progress, the genetic landscape remains complex, involving multiple genes and inheritance patterns. Ongoing research is essential to better understand the genetic underpinning of moyamoya, which is critical for elucidating its pathogenesis and clinical variability and for developing targeted therapies. facilitating international data sharing in genomic research empowered by joint efforts and by global collaboration to increase the availability of large genomic datasets may yield novel insights into biological mechanisms involved in moyamoya and open new avenues for biomarker discoveries and therapeutic innovation. Early genetic evaluation, alongside traditional diagnostic methods, is a vital step towards accurate diagnosis, risk stratification, and personalized management, in an attempt to improve patient outcomes.
References
1. Scott RM, Smith ER. Moyamoya disease and moyamoya syndrome. N Engl J Med. 2009;360(12):1226-37.
2. Dlamini N, Muthusami P, Amlie-Lefond C. Childhood Moyamoya: Looking Back to the Future. Pediatr Neurol. 2019;91:11-9.
3. Dorschel KB, Wanebo JE. Genetic and Proteomic Contributions to the Pathophysiology of Moyamoya Angiopathy and Related Vascular Diseases. Appl Clin Genet. 2021;14:145-71.
4. Mertens R, Graupera M, Gerhardt H, Bersano A, Tournier-Lasserve E, Mensah MA, et al. The Genetic Basis of Moyamoya Disease. Transl Stroke Res. 2022;13(1):25-45.
5. Guey S, Tournier-Lasserve E, Herve D, Kossorotoff M. Moyamoya disease and syndromes: from genetics to clinical management. Appl Clin Genet. 2015;8:49-68.
6. Liu W, Morito D, Takashima S, Mineharu Y, Kobayashi H, Hitomi T, et al. Identification of RNF213 as a susceptibility gene for moyamoya disease and its possible role in vascular development. PLoS One. 2011;6(7):e22542.
7. Kundishora AJ, Peters ST, Pinard A, Duran D, Panchagnula S, Barak T, et al. DIAPH1 Variants in Non-East Asian Patients With Sporadic Moyamoya Disease. JAMA Neurol. 2021;78(8):993-1003.
8. Pinard A, Ye W, Fraser SM, Rosenfeld JA, Pichurin P, Hickey SE, et al. Rare variants in ANO1, encoding a calcium-activated chloride channel, predispose to moyamoya disease. Brain. 2023;146(9):3616-23.
9. Kim EH, Yum MS, Ra YS, Park JB, Ahn JS, Kim GH, et al. Importance of RNF213 polymorphism on clinical features and long-term outcome in moyamoya disease. J Neurosurg. 2016;124(5):1221-7.
10. Gatti JR, Torriente AG, Sun LR. Clinical Presentation and Stroke Incidence Differ by Moyamoya Etiology. J Child Neurol. 2021;36(4):272-80.
11. Kaseka ML, Slim M, Muthusami P, Dirks PB, Westmacott R, Kassner A, et al. Distinct Clinical and Radiographic Phenotypes in Pediatric Patients With Moyamoya. Pediatr Neurol. 2021;120:18-26.
12. Bang OY, Chung JW, Kim DH, Won HH, Yeon JY, Ki CS, et al. Moyamoya Disease and Spectrums of RNF213 Vasculopathy. Transl Stroke Res. 2020;11(4):580-9.
13. Pinard A, Fiander MDJ, Cecchi AC, Rideout AL, Azouz M, Fraser SM, et al. Association of De Novo RNF213 Variants With Childhood Onset Moyamoya Disease and Diffuse Occlusive Vasculopathy. Neurology. 2021;96(13):e1783-e91.
14. 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):2168-74.
15. Brunet T, Zott B, Lieftüchter V, Lenz D, Schmidt A, Peters P, et al. De novo variants in RNF213 are associated with a clinical spectrum ranging from Leigh syndrome to early-onset stroke. Genet Med. 2024;26(2):101013.
16. Guo DC, Duan XY, Regalado ES, Mellor-Crummey L, Kwartler CS, Kim D, et al. Loss-of-Function Mutations in YY1AP1 Lead to Grange Syndrome and a Fibromuscular Dysplasia-Like Vascular Disease. Am J Hum Genet. 2017;100(1):21-30.
17. Hebron KE, Hernandez ER, Yohe ME. The RASopathies: from pathogenetics to therapeutics. Dis Model Mech. 2022;15(2).
18. Lehman LL, Ullrich NJ. Cerebral Vasculopathy in Children with Neurofibromatosis Type 1. Cancers (Basel). 2023;15(20).
19. Alhazmi AM, Alsubaie MA, Alanazi RR. Concurrent Presentation of Euryblepharon and Moyamoya Syndrome in Costello Syndrome: A Rare Clinical Case. Cureus. 2023;15(6):e40808.
20. Choi JH, Oh MY, Yum MS, Lee BH, Kim GH, Yoo HW. Moyamoya syndrome in a patient with Noonan-like syndrome with loose anagen hair. Pediatr Neurol. 2015;52(3):352-5.
21. Pabst L, Carroll J, Lo W, Truxal KV. Moyamoya syndrome in a child with Legius syndrome: Introducing a cerebral vasculopathy to the SPRED1 phenotype? Am J Med Genet A. 2021;185(1):223-7.
22. Kehrer-Sawatzki H, Cooper DN. Challenges in the diagnosis of neurofibromatosis type 1 (NF1) in young children facilitated by means of revised diagnostic criteria including genetic testing for pathogenic NF1 gene variants. Hum Genet. 2022;141(2):177-91.
23. Bajaj A, Li QF, Zheng Q, Pumiglia K. Loss of NF1 expression in human endothelial cells promotes autonomous proliferation and altered vascular morphogenesis. PLoS One. 2012;7(11):e49222.
24. Xu J, Ismat FA, Wang T, Yang J, Epstein JA. NF1 regulates a Ras-dependent vascular smooth muscle proliferative injury response. Circulation. 2007;116(19):2148-56.
25. Phi JH, Choi JW, Seong MW, Kim T, Moon YJ, Lee J, et al. Association between moyamoya syndrome and the RNF213 c.14576G>A variant in patients with neurofibromatosis Type 1. J Neurosurg Pediatr. 2016;17(6):717-22.
26. Zanoni P, Steindl K, Sticht H, Oneda B, Joset P, Ivanovski I, et al. The genetic landscape and clinical implication of pediatric Moyamoya angiopathy in an international cohort. Eur J Hum Genet. 2023;31(7):784-92.
27. Miyatake S, Miyake N, Touho H, Nishimura-Tadaki A, Kondo Y, Okada I, et al. Homozygous c.14576G>A variant of RNF213 predicts early-onset and severe form of moyamoya disease. Neurology. 2012;78(11):803-10.
28. Ge P, Ye X, Liu X, Deng X, Wang R, Zhang Y, et al. Association Between p.R4810K Variant and Long-Term Clinical Outcome in Patients With Moyamoya Disease. Front Neurol. 2019;10:662.
29. Hervé D, Philippi A, Belbouab R, Zerah M, Chabrier S, Collardeau-Frachon S, et al. Loss of α1β1 soluble guanylate cyclase, the major nitric oxide receptor, leads to moyamoya and achalasia. Am J Hum Genet. 2014;94(3):385-94.
30. Lilly B, Dammeyer K, Marosis S, McCallinhart PE, Trask AJ, Lowe M, et al. Endothelial cell-induced cytoglobin expression in vascular smooth muscle cells contributes to modulation of nitric oxide. Vascul Pharmacol. 2018;110:7-15.
31. Zhao D, Xue C, Lin S, Shi S, Li Q, Liu M, et al. Notch Signaling Pathway Regulates Angiogenesis via Endothelial Cell in 3D Co-Culture Model. J Cell Physiol. 2017;232(6):1548-58.
32. Mikami T, Suzuki H, Komatsu K, Mikuni N. Influence of Inflammatory Disease on the Pathophysiology of Moyamoya Disease and Quasi-moyamoya Disease. Neurol Med Chir (Tokyo). 2019;59(10):361-70.
33. Dorschel KB, Wanebo JE. Physiological and pathophysiological mechanisms of the molecular and cellular biology of angiogenesis and inflammation in moyamoya angiopathy and related vascular diseases. Front Neurol. 2023;14:661611.
34. Masuda J, Ogata J, Yutani C. Smooth muscle cell proliferation and localization of macrophages and T cells in the occlusive intracranial major arteries in moyamoya disease. Stroke. 1993;24(12):1960-7.
35. Chen JB, Liu Y, Zhou LX, Sun H, He M, You C. Prevalence of autoimmune disease in moyamoya disease patients in Western Chinese population. J Neurol Sci. 2015;351(1-2):184-6.
36. Bower RS, Mallory GW, Nwojo M, Kudva YC, Flemming KD, Meyer FB. Moyamoya disease in a primarily white, midwestern US population: increased prevalence of autoimmune disease. Stroke. 2013;44(7):1997-9.
37. Mejia-Munne JC, Ellis JA, Feldstein NA, Meyers PM, Connolly ES. Moyamoya and Inflammation. World Neurosurg. 2017;100:575-8.
38. Xin B, Jones S, Puffenberger EG, Hinze C, Bright A, Tan H, et al. Homozygous mutation in SAMHD1 gene causes cerebral vasculopathy and early onset stroke. Proc Natl Acad Sci U S A. 2011;108(13):5372-7.
39. Santoro JD, Lee S, Wang AC, Ho E, Nagesh D, Khoshnood M, et al. Increased Autoimmunity in Individuals With Down Syndrome and Moyamoya Disease. Front Neurol. 2021;12:724969.
40. Henrickson M, Wang H. Tocilizumab reverses cerebral vasculopathy in a patient with homozygous SAMHD1 mutation. Clin Rheumatol. 2017;36(6):1445-51.
41. Kobayashi H, Matsuda Y, Hitomi T, Okuda H, Shioi H, Matsuda T, et al. Biochemical and Functional Characterization of RNF213 (Mysterin) R4810K, a Susceptibility Mutation of Moyamoya Disease, in Angiogenesis In Vitro and In Vivo. J Am Heart Assoc. 2015;4(7).
42. Ohkubo K, Sakai Y, Inoue H, Akamine S, Ishizaki Y, Matsushita Y, et al. Moyamoya disease susceptibility gene RNF213 links inflammatory and angiogenic signals in endothelial cells. Sci Rep. 2015;5:13191.
43. Aloui C, Guey S, Pipiras E, Kossorotoff M, Guéden S, Corpechot M, et al. Xq28 copy number gain causing moyamoya disease and a novel moyamoya syndrome. J Med Genet. 2020;57(5):339-46.
44. Pinard A, Guey S, Guo D, Cecchi AC, Kharas N, Wallace S, et al. The pleiotropy associated with de novo variants in CHD4, CNOT3, and SETD5 extends to moyamoya angiopathy. Genet Med. 2020;22(2):427-31.
45. Kaseka ML, Dlamini N. Investigation and management of pediatric moyamoya arteriopathy in the era of genotype-phenotype correlation studies. Eur J Hum Genet. 2023;31(7):735-7.
46. Ahn HS, Kazmi SZ, Kang T, Kim DS, Ryu T, Oh JS, et al. Familial Risk for Moyamoya Disease Among First-Degree Relatives, Based on a Population-Based Aggregation Study in Korea. Stroke. 2020;51(9):2752-60.
47. Grangeon L, Guey S, Schwitalla JC, Bergametti F, Arnould M, Corpechot M, et al. Clinical and Molecular Features of 5 European Multigenerational Families With Moyamoya Angiopathy. Stroke. 2019;50(4):789-96.
48. Tigchelaar SS, Wang AR, Vaca SD, Li Y, Steinberg GK. Incidence and Outcomes of Posterior Circulation Involvement in Moyamoya Disease. Stroke. 2024;55(5):1254-60.
49. Torazawa S, Miyawaki S, Imai H, Hongo H, Ono H, Ogawa S, et al. Association of Genetic Variants with Postoperative Donor Artery Development in Moyamoya Disease: RNF213 and Other Moyamoya Angiopathy-Related Gene Analysis. Transl Stroke Res. 2024.
Affiliations
Moran Hausman-Kedem, MD
Pediatric Neurology Institute, Dana-Dwek Children’s Hospital, Tel Aviv Medical Center, Tel Aviv, Israel, Faculty of Medical and Health Science, Tel Aviv University, Tel Aviv, Israel
Matsanga Leyila Kaseka MD, MSc
Department of Neurology, CHU Sainte-Justine, Montreal, Quebec, Canada; Université de Montréal, Montreal, Quebec, Canada.
Lauren A. Beslow, MD MSCE
Division of Neurology, Children’s Hospital of Philadelphia, Departments of Neurology and Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
Mubeen F. Rafay MB. BS, FCPS, MSc
Section of Neurology, Children’s Hospital Winnipeg, Department of Pediatrics and Child Health, University of Manitoba, Children’s Hospital Research Institute of Manitoba, Manitoba, Canada
Sandro Benichi, MD
Department of Pediatric Neurosurgery, Necker Hospital for Sick Children, Necker Institute, Paris-Cité University, Paris, France
Siddharth Srivastava MD
Rosamund Stone Zander Translational Neuroscience Center and Department of Neurology, Boston Children’s Hospital, Boston, MA, USA
Heather J. Fullerton, MD, MAS
Departments of Neurology and Pediatrics, University of California, San Francisco
Nomazulu Dlamini, MD, PhD
Division of Neurology, The Hospital for Sick Children, Toronto, Ontario, Canada, Program in Neurosciences and Mental Health, The Hospital for Sick Children, Toronto, Ontario, Canada
Moyamoya – From Genes to Care
